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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.
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Does cannabidiol make cannabis safer? A randomised, double-
blind, cross-over trial of cannabis with four different CBD:THC
Amir Englund
, Dominic Oliver
, Edward Chesney
, Lucy Chester
, Jack Wilson
, Simina Sovi
, Andrea De Micheli
John Hodsoll
, Paolo Fusar-Poli
, John Strang
, Robin M. Murray
, Tom P. Freeman
and Philip McGuire
© 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
). These effects were not signicantly 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.
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 [24]. 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
These ndings 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 reect 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
Received: 23 June 2022 Revised: 5 October 2022 Accepted: 10 October 2022
National Addiction Centre, Institute of Psychiatry, Psychology and Neuroscience, Kings College London, 4 Windsor Walk, SE5 8AF London, UK.
Department of Psychosis Studies,
Institute of Psychiatry, Psychology and Neuroscience, Kings College London, 16 De Crespigny Park, SE5 8AF London, UK.
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.
Department of Biostatistics and Health Informatics, Institute of
Psychiatry, Psychology and Neuroscience, Kings College London, 16 De Crespigny Park, SE5 8AF London, UK.
Department of Brain and Behavioural Sciences, University of Pavia,
Pavia, Italy.
South London & Maudsley, NHS Foundation Trust, Maudsley Hospital, London, UK.
Department of Psychology, University of Bath, Claverton Down, Bath BA2 7AY,
UK. email:
The study was approved by the Kings 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 ( and (NCT05170217).
This randomised, double-blind, four-arm, within-subjects study was
conducted at the NIHR Wellcome Trust Clinical Research Facility (CRF) at
Kings 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).
Forty-six healthy volunteers (age 2150 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
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 (3035 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 eld sobriety test, having
been informed of safety protocols, and provided with a 24 h emergency
Study drug and administration
The study drug was provided in the form of granulated cannabis
inorescence by Bedrocan BV (Netherlands) produced in accordance with
Good Manufacturing Practice and conrms to the European Medicines
Agencys 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 lled, 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 nal 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 taskRevised (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. 2025 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.
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 dened 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 oclock
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 scalepositive 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
researchers 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 Experiencesstate (CAPE-state) [24]. The
CAPE-state is a self-rated scale and was used to assess psychotic-like
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 allto
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 nally 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 xed
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 xed 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 [26]. Potential differences in VAS
scores for feel paranoidbetween the post-cognitionand 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 Pearsons correlation coefcients.
We additionally categorised clinically signicant psychotic-like reactions
as increases in PANSS scores from baseline of 3 points, as in previous
studies due to oor 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 Pearsons 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 Littles MCAR test.
All analyses were conducted using R version 3.5.3. lme4 (version 1.1-26)
[30] was used to t the linear mixed effects models and estimated marginal
mean (EMM) contrasts were calculated using the emmeans package
(version 1.5.2-1) [31].
Participants and demographics
80 potential participants were screened from which 64 were
randomised and 46 completed the study (Fig. 2) between
Fig. 2 Study ow diagram.
A. Englund et al.
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 rst 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 rst visit signicantly more dropped out after
receiving 3:1, although there was no statistical difference between
number of sessions stratied 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.
There were no signicant 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 pp612). In contrast,
there was a signicant, dose-dependent increase in peak plasma
CBD, and in plasma CBD AUC, as CBD:THC ratio increased (p<0.001,
Fig. 3B, Appendix pp612). 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
) 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
) and 1:1 (EMM difference =6.843, 95% CI: 4.811,
8.875, p=3.57 × 10
). Logarithmic concentrations of THC and CBD
over time, with intercept and slope across ratios are presented in
Appendix pp1314.
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
) 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
; t(45) =3.322, d=0.49, p=0.002). However,
there were no signicant differences on any measure of
performance between the different CBD:THC ratios (p> 0.008,
Fig. 4A, B, Appendix pp1523).
Digit span. There was signicant 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 signicant differences in either
Table 1. Demographics and cannabis use at baseline.
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)
qualication (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
); 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 rst 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, stratied 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.
forward or reverse digit span between the CBD:THC ratios
(p> 0.008, Appendix pp1620).
Spatial N-Back. There were no signicant differences between
baseline and 0:1, or between CBD:THC ratios (p> 0.008,
Appendix pp1621).
Psychological effects
PANSS positive subscale. There was a signicant increase in
PANSS positive score between baseline and 0:1 (t(45) =4.709,
d=0.69, p=2.41 × 10
). 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
signicant differences in PANSS positive scores (p> 0.008, Fig. 4C,
Appendix pp2526) or PANSS response (X
(3, n=46) =2.202,
d=0.44, p=0.532) between CBD:THC ratios.
SSPS. There were no signicant differences in SSPS scores
between baseline and 0:1, between CBD:THC ratios
(t(45) =1.096, d=0.16, p=0.279, Appendix pp2427), or SSPS
response between CBD:THC ratios (X
(3, n=46) =5.4474,
d=0.73, p=0.142).
CAPE. There was a signicant 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 pp2426).
PSI. There was a signicant increase in total PSI score between
baseline and 0:1 (t(39) =7.461, d=1.18, p=5.025 × 10
) but
not between CBD:THC ratios (p> 0.008, Appendix pp2427).
VAS. There were no signicant differences in subjective effects
between CBD:THC ratios in terms of either VAS AUC or peak VAS
ratings (p> 0.008, Appendix pp2842). There were no signicant
correlations between VAS measures of feeling high (either peak or
AUC) with plasma THC or CBD (either peak or AUC) (p > 0.008,
Appendix pp5152).
Pleasurable responses. All CBD:THC ratios increased scores for
both chocolate and music compared to baseline, but there were
no signicant differences between the CBD:THC ratios (p> 0.008,
Appendix pp4345).
Physiological effects
Blood pressure. There were no signicant 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 signicant differences between
CBD:THC ratios in peak systolic, diastolic blood pressure or AUC
(p> 0.008, Appendix pp46-49).
Heart rate. There was a signicant increase in heart rate in the 0:1
condition compared to baseline (t(44) =9.35, d=1.39, p=5.06 ×
).There were no signicant differences between CBD:THC
ratios in peak heart rate or AUC (p> 0.008, Appendix pp4649).
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.
Body temperature. There were no signicant differences in body
temperature between any of the conditions (Appendix pp4650).
Inhalation and coughing. There was evidence of greater CBD:THC
ratios increasing inhalation time and coughing in a dose
responsive manner (Appendix pp4650). Greater inhalation time
was correlated with lower peak and AUC concentrations of
cannabinoids at higher CBD:THC ratios (Appendix pp5152).
Order and sex effects. Adding order to the models did not have
any impact on the signicance 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 signicant practice or fatigue effects (Appendix pp53). There
were no additional signicant differences when analysis was
stratied by sex on any measure (Appendix pp5490).
Our main nding 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
inuence 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 signicant effect on reverse
digit span, spatial N-back, SSPS, blood pressure and body
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 signicant changes on three
independent psychopathological instruments, as well as signi-
cant impairments in memory and attention. Furthermore, there
was a signicantly greater number of participants who dropped
out on their rst visit when administered the 3:1 ratio. However, as
we did not observe a dose response, we nd it unlikely that there
was a specic 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 ndings 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 ndings 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.
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 denition 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.
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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 Kings 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.
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 nal submitted version. The corresponding authors
had nal responsibility for the decision to submit for publication.
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 Kings College London. The views expressed are those of the
A. Englund et al.
author(s) and not necessarily those of the NHS, the NIHR or the Department of Health
and Social Care.
AE has received speakershonoraria from GW Pharmaceuticals. RMM has received
speakershonoraria from Lundbeck, Sunovian, Otsuka, and Janssen. JS has
undertaken research supported nancially by various pharmaceutical companies,
but this has not involved studies of cannabis or cannabis-related products. All
remaining authors report no conicting interests.
Supplementary information The online version contains supplementary material
available at
Correspondence and requests for materials should be addressed to Amir Englund .
Reprints and permission information is available at
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© The Author(s) 2022
A. Englund et al.
... 10 As such, not all individuals will experience the same effects of cannabis on their mental health and cognition. Nonetheless, a crossover trial of 64 volunteers found that short term detrimental effects of 10 mg of inhaled tetrahydrocannabinol on psychological measures and cognition was not influenced by the co-administration of up to 30 mg of cannabidiol, potentially mitigating potential concerns with a role of tetrahydrocannabinol or cannabidiol ratio as a confounder of findings of this 165 However, this trial was limited by a very short follow-up (90 min) and high loss to follow-up (28%). Furthermore, cannabidiol products that contain either no tetrahydrocannabinol, or subclinical amounts, are unlikely to result in psychological or cognitive impairment. ...
Full-text available
Objective To systematically assess credibility and certainty of associations between cannabis, cannabinoids, and cannabis based medicines and human health, from observational studies and randomised controlled trials (RCTs). Design Umbrella review. Data sources PubMed, PsychInfo, Embase, up to 9 February 2022. Eligibility criteria for selecting studies Systematic reviews with meta-analyses of observational studies and RCTs that have reported on the efficacy and safety of cannabis, cannabinoids, or cannabis based medicines were included. Credibility was graded according to convincing, highly suggestive, suggestive, weak, or not significant (observational evidence), and by GRADE (Grading of Recommendations, Assessment, Development and Evaluations) (RCTs). Quality was assessed with AMSTAR 2 (A Measurement Tool to Assess Systematic Reviews 2). Sensitivity analyses were conducted. Results 101 meta-analyses were included (observational=50, RCTs=51) (AMSTAR 2 high 33, moderate 31, low 32, or critically low 5). From RCTs supported by high to moderate certainty, cannabis based medicines increased adverse events related to the central nervous system (equivalent odds ratio 2.84 (95% confidence interval 2.16 to 3.73)), psychological effects (3.07 (1.79 to 5.26)), and vision (3.00 (1.79 to 5.03)) in people with mixed conditions (GRADE=high), improved nausea/vomit, pain, spasticity, but increased psychiatric, gastrointestinal adverse events, and somnolence among others (GRADE=moderate). Cannabidiol improved 50% reduction of seizures (0.59 (0.38 to 0.92)) and seizure events (0.59 (0.36 to 0.96)) (GRADE=high), but increased pneumonia, gastrointestinal adverse events, and somnolence (GRADE=moderate). For chronic pain, cannabis based medicines or cannabinoids reduced pain by 30% (0.59 (0.37 to 0.93), GRADE=high), across different conditions (n=7), but increased psychological distress. For epilepsy, cannabidiol increased risk of diarrhoea (2.25 (1.33 to 3.81)), had no effect on sleep disruption (GRADE=high), reduced seizures across different populations and measures (n=7), improved global impression (n=2), quality of life, and increased risk of somnolence (GRADE=moderate). In the general population, cannabis worsened positive psychotic symptoms (5.21 (3.36 to 8.01)) and total psychiatric symptoms (7.49 (5.31 to 10.42)) (GRADE=high), negative psychotic symptoms, and cognition (n=11) (GRADE=moderate). In healthy people, cannabinoids improved pain threshold (0.74 (0.59 to 0.91)), unpleasantness (0.60 (0.41 to 0.88)) (GRADE=high). For inflammatory bowel disease, cannabinoids improved quality of life (0.34 (0.22 to 0.53) (GRADE=high). For multiple sclerosis, cannabinoids improved spasticity, pain, but increased risk of dizziness, dry mouth, nausea, somnolence (GRADE=moderate). For cancer, cannabinoids improved sleep disruption, but had gastrointestinal adverse events (n=2) (GRADE=moderate). Cannabis based medicines, cannabis, and cannabinoids resulted in poor tolerability across various conditions (GRADE=moderate). Evidence was convincing from observational studies (main and sensitivity analyses) in pregnant women, small for gestational age (1.61 (1.41 to 1.83)), low birth weight (1.43 (1.27 to 1.62)); in drivers, car crash (1.27 (1.21 to 1.34)); and in the general population, psychosis (1.71 (1.47 to 2.00)). Harmful effects were noted for additional neonatal outcomes, outcomes related to car crash, outcomes in the general population including psychotic symptoms, suicide attempt, depression, and mania, and impaired cognition in healthy cannabis users (all suggestive to highly suggestive). Conclusions Convincing or converging evidence supports avoidance of cannabis during adolescence and early adulthood, in people prone to or with mental health disorders, in pregnancy and before and while driving. Cannabidiol is effective in people with epilepsy. Cannabis based medicines are effective in people with multiple sclerosis, chronic pain, inflammatory bowel disease, and in palliative medicine but not without adverse events. Study registration PROSPERO CRD42018093045. Funding None.
... Only a few studies supported this, however, with inconsistent results. An RCT study performed by Englund et al. [55] investigated four different THC:CBD ratios (i.e., 10 mg THC and 0, 10, 20, or 30 mg CBD) to determine if the presence of CBD in different doses improves the safety of Cannabis consumption. Forty-six (46) healthy infrequent Cannabis users reported negative outcomes from inhaling vaporized 10:0 THC:CBD mg Cannabis. ...
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The ‘entourage effect’ term was originally coined in a pre-clinical study observing endogenous bio-inactive metabolites potentiating the activity of a bioactive endocannabinoid. As a hypothetical afterthought, this was proposed to hold general relevance to the usage of products based on Cannabis sativa L. The term was later juxtaposed to polypharmacy pertaining to full-spectrum medicinal Cannabis products exerting an overall higher effect than the single compounds. Since the emergence of the term, a discussion of its pharmacological foundation and relevance has been ongoing. Advocates suggest that the ‘entourage effect’ is the reason many patients experience an overall better effect from full-spectrum products. Critics state that the term is unfounded and used primarily for marketing purposes in the Cannabis industry. This scoping review aims to segregate the primary research claiming as well as disputing the existence of the ‘entourage effect’ from a pharmacological perspective. The literature on this topic is in its infancy. Existing pre-clinical and clinical studies are in general based on simplistic methodologies and show contradictory findings, with the clinical data mostly relying on anecdotal and real-world evidence. We propose that the ‘entourage effect’ is explained by traditional pharmacological terms pertaining to other plant-based medicinal products and polypharmacy in general (e.g., synergistic interactions and bioenhancement).
... In human imaging studies, CBD in contrast to THC selectively augmented cognitive brain functions and connectivity without effects on psychotic or anxiety symptoms (Davies & Bhattacharyya, 2019). While there is some evidence that CBD reduces THC-induced psychotomimetic symptom effects (Davies & Bhattacharyya, 2019), a recent RCT of inhaled cannabis with different THC/CBD dose ratios did not find any significant effects by CBD dose on psychosis-related symptom outcomes (Englund et al., 2023). ...
Objective: Cannabis use is increasingly normalized; psychosis is a major adverse health outcome. We reviewed evidence on cannabis use-related risk factors for psychosis outcomes at different stages toward recommendations for risk reduction by individuals involved in cannabis use. Methods: We searched primary databases for pertinent literature/data 2016 onward, principally relying on reviews and high-quality studies which were narratively summarized and quality-graded; recommendations were developed by international expert consensus. Results: Genetic risks, and mental health/substance use problem histories elevate the risks for cannabis-related psychosis. Early age-of-use-onset, frequency-of-use, product composition (i.e., THC potency), use mode and other substance co-use all influence psychosis risks; the protective effects of CBD are uncertain. Continuous cannabis use may adversely affect psychosis-related treatment and medication effects. Risk factor combinations further amplify the odds of adverse psychosis outcomes. Conclusions: Reductions in the identified cannabis-related risks factors-short of abstinence-may decrease risks of related adverse psychosis outcomes, and thereby protect cannabis users' health.
... Moreover, the habitual use of Cannabis preparations with relatively high CBD concentrations produces fewer psychotic experiences than those with lower CBD content 94 . Notwithstanding, a recent controlled study found no evidence of CBD modulating Δ 9 -THC-elicited effects 95 . ...
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The consumption of Cannabis sativa plant, known as marijuana in the Western world, for different purposes (therapeutic, intoxicating, and spiritual) due to its psychoactive effects, can be traced back to ancient times. Cannabis is the most used illicit drug worldwide; however, its legal status is changing rapidly. Cannabis regulation will allow a better understanding of its effects as a misused drug, including new challenges, such as the availability of highly potent Cannabis extracts. Furthermore, scientific research is making significant efforts to take advantage of the potential therapeutic uses of Cannabis active compounds. The science of Cannabis derivatives started with the identification of the phytocannabinoids Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD), allowing the formal study of the complex set of effects triggered by Cannabis consumption and the deciphering of its pharmacology. Δ9-THC is recognized as the compound responsible for the psychoactive and intoxicating effects of Cannabis. Its study led to the discovery of the endocannabinoid system, a neuromodulatory system widespread in the human body. CBD does not induce intoxication and for that reason, it is the focus of the search for cannabinoid potential clinical applications. This review examines the current state of knowledge about contrasting perspectives on the effects of Cannabis, Δ9-THC, and CBD: their abuse liability and potential therapeutic use; two sides of the same coin.
... Previously, it was thought that CBD protects against the psychoactive effects of THC, with a higher CBD:THC ratio associated with a lower risk of adverse psychological effects [157]. However, a recent study found that this diminished risk is not due to the presence of CBD itself, but rather the decreased exposure to THC [158]. ...
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Sleep is an essential biological phase of our daily life cycle and is necessary for maintaining homeostasis, alertness, metabolism, cognition, and other key functions across the animal kingdom. Dysfunctional sleep leads to deleterious effects on health, mood, and cognition, including memory deficits and an increased risk of diabetes, stroke, and neurological disorders. Sleep is regulated by several brain neuronal circuits, neuromodulators, and neurotransmitters, where cannabinoids have been increasingly found to play a part in its modulation. Cannabinoids, a group of lipid metabolites, are regulatory molecules that bind mainly to cannabinoid receptors (CB1 and CB2). Much evidence supports the role of cannabinoid receptors in the modulation of sleep, where their alteration exhibits sleep-promoting effects, including an increase in non-rapid-eye movement sleep and a reduction in sleep latency. However, the pharmacological alteration of CB1 receptors is associated with adverse psychotropic effects, which are not exhibited in CB2 receptor alteration. Hence, selective alteration of CB2 receptors is also of clinical importance, where it could potentially be used in treating sleep disorders. Thus, it is crucial to understand the neurobiological basis of cannabinoids in sleep physiology. In this review article, the alteration of the endocannabinoid system by various cannabinoids and their respective effects on the sleep-wake cycle are discussed based on recent findings. The mechanisms of the cannabinoid receptors on sleep and wakefulness are also explored for their clinical implications and potential therapeutic use on sleep disorders.
... The phytocannabinoid cannabidiol (CBD), which is an allosteric modulator of the CB1R and enhances anandamide levels (Britch et al. 2021), has been shown in pre-clinical and clinical settings to have anxiolytic effects (Allsop et al. 2014;Bergamaschi et al. 2011;Garcia-Gutierrez et al. 2020), whereas the other prominent phytocannabinoid delta-9-tetrahydocannabinol (THC), a partial CB1R agonist, has sometimes been associated with acute increases in anxiety (Martin-Santos et al. 2012). The interaction of these two phytocannabinoids is complex, and whilst some research has shown that CBD can ameliorate the negative effects of THC, other studies have found potentiation or no effect (Englund et al. 2022;Karniol et al. 1974;Martin-Santos et al. 2012;Pennypacker et al. 2022;Sharpe et al. 2020). These studies contain heterogeneity in dose, route of administration, length of treatment and THC:CBD ratio, and the exact nature of their ratio remains to be elucidated (Freeman et al. 2019). ...
Full-text available
Rationale Cannabis-based medicinal products (CBMPs) have been identified as novel therapeutics for generalised anxiety disorder (GAD) based on pre-clinical models; however, there is a paucity of high-quality evidence on their effectiveness and safety. Objectives This study aimed to evaluate the clinical outcomes of patients with GAD treated with dried flower, oil-based preparations, or a combination of both CBMPs. Methods A prospective cohort study of patients with GAD (n = 302) enrolled in the UK Medical Cannabis Registry prescribed oil or flower-based CBMPs was performed. Primary outcomes were changes in generalised anxiety disorder-7 (GAD-7) questionnaires at 1, 3, and 6 months compared to baseline. Secondary outcomes were single-item sleep quality scale (SQS) and health-related quality of life index (EQ-5D-5L) questionnaires at the same time points. These changes were assessed by paired t-tests. Adverse events were assessed in line with CTCAE (Common Terminology Criteria for Adverse Events) v4.0. Results Improvements in anxiety, sleep quality and quality of life were observed at each time point (p < 0.001). Patients receiving CBMPs had improvements in GAD-7 at all time points (1 month: difference −5.3 (95% CI −4.6 to −6.1), 3 months: difference −5.5 (95% CI −4.7 to −6.4), 6 months: difference −4.5 (95% CI −3.2 to −5.7)). Thirty-nine participants (12.9%) reported 269 adverse events in the follow-up period. Conclusions Prescription of CBMPs in those with GAD is associated with clinically significant improvements in anxiety with an acceptable safety profile in a real-world setting. Randomised trials are required as a next step to investigate the efficacy of CBMPs.
... Recent analyses lend some support to the use of THC in treating chronic pain, multiple sclerosis spasticity, anorexia/cachexia and Tourette syndrome (National Academies of Sciences, 2017; Therapeutic Goods Administration, 2019) while evidence supports CBD efficacy in the treatment of epilepsy (Devinsky et al., 2017;Devinsky et al., 2018). CBD may attenuate some of the intoxicating and other adverse psychological effects of THC, although the evidence for this is mixed (Arkell et al., 2019;Freeman et al., 2019;Englund et al., 2022;Hutten et al., 2022;Zamarripa et al., 2023). ...
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Objective: Evidence is accumulating that components of the Cannabis sativa plant may have therapeutic potential in treating psychiatric disorders. Medicinal cannabis (MC) products are legally available for prescription in Australia, primarily through the Therapeutic Goods Administration (TGA) Special Access Scheme B (SAS-B). Here we investigated recent prescribing practices for psychiatric indications under SAS-B by Australian doctors. Methods: The dataset, obtained from the TGA, included information on MC applications made by doctors through the SAS-B process between 1st November 2016 and 30th September 2022 inclusive. Details included the primary conditions treated, patient demographics, prescriber location, product type (e.g., oil, flower or capsule) and the general cannabinoid content of products. The conditions treated were categorized according to the Diagnostic and Statistical Manual of Mental Disorders, 5th edition, text revision (DSM-5-TR). Trends in prescribing for conditions over time were analyzed via polynomial regression, and relationships between categorical variables determined via correspondence analyses. Results: Approximately 300,000 SAS-B approvals to prescribe MC had been issued in the time period under investigation. This included approvals for 38 different DSM-5-TR defined psychiatric conditions (33.9% of total approvals). The majority of approvals were for anxiety disorders (66.7% of psychiatry-related prescribing), sleep-wake disorders (18.2%), trauma- and stressor-related disorders (5.8%), and neurodevelopmental disorders (4.4%). Oil products were most prescribed (53.0%), followed by flower (31.2%) and other inhaled products (12.4%). CBD-dominant products comprised around 20% of total prescribing and were particularly prevalent in the treatment of autism spectrum disorder. The largest proportion of approvals was for patients aged 25–39 years (46.2% of approvals). Recent dramatic increases in prescribing for attention deficit hyperactivity disorder were identified. Conclusion: A significant proportion of MC prescribing in Australia is for psychiatry-related indications. This prescribing often appears somewhat “experimental”, given it involves conditions (e.g., ADHD, depression) for which definitive clinical evidence of MC efficacy is lacking. The high prevalence of THC-containing products being prescribed is of possible concern given the psychiatric problems associated with this drug. Evidence-based clinical guidance around the use of MC products in psychiatry is lacking and would clearly be of benefit to prescribers.
... Similarly, the literature has not properly addressed whether concentrates and flower differ with respect to the ratio of THC to CBD content. Given mixed evidence of modulating effects of CBD on cognition 17,55,57,58 , future research should measure and consider ratios of THC to CBD in products used (although these would likely vary across cannabis use sessions). ...
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Extremely high-potency cannabis concentrates are becoming increasingly available and popular among consumers. While prior research indicates these products are perceived to have greater detrimental effects relative to cannabis flower, few studies have examined their relative objective effects, and no existing studies have compared the cognitive test performance of sober flower users, concentrate users, and non-users. A total of 198 healthy adults (98 non-users, 46 exclusive flower users, and 54 concentrate users) were administered a battery of tests of memory, psychomotor speed, attention, and executive functioning under sober laboratory-controlled conditions. Significant group differences were detected on tests of verbal free recall and episodic prospective memory, with both the flower users and concentrate users demonstrating significantly worse performance than non-users. Concentrate (but not flower) users performed worse than non-users on a measure of source memory, but contrary to our hypothesis, there were no significant differences between flower and concentrate users on any of the cognitive tests. Results indicate that, under sober conditions, individuals who regularly use concentrates are no more cognitively impacted than those who exclusively use flower. These null findings may reflect the tendency for concentrate users to self-titrate and use significantly lower quantities of concentrates than flower.
Chronic neuropathic pain is a debilitating pain syndrome caused by damage to the nervous system that is poorly served by current medications. Given these problems, clinical studies have pursued extracts of the plant Cannabis sativa as alternative treatments for this condition. The vast majority of these studies have examined cannabinoids which contain the psychoactive constituent delta‐9‐tetrahydrocannabinol (THC). While there have been some positive findings, meta‐analyses of this clinical work indicates that this effectiveness is limited and hampered by side‐effects. This review focuses on how recent preclinical studies have predicted the clinical limitations of THC‐containing cannabis extracts, and importantly, point to how they might be improved. This work highlights the importance of targeting channels and receptors other than cannabinoid CB1 receptors which mediate many of the side‐effects of cannabis. image
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Background In an observational study in Geneva (Switzerland), we found that administering a standardized THC/CBD oil was feasible, safe, and beneficial in an elderly polymedicated population with severe dementia, behavioral troubles, and pain. Those findings need to be confirmed in a randomized clinical trial. Objectives The MedCanDem trial is a randomized, double-blind cross-over placebo-controlled trial to study the efficacy of cannabinoids in improving painful symptoms during severe dementia disorders in patients living in long-term care facilities in Geneva. This manuscript describes the MedCanDem trial protocol. Materials and methods Participants will be patients suffering from severe dementia associated with pain and behavioral troubles and living in long-term care facilities. We selected five facilities specialized in caring for severely demented patients in Geneva (Switzerland). A total of 24 subjects will be randomized 1:1 to the sequence study intervention/placebo or the sequence placebo/study intervention. Patients will receive study intervention treatment or placebo for eight weeks, and then after a one-week wash-out, treatments will be inversed for another eight weeks. The intervention will be a standardized THC/CBD 1:2 oil extract, and the placebo will be a hemp seed oil. The primary outcome is the reduction from the baseline of the Cohen-Mansfield score; secondary outcomes include the reduction in the Doloplus scale, the reduction of rigidity, the monitoring of concomitant drugs prescription and de-prescription, the safety assessment, and a pharmacokinetic evaluation. The primary and secondary outcomes will be assessed at the baseline, after 28 days, and at the end of both study periods. In addition, safety laboratory analysis, pharmacokinetic evaluation, and therapeutic drug monitoring for the cannabinoids will be evaluated through a blood sample analysis conducted at the beginning and the end of both study periods. Discussion and conclusion This study will allow us to confirm the clinical results observed during the observational study. It represents one of the few studies aiming to prove natural medical cannabis efficacy in a population of non-communicating patients with severe dementia, experimenting with behavioral troubles, pain, and rigidity. Trial registration The trial has Swissethics authorization (BASEC 2022-00999), and it is registered on (NCT05432206) and the SNCTP (000005168).
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Background and aims: The effects exuded by cannabis are a result of the cannabinoids trans-Δ⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD), and is dependent upon their pharmacological interaction and linked to the two cannabinoids’ concentrations and ratios. Based on current literature and trends of increasing cannabis potency, we postulate that most medical cannabis products with THC and CBD have ratios capable of producing significant acute intoxication and are similar to recreational products. We will test this by organizing products into clinically distinct categories according to TCH:CBD ratios, evaluating the data in terms of therapeutic potential, and comparing the data obtained from medical and recreational programs and from states with differing market policies. Methods: We utilized data encompassing online herbal dispensary product offerings from nine U.S. states. The products were analyzed after being divided into four clinically significant THC:CBD ratio categories identified based on the literature: CBD can enhance THC effects (THC:CBD ratios ≥1:1), CBD has no significant effect on THC effects (ratios ∼ 1:2), CBD can either have no effect or can mitigate THC effects (ratios 1:>2 < 6), or CBD is protective against THC effects (ratios ≤1:6). Results: A significant number of products (58.5%) did not contain any information on CBD content. Across all states sampled, the majority (72–100%) of both medical and recreational products with CBD (>0%) fall into the most intoxicating ratio category (≥1:1 THC:CBD), with CBD likely enhancing THC’s acute effects. The least intoxicating categories (1:>2 < 6 and ≤1:6 THC:CBD) provided the smallest number of products. Similarly, the majority of products without CBD (0%) contained highly potent amounts of THC (>15%). These results were consistent, regardless of differing market policies in place. Conclusions: Despite the distinct goals of medical and recreational cannabis users, medical and recreational program product offerings are nearly identical. Patients seeking therapeutic benefits from herbal cannabis products are therefore at a substantial risk of unwanted side effects, regardless of whether they obtain products from medical or recreational programs. Efforts are needed to better inform patients of the risks associated with high potency cannabis and the interaction between THC and CBD, and to help shape policies that promote more therapeutic options.
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Background and aims Cannabis products with high delta‐9‐tetrahydrocannabinol (THC) concentrations carry an increased risk of addiction and mental health disorders, while it has been suggested that cannabidiol (CBD) may moderate the effects of THC. This study aimed to systematically review and meta‐analyse changes in THC and CBD concentrations in cannabis over time (PROSPERO registration: CRD42019130055). Design Embase, MEDLINE® and Epub Ahead of Print, In‐Process and Other Non‐Indexed Citations and Daily, Global Health, PsycINFO and Scopus were searched from inception to 27/03/2019 for observational studies reporting changes in mean THC and/or CBD concentration in cannabis over at least three annual time points. Searches and extraction were conducted by two independent reviewers. Random effects meta‐regression models estimated annual changes in THC and CBD for each product within each study; these estimates were pooled across studies in random effects models. Results We identified 12 eligible studies from the USA, UK, Netherlands, France, Denmark, Italy and New Zealand. For all herbal cannabis, THC concentrations increased by 0.29% each year (95% CI: 0.11, 0.47), P < 0.001 based on 66 747 cannabis samples from eight studies, 1970–2017. For cannabis resin, THC concentrations increased by 0.57% each year (95% CI: 0.10, 1.03), P = 0.017 based on 17 371 samples from eight studies, 1975–2017. There was no evidence for changes in CBD in herbal cannabis [−0.01% (95% CI: −0.02, 0.01), P = 0.280; 49 434 samples from five studies, 1995–2017] or cannabis resin [0.03% (95% CI: −0.11, 0.18), P = 0.651; 11 382 samples from six studies, 1992–2017]. Risk of bias was low apart from non‐random sampling in most studies. There was evidence of moderate to substantial heterogeneity. Conclusions Concentrations of delta‐9‐tetrahydrocannabinol (THC) in international cannabis markets increased from 1970 to 2017 while cannabidiol (CBD) remained stable. Increases in THC were greater in cannabis resin than herbal cannabis. Rising THC in herbal cannabis was attributable to an increased market share of high‐THC sinsemilla relative to low‐THC traditional herbal cannabis.
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The two main phytocannabinoids—delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD)—have been extensively studied, and it has been shown that THC can induce transient psychosis. At the same time, CBD appears to have no psychotomimetic potential. On the contrary, emerging evidence for CBD's antipsychotic properties suggests that it may attenuate effects induced by THC. Thus, we investigated and compared the effects of THC and CBD administration on emotion, cognition, and attention as well as the impact of CBD pre-treatment on THC effects in healthy volunteers. We performed a placebo-controlled, double-blind, experimental trial (GEI-TCP II; identifier: NCT02487381) with 60 healthy volunteers randomly allocated to four parallel intervention groups, receiving either placebo, 800 mg CBD, 20 mg THC, or both cannabinoids. Subjects underwent neuropsychological tests assessing working memory (Letter Number Sequencing test), cognitive processing speed (Digit Symbol Coding task), attention (d2 Test of Attention), and emotional state (adjective mood rating scale [EWL]). Administration of CBD alone did not influence the emotional state, cognitive performance, and attention. At the same time, THC affected two of six emotional categories—more precisely, the performance-related activity and extraversion—, reduced the cognitive processing speed and impaired the performance on the d2 Test of Attention. Interestingly, pre-treatment with CBD did not attenuate the effects induced by THC. These findings show that the acute intake of CBD itself has no effect per se in healthy volunteers and that a single dose of CBD prior to THC administration was insufficient to mitigate the detrimental impact of THC in the given setting. This is in support of a complex interaction between CBD and THC whose effects are not counterbalanced by CBD under all circumstances. © Copyright © 2020 Woelfl, Rohleder, Mueller, Lange, Reuter, Schmidt, Koethe, Hellmich and Leweke.
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Rationale Animal studies have found robust sex differences in the pharmacokinetics and pharmacodynamics of Δ⁹-tetrahydrocannabinol (THC). However, the human evidence remains equivocal, despite findings that women may experience more severe consequences of cannabis use than men. Objectives The objective of this secondary analysis was to examine sex differences in THC pharmacokinetics and in acute subjective, physiological, and cognitive effects of smoked cannabis in a sample of regular cannabis users (use 1–4 days per week) aged 19–25 years. Methods Ninety-one healthy young adults were randomized to receive active (12.5% THC; 17 females, 43 males) or placebo (< 0.1% THC; 9 females, 21 males) cannabis using a 2:1 allocation ratio. Blood samples to quantify concentrations of THC, 11-OH-THC, and 11-Nor-carboxy-THC (THC-COOH), as well as measures of subjective drug effects, vital signs, and cognition were collected over a period of 6 h following ad libitum smoking of a 750-mg cannabis cigarette. Results Females smoked less of the cannabis cigarette than males (p = 0.008) and had a lower peak concentration of THC and THC-COOH than males (p ≤ 0.01). Blood THC concentrations remained lower in females even when adjusting for differences in estimated dose of THC inhaled. There was very little evidence of sex differences in visual analog scale (VAS) ratings of subjective drug effects, mood, heart rate, blood pressure, or cognitive effects of cannabis. Conclusions Females experienced the same acute effects of smoked cannabis as males at a lower observed dose, highlighting the need for more research on sex differences in the pharmacology of THC, especially when administered by routes in which titrating to the desired effect is more difficult (e.g., cannabis edibles).
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Background: Cannabis products are becoming increasingly diverse, and they vary considerably in concentrations of ∆9 -tetrahydrocannabinol (THC) and cannabidiol (CBD). Higher doses of THC can increase the risk of harm from cannabis, while CBD may partially offset some of these effects. Lower Risk Cannabis Use Guidelines currently lack recommendations based on quantity of use, and could be improved by implementing standard units. However, there is currently no consensus on how units should be measured or standardised across different cannabis products or methods of administration. Argument: Existing proposals for standard cannabis units have been based on specific methods of administration (e.g. joints) and these may not capture other methods including pipes, bongs, blunts, dabbing, vaporizers, vape pens, edibles and liquids. Other proposals (e.g. grams of cannabis) cannot account for heterogeneity in THC concentrations across different cannabis products. Similar to alcohol units, we argue that standard cannabis units should reflect the quantity of active pharmacological constituents (dose of THC). On the basis of experimental and ecological data, public health considerations, and existing policy we propose that a 'Standard THC Unit' should be fixed at 5 milligrams of THC for all cannabis products and methods of administration. If supported by sufficient evidence in future, consumption of Standard CBD Units might offer an additional strategy for harm reduction. Conclusions: Standard THC Units can potentially be applied across all cannabis products and methods of administration to guide consumers and promote safer patterns of use.
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The Bayesian framework for statistics is quickly gaining in popularity among scientists, for reasons such as reliability and accuracy (particularly in noisy data and small samples), the possibility of incorporating prior knowledge into the analysis, and the intuitive interpretation of results (Andrews & Baguley, 2013; Etz & Vandekerckhove, 2016; Kruschke, 2010; Kruschke, Aguinis, & Joo, 2012; Wagenmakers et al., 2017). Adopting the Bayesian framework is more of a shift in the paradigm than a change in the methodology; all the common statistical procedures (t-tests, correlations, ANOVAs, regressions, etc.) can also be achieved within the Bayesian framework. One of the core difference is that in the frequentist view, the effects are fixed (but unknown) and data are random. On the other hand, instead of having single estimates of the “true effect”, the Bayesian inference process computes the probability of different effects given the observed data, resulting in a distribution of possible values for the parameters, called the posterior distribution. The bayestestR package provides tools to describe these posterior distributions.
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Background The main psychoactive component of cannabis, delta-9-tetrahydrocannabinol (THC), can impair driving performance. Cannabidiol (CBD), a non-intoxicating cannabis component, is thought to mitigate certain adverse effects of THC. It is possible then that cannabis containing equivalent CBD and THC will differentially affect driving and cognition relative to THC-dominant cannabis. Aims The present study investigated and compared the effects of THC-dominant and THC/CBD equivalent cannabis on simulated driving and cognitive performance. Methods In a randomized, double-blind, within-subjects crossover design, healthy volunteers (n = 14) with a history of light cannabis use attended three outpatient experimental test sessions in which simulated driving and cognitive performance were assessed at two timepoints (20–60 min and 200–240 min) following vaporization of 125 mg THC-dominant (11% THC; < 1% CBD), THC/CBD equivalent (11% THC, 11% CBD), or placebo (< 1% THC/CBD) cannabis. Results/outcomes Both active cannabis types increased lane weaving during a car-following task but had little effect on other driving performance measures. Active cannabis types impaired performance on the Digit Symbol Substitution Task (DSST), Divided Attention Task (DAT) and Paced Auditory Serial Addition Task (PASAT) with impairment on the latter two tasks worse with THC/CBD equivalent cannabis. Subjective drug effects (e.g., “stoned”) and confidence in driving ability did not vary with CBD content. Peak plasma THC concentrations were higher following THC/CBD equivalent cannabis relative to THC-dominant cannabis, suggesting a possible pharmacokinetic interaction. Conclusions/interpretation Cannabis containing equivalent concentrations of CBD and THC appears no less impairing than THC-dominant cannabis, and in some circumstances, CBD may actually exacerbate THC-induced impairment.
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Background: Cannabis use is associated with increased risk of later psychotic disorder but whether it affects incidence of the disorder remains unclear. We aimed to identify patterns of cannabis use with the strongest effect on odds of psychotic disorder across Europe and explore whether differences in such patterns contribute to variations in the incidence rates of psychotic disorder. Methods: We included patients aged 18-64 years who presented to psychiatric services in 11 sites across Europe and Brazil with first-episode psychosis and recruited controls representative of the local populations. We applied adjusted logistic regression models to the data to estimate which patterns of cannabis use carried the highest odds for psychotic disorder. Using Europe-wide and national data on the expected concentration of Δ9-tetrahydrocannabinol (THC) in the different types of cannabis available across the sites, we divided the types of cannabis used by participants into two categories: low potency (THC <10%) and high potency (THC ≥10%). Assuming causality, we calculated the population attributable fractions (PAFs) for the patterns of cannabis use associated with the highest odds of psychosis and the correlation between such patterns and the incidence rates for psychotic disorder across the study sites. Findings: Between May 1, 2010, and April 1, 2015, we obtained data from 901 patients with first-episode psychosis across 11 sites and 1237 population controls from those same sites. Daily cannabis use was associated with increased odds of psychotic disorder compared with never users (adjusted odds ratio [OR] 3·2, 95% CI 2·2-4·1), increasing to nearly five-times increased odds for daily use of high-potency types of cannabis (4·8, 2·5-6·3). The PAFs calculated indicated that if high-potency cannabis were no longer available, 12·2% (95% CI 3·0-16·1) of cases of first-episode psychosis could be prevented across the 11 sites, rising to 30·3% (15·2-40·0) in London and 50·3% (27·4-66·0) in Amsterdam. The adjusted incident rates for psychotic disorder were positively correlated with the prevalence in controls across the 11 sites of use of high-potency cannabis (r = 0·7; p=0·0286) and daily use (r = 0·8; p=0·0109). Interpretation: Differences in frequency of daily cannabis use and in use of high-potency cannabis contributed to the striking variation in the incidence of psychotic disorder across the 11 studied sites. Given the increasing availability of high-potency cannabis, this has important implications for public health. Funding source: Medical Research Council, the European Community's Seventh Framework Program grant, São Paulo Research Foundation, National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) at South London and Maudsley NHS Foundation Trust and King's College London and the NIHR BRC at University College London, Wellcome Trust.
Background: Ten U.S. states, Canada, and Uruguay have passed laws to legalize the production and sale of cannabis for non-medical purposes. Available research has documented rapidly falling prices and changing product mixes, but many details are not well understood: particularly, the popularity, prices, and product characteristics of different cannabis edibles and extract-based products - each offering different ways to consume cannabis, with unclear health consequences. Methods: This paper analyzes data from Washington's recreational cannabis market, which has recorded over 110 million retail item-transactions from July 2014 to October 2017. Previous research on price and product trends has focused mostly on herbal cannabis, which accounts for the majority, but a decreasing share, of sales. This paper applies advanced text-analytic methods to provide new insights, including (A) estimating potency data for edibles and (B) identifying extract sub-types. Patterns and trends are described, across product types, regarding THC and CBD profiles and price per THC. Results: Extracts accounted for 28.5% of sales in October 2017. Of extracts categorized to subtype, nearly half were identified as "dabs", and another half "cartridges". In October 2017, price per 10 mg THC was roughly $3 among edibles, 70 cents among extract cartridges, and 30-40 cents for other flower and other extracts; solid concentrates offered the lowest priced THC among extract products. Price declines continue but have slowed. High-CBD chemovars are becoming more common, but still are almost non-existent in flower marijuana and rare (1% of sales) among extract products. Conclusion: As Washington's recreational cannabis market has developed over three and a half years, trends identified in that market may serve as an early indication of potential issues in other states. Legislators and regulators in other jurisdictions with commercial non-medical cannabis markets may wish to establish policies responsive to these trends in product popularity, price, and potency.