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Anxiolytic Effects of Repeated Cannabidiol Treatment in Teenagers With Social Anxiety Disorders

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Accumulated evidence indicates that cannabidiol (CBD), a nonpsychotomimetic and nonaddictive main component of the Cannabis sativa plant, reverses anxiety-like behavior. The purpose of the present study was to assess the efficacy of CBD treatment for Japanese late teenagers with social anxiety disorder (SAD). Thirty-seven 18–19-year-old Japanese teenagers with SAD and avoidant personality disorder received, in a double-blind study, cannabis oil (n = 17) containing 300 mg CBD or placebo (n = 20) daily for 4 weeks. SAD symptoms were measured at the beginning and end of the treatment period using the Fear of Negative Evaluation Questionnaire and the Liebowitz Social Anxiety Scale. CBD significantly decreased anxiety measured by both scales. The results indicate that CBD could be a useful option to treat social anxiety.
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Frontiers in Psychology | www.frontiersin.org 1 November 2019 | Volume 10 | Article 2466
ORIGINAL RESEARCH
published: 08 November 2019
doi: 10.3389/fpsyg.2019.02466
Edited by:
Changiz Mohiyeddini,
Northeastern University,
UnitedStates
Reviewed by:
Francisco Silveira Guimaraes,
University of São Paulo, Brazil
Sagnik Bhattacharyya,
King’s College London,
UnitedKingdom
*Correspondence:
Nobuo Masataka
masataka.nobuo.7r@kyoto-u.ac.jp;
masataka@pri.kyoto-u.ac.jp
Specialty section:
This article was submitted to
Psychology for Clinical Settings,
a section of the journal
Frontiers in Psychology
Received: 14 June 2019
Accepted: 18 October 2019
Published: 08 November 2019
Citation:
Masataka N (2019) Anxiolytic
Effects of Repeated Cannabidiol
Treatment in Teenagers With Social
Anxiety Disorders.
Front. Psychol. 10:2466.
doi: 10.3389/fpsyg.2019.02466
Anxiolytic Effects of Repeated
Cannabidiol Treatment in Teenagers
With Social Anxiety Disorders
NobuoMasataka*
Primate Research Institute, Kyoto University, Inuyama, Japan
Accumulated evidence indicates that cannabidiol (CBD), a nonpsychotomimetic and
nonaddictive main component of the Cannabis sativa plant, reverses anxiety-like behavior.
The purpose of the present study was to assess the efcacy of CBD treatment for Japanese
late teenagers with social anxiety disorder (SAD). Thirty-seven 18–19-year-old Japanese
teenagers with SAD and avoidant personality disorder received, in a double-blind study,
cannabis oil (n=17) containing 300mg CBD or placebo (n=20) daily for 4weeks. SAD
symptoms were measured at the beginning and end of the treatment period using the
Fear of Negative Evaluation Questionnaire and the Liebowitz Social Anxiety Scale. CBD
signicantly decreased anxiety measured by both scales. The results indicate that CBD
could bea useful option to treat social anxiety.
Keywords: cannabidiol, social anxiety disorder, cannabis, cannabinoid, social phobia, avoidant personality disorder,
social withdrawal
INTRODUCTION
e primary noneuphorizing and nonaddictive compound of cannabis, cannabidiol (CBD),
has recently been shown to possess considerable therapeutic potential for treating a wide
range of neuropsychiatric disorders (De Gregorio et al., 2019). ey include chronic pain
(Costa et al., 2007), nausea (Parker et al., 2006), epilepsy (Devinsky et al., 2016), psychosis
(McGuire et al., 2018), and anxiety (Scuderi et al., 2009; Whiting et al., 2015). CBD in
therapeutics is used within a large therapeutic window, which ranges from 2.85 to 50 mg/
kg/day (Whiting et al., 2015; Devinsky et al., 2016). While this fact indicates that its
therapeutic dose is still mostly unknown, clinical studies have revealed that CBD could
produce analgesic and anxiolytic eects exerted through its interaction with 5HT1A receptors
(De Gregorio et al., 2019). As a potential anxiolytic treatment, in particular, it has drawn
increasing interest. A review (Blessing etal., 2015) concluded that existing preclinical evidence
strongly supports CBD as a treatment for generalized anxiety disorder, panic disorder,
obsessive-compulsive disorder, and posttraumatic disorder when administered acutely.
Clinical data showing therapeutic eects of CBD in patients with anxiety disorders, however,
are still meager (Bergamaschi et al., 2011; Crippa et al., 2011). e purpose of the present
study was to investigate these eects in patients with social anxiety disorder (SAD).
SAD is characterized by excessive anxiety in situations where a person might feel judged,
such as performance situations, and situations involving interpersonal contact with others (American
Psychiatric Association, 2000). is is the fear of social situations that may cause humiliation
or embarrassment. While it is one of the common anxiety disorders (Craske et al., 2017), it is
a relatively new area of research, and thus, its etiology, eects, and treatment are not clearly
Masataka Cannabidiol and Social Anxiety
Frontiers in Psychology | www.frontiersin.org 2 November 2019 | Volume 10 | Article 2466
understood. Even prevalence rates reported in the literature vary
across studies (Antony and Rowa, 2008). For instance, lifetime
prevalence estimates for SAD based on large community samples
in the United States range from 3 to 13%. In addition, some
studies report that SAD has a higher incidence in females than
in males (Kessler et al., 2005).
Developmentally, SAD is likely to not only begin in adolescence
(mid to late teens) but can also occur earlier in childhood
(Somers et al., 2006). A signicant number of adults report
that they have had problems with social anxiety for their entire
lives or as long as they can remember (Brown et al., 2001;
Masataka, 2003). A large-scale study of individuals presenting
at an anxiety clinic found a mean age of onset of 15.7 years,
a number that was younger than the onset of other anxiety
disorders (Merikangas et al., 2011).
SAD is best treated with psychotropic medication and
cognitive behavioral therapies (CBT), and the most eective
treatments are a combination of both (Nordahl et al., 2016).
ey consist of monoamine oxidase inhibitors, the serotonin
reuptake inhibitors, benzodiazepines, and individual cognitive
behavioral therapy. CBT typically includes 10–15 weekly sessions
and consists of a variety of strategies, such as self-monitoring,
psychoeducation, cognitive therapy, exposure-based techniques,
and social skills training. While this method has been proven
to be eective for SAD if it is executed, it is also true that
people with the disorder quite oen show unwillingness (Ryan
and Warner, 2012) to receive CBT. In fact, a study reported
that 92% of individuals with SAD expressed concerns about
starting treatment and that is the biggest barrier to treatment
that should be overcome (Kessler et al., 2005).
In this regard, preliminary ndings reported by a study
(Bergamaschi et al., 2011) that investigated the ecacy of CBD
with patients with SAD are noteworthy. In that study, 12 patients
with SAD were provided with a single dose of CBD (600 mg).
When the anxiety induced by simulated public speaking was
compared between pretreatment and posttreatment, its level
showed a signicant decrease aer the treatment, whereas no
such change was observed in the placebo group of 12 other patients.
e purpose of the current study was to pursue this issue
further and to investigate the possible ecacy of CBD as at
least an adjunctive option for intervention in people with SAD.
While SAD has been classied into several subtypes so far (Antony
and Rowa, 2008), here, the author concentrated the research on
that with avoidant personality disorder because this subtype is
the most commonly diagnosed and is becoming a serious social
problem in Japan, where the current study was conducted (Ogino,
2004; Saito, 2007; Teo, 2010). e author attempted to systematically
assess the ecacy of CBD in a total of 37 18–19-year-old Japanese
with SAD, all of whom had been naive to any form of treatment,
by measuring the level of the symptoms of SAD with both the
Fear of Negative Evaluation Questionnaire (FNE; Watson and
Friend, 1969) and the Liebowitz Social Anxiety Scale (LSAS;
Liebowitz, 1987) using an exploratory double-blind parallel-group
trial experimental paradigm.
FNE is a 30-item measure of apprehension and anxiety over
anticipated social evaluations. is measure uses a true-false scale
and is known to show good internal consistency and test-retest
reliability (Watson and Friend, 1969). FNE has a range from 0
to 30, with high scores indicating higher levels of social anxiety.
LSAS is a short questionnaire to assess the range of social
interaction and performance situations feared by a person in
order to assist in the diagnosis of SAD (Liebowitz, 1987). It has
been commonly used to investigate outcomes in clinical trials
and, more recently, to evaluate the eectiveness of psychological
treatments (De Gregorio etal., 2019). e scale features 24 items,
which are divided into two subscales. irteen questions relate
to performance, and 11 relate to situations.
e author attempted to assess the ecacy of CBD by
comparing the FNE and the LSAS scores measured before the
commencement of the 4-week-long intervention (preintervention)
and the scores measured aer the completion of the intervention
(postintervention) in the group of participants who were provided
with CBD (the CBD group) and in the group whose participants
were provided with placebo (the placebo group). e author
hypothesized that CBD would signicantly decrease anxiety
measured by both of the two scales employed.
MATERIALS AND METHODS
Ethics Statement
is investigation was conducted according to the principles
expressed in the Declaration of Helsinki. All experimental
protocols were consistent with the Guide for Experimentation
with Humans and were approved by the Institutional Ethics
Committee of Kyoto University (#2018-150), the regional
committee for medical and health research ethics (#2018/1783),
and the Japanese Data Inspectorate for clinical trials
(JCT0018004564). e author obtained written informed consent
from all of the participants involved in the study. Written
informed consent was additionally obtained from the parent/
legal guardian of all participants who were younger than the
age of consent at the time of the study.
Design and Participants
A randomized, placebo-controlled, comparative study with a
total of 37 Japanese adolescents was undertaken. Double masking
was conducted, and the participants and the investigator were
blinded regarding which condition (CBD oil or placebo) under
which each participant was studied.
At the commencement of the study, 40 teenagers with SAD
participated, and 20 of them were assigned to the CBD group
and the other 20 to the placebo group. is sample size was
determined because the current study had been approved by the
ethics committee on the condition that, as a pilot study, no more
than 20 teenagers take CBD oil. Of the 40 participants, three in
the CBD group declined daily treatment with CBD oil during
the study because they disliked the smell and the taste of the oil.
In all, 26 males and 11 females 18–19-year olds were included
in the study (12 males and 5 females for the CBD group and
14 males and 6 females for the placebo group). ey were all
naive to cannabis and diagnosed by psychiatrists in several
hospitals located in the vicinity of Osaka Prefecture, Japan, using
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Frontiers in Psychology | www.frontiersin.org 3 November 2019 | Volume 10 | Article 2466
the Structured Clinical Interview for DSM-IV Axis I Disorders
(SCID-I/P; Di Nardo etal., 1994) and Axis II Personality Disorders
(First et al., 1997). For all of the participants, symptoms had
lasted for at least 6 months at the commencement of the study.
Exclusion criteria were experience of receiving previous or
concurrent psychological or drug treatment, any form of psychotic
or organic illness, diagnosis of cluster A or B personality disorder,
acute suicidality, and drug and alcohol dependence. ey have
not had a comorbid diagnosis of other anxiety or mood disorders.
Assessment
e participants were invited to attend an assessment interview
for possible participation in the present study. None of them
were under CBT. Assessment of all of them was undertaken by
psychiatrists who were trained in administering the Structured
Clinical Interview for DSM-IV (SCID I and II; Liebowitz, 1987;
Di Nardo etal., 1994; First etal., 1997). e participants completed
the rst battery of self-report measures before attending the
assessment interview. e baseline period for them was a minimum
of 3weeks showing stable FNE scores (Watson and Friend, 1969;
the primary outcome measure). Subsequently, aer the assessment
interview, they rated themselves on the FNE and LSAS (Liebowitz,
1987) over the succeeding weeks (preintervention). All of the
participants had a stable FNE score over the 3 consecutive weeks
and were therefore scheduled for intervention within a week
aer the third-baseline measuring point.
When the 4-week-intervention ended, the FNE and LSAS
were completed again by each participant (postintervention),
and their scores were compared with those recorded at
preintervention. en, the SCID I and II were administered
again by the same psychiatrists who met the participants
at preintervention.
Aer the completion of the intervention, at the follow-up,
the clinical psychologists who had been responsible for the
intervention visited the participants briey at their home once
a week to check for any eect of it on their health. is
follow-up continued for up to a 6-month-period.
Intervention
All of the participants were randomly assigned into either
the CBD group, in which they were to daily receive 300 mg
of CBD administered in a single dose in the aernoon, or
the placebo group, in which they were to daily receive a
matching placebo. e CBD dose was based on that used in
the rst study showing acute anxiolytic eects in healthy
subjects exposed to a simulated public speaking test (Zuardi
etal., 1993). is assignment was conducted by an independent
statistician who did not know about the purpose of the present
research. e CBD used was RSHO-X Hemp Oil (the product
of HempMeds, USA) that was produced from the stalk of
hemp plants. A 236-ml bottle of the product that was for
sale by the company contained 5,000 mg of CBD (21.4 mg/
ml) but no delta-9-tetrahydrocannabinol (THC). It did not
contain other cannabinoids or terpenes.
e placebo contained olive oil. e CBD oil containing
300 mg of CBD or the equivalent amount of the placebo
was administered orally to each of the participants of the
CBD group and each of the participants of the placebo group,
respectively. For each participant, roughly 420 ml of the
CBD oil or the same amount of the placebo was rebottled
in a container that was dierent from that in which it had
been originally bottled and that was identical in size and
color as well as appearance to the oil administered to the
other group.
e container was provided to a clinical psychologist who
was employed by the principal investigator and was
predetermined to be responsible for each participant. e
psychologist who did not know whether the bottle contained
CBD or not visited the home of the participant with the
container every aernoon and administered the necessary
amount of the prepared oil to the participant, using a syringe,
during the 4-week intervention period.
While CBD oil had a characteristic smell and taste, all of
the psychologists and the participants had been naive to the
CBD oil as well as the placebo. e interview with them that
was conducted aer the completion of the study revealed that
none of them noticed the dierence between the two.
RESULTS
e results of the measurements with FNE of the level of
the symptoms that were associated with SAD are shown in
Figure1. When the collected data were analyzed by a 2 (period
of measurements: preintervention versus postintervention,
MEASUREMENT) × 2 (participant group: the CBD group
versus the Placebo group, PARTICIPANT) repeated-measures
ANOVA (analysis of variance), the main eect was statistically
signicant for MEASUREMENT (F1,35 = 10.35, p = 0.003,
h
p
2=0.0228) but not for PARTICIPANT (F1,35=2.69, p=0.11,
h
p
2 = 0.071). e interaction between these factors was
signicant (F1,35 = 44.81, p < 0.001,
h
p
2 = 0.561). e mean
FNE score (SD) of the CBD group was 24.4 (2.7) in the
preintervention measurement and 19.1 (2.1) in the
postintervention measurement and that of the placebo group
was 23.5 (2.1) in the preintervention measurement and 23.3
(2.9) in the postintervention measurement.
Subsequent analyses of simple main effects (using
Bonferroni correction), which were performed because of
the significant interactions between MEASUREMENT and
PARTICIPANT, revealed that the mean score of the CBD
group was lower in the postintervention measurement than
in the preintervention measurement (p = 0.02), while no
such difference was found in the placebo group (p =0.29).
Scores of the participants in the CBD group were lower
than those of the placebo group in the postintervention
measurement (p=0.0002), but the scores were not statistically
significantly different from one another in the preintervention
measurement (p = 0.71).
Figure 2 presents the results of the measurements with LSAS
of the level of the symptoms that are associated with SAD. e
results were strikingly similar to those shown in Figure 1. e
main eect was statistically signicant for MEASUREMENT
Masataka Cannabidiol and Social Anxiety
Frontiers in Psychology | www.frontiersin.org 4 November 2019 | Volume 10 | Article 2466
(F1,35= 10.35, p= 0.003,
h
p
2=0.023) but not for PARTICIPANT
(F1,35 = 0.45, p = 0.57,
h
p
2 = 0.011). e interaction between
these factors was signicant (F1,35=39.16, p<0.001,
h
p
2= 0.528).
e mean LSAS score (SD) of the CBD group was 74.2 (7.5)
in the preintervention measurement and 62.1 (8.7) in the
postintervention measurement and that of the placebo group
was 69.9 (10.3) in the preintervention measurement and 66.8
(11.2) in the postintervention measurement.
Another post hoc test revealed that the mean LSAS score
of the CBD group was lower in the postintervention measurement
than in the preintervention measurement (p = 0.03), but no
such dierence was found in the placebo group (p = 0.42).
FIGURE 1 | Scores of Fear of Negative Evaluation Questionnaire (FNE) in the participants who received the intervention with cannabidiol (CBD; n=17) and in the
participants who received the intervention with placebo (Placebo; n=20). The participants were evaluated before (Pre) and after (Post) treatment. Error bars
represent SDs. * indicates signicant difference from pretreatment measurement.
FIGURE 2 | Scores of Liebowitz Social Anxiety Scale (LSAS) in the participants who received the intervention with cannabidiol (CBD; n=17) and in the participants
who received the intervention with placebo (Placebo; n=20). The participants were evaluated before (Pre) and after (Post) treatment. Error bars represent SDs.
*indicates signicant difference from pretreatment measurement.
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Frontiers in Psychology | www.frontiersin.org 5 November 2019 | Volume 10 | Article 2466
Scores of the participants in the CBD group were smaller
than those of the placebo group in the postintervention
measurement (p = 0.0018), but the scores in the two groups
were not statistically signicantly dierent from one another
in the preintervention measurement (p = 0.66).
At the follow-up conducted aer the completion of the
intervention, none of the participants had any signicant
health complaint, although no systematic evaluation of side
eects was conducted. At that time, among the 17 participants
included in the CBD group, nine reported that they decided
to receive some form of treatment (medication and CBT)
by regularly visiting hospitals, while none of the 20 participants
in the control group was found to make such a decision.
e participants of the CBD group were more likely to make
such decision than those of the placebo group were
(χ2(1) = 13.99, p < 0.001).
DISCUSSION
e anxiolytic eects of CBD have been extensively demonstrated
in animal studies and in healthy volunteers subjected to anxiety
induced by several procedures, including the simulation of public
speaking (Zuardi etal., 1993; Blessing etal., 2015). A pioneering
study that investigated the eects on SAD patients showed that
CBD reduces anticipatory anxiety (Crippa etal., 2011). Moreover,
CBD was found to exert a signicant eect on increased brain
activity in the right posterior cingulated cortex that is thought
to be involved in the processing of emotional information. A
subsequent study (Bergamaschi et al., 2011) experimentally
demonstrated a reduction in the anxiety provoked by simulated
public speaking by a single dose of CBD in patients with SAD,
although the ndings were preliminary. Based on these ndings,
the current study was conceived to extend the published research
into a more systematic study on the eect of CBD on teenagers
with SAD with avoidant personality disorder for a longer period.
Its results are consistent with those obtained by the previous
research and indicate that intervention with CBD for a 4-week
period reduced the level of symptoms in teenagers with SAD,
as measured by FSE and LSAS.
As an option for medication treatment for SAD, so far, the
use of paroxetine has been reported to be most eective
(Nordahl et al., 2016). at study reported that a 26-week
daily treatment with paroxetine alone produced a 5.2-point
decrease in the FNE score and a 10.2-point decrease in the
LSAS score. ose reported decreases in symptoms were almost
equivalent to the observed decreases induced by CBD here,
although the treatment groups studied in the two studies were
not closely compatible.
In children and adolescents, SAD is known to be among
the most common mental disorders (De Gregorio et al.,
2019). A survey conducted in the United States showed
that the disorder starts as early as age 5 and peaks around
age 12 (Merikangas et al., 2011). When untreated, it runs
a chronic course into adolescence and eventually adulthood.
In Japan, notably, the population of such teenagers with
avoidant personality disorder who “seclude themselves for
more than six months at home” (Saito, 2007) and “typically
withdraw from most social activities and retreat into their
living spaces” (Teo, 2010) is estimated to have reached
1,000,000 (Ogino, 2004), and this has become a serious
social problem. When they are provided with a higher level
of social support, their quality of life (QOL) is likely to
increase, whereas it deteriorates with poor support. The
teenagers with SAD in Japan who have higher levels of
social withdrawal along with such poor support are likely
to develop a stronger sense of loneliness and to suffer from
poorer QOL (Teo, 2010).
Despite such negative impacts of the disorder, the majority
of teenagers with SAD are likely to beuntreated. Psychotropic
medication and CBT are the most common therapeutic
options for SAD. However, socially anxious teenagers rarely
seek help due to the potential stigma associated with mental
issues and fear of interacting therapists and psychiatrists
(Ogino, 2004; Teo, 2010). As revealed by the follow-up
conducted in the current study, many of the participants
treated with CBD became positive in their attitude toward
seeking treatment. To overcome the dilemma of teenagers
with SAD described above, delivering interventions with CBD
could be an eective option for reducing the barriers facing
SAD patients in need of treatment.
In all, the results of the current study provide evidence for
anxiolytic eects of repeated CBD administration in teenagers
with SAD. At the same time, however, the author acknowledges
several limitations of the current study. No assay of the blood
level of CBD was undertaken. A more detailed baseline
sociodemographic evaluation could have been performed to
ensure the pretreatment similarity of the treatment groups.
Measurements need to beperformed at additional times between
the baseline and the end of the study. ese measures would
be essential to show, for example, if CBD could produce rapid
improvement of social anxiety (a putative advantage over
paroxetine). Moreover, possible side eects should be evaluated
systematically. Clearly, these are issues for future research that
should also be long-term studies with a positive control (e.g.,
paroxetine) to better assess the potential usefulness of CBD
in the therapy of SAD.
DATA AVAILABILITY STATEMENT
All datasets generated for this study are included in the article/
supplementary material.
ETHICS STATEMENT
e studies involving human participants were reviewed and
approved by the Institutional Ethics Committee of Kyoto
University (#2018-150), the Regional committee for medical
and health research ethics (#2018/1783), and the Japanese Data
Inspectorate for clinical trials (JCT0018004564). e patients/
participants provided their written informed consent to
participate in this study.
Masataka Cannabidiol and Social Anxiety
Frontiers in Psychology | www.frontiersin.org 6 November 2019 | Volume 10 | Article 2466
AUTHOR CONTRIBUTIONS
NM conceived the study, collected and analyzed the data, and
draed the manuscript.
FUNDING
is research was supported by a grant-in-aid (JSPS#25285201)
as well as by the Grants for Excellent Graduate Schools program
from the Ministry of Education, Science, Sports, and Culture,
Japanese Government. e funder had no role in study design,
data collection and analysis, decision to publish, or preparation
of the manuscript.
ACKNOWLEDGMENTS
e author is grateful to Dr. Satomi Yamada, Yoshiyuki Nagai,
Atsushi Ishige, Ryohei Tatsumi, and Koji Maki for their assistance
in conducting experimentation and Elizabeth Nakajima for
making comments on an earlier version of this manuscript.
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Conict of Interest: e author declares that the research was conducted in
the absence of any commercial or nancial relationships that could beconstrued
as a potential conict of interest.
Copyright © 2019 Masataka. is is an open-access article distributed under the
terms of the Creative Commons Attribution License (CC BY). e use, distribution
or reproduction in other forums is permitted, provided the original author(s) and
the copyright owner(s) are credited and that the original publication in this journal
is cited, in accordance with accepted academic practice. No use, distribution or
reproduction is permitted which does not comply with these terms.
... Acute administration studies have demonstrated anxiolytic effects of CBD in healthy adults during pharmacologically-induced anxiety 8 and a simulated public speaking task (SPST) 9 as well as in patients with social anxiety disorder (SAD) 10 , including during the SPST 11 . To date, only one double-blind clinical trial has examined CBD for anxiety; teenagers with SAD exhibited reduced anxiety following 4 weeks of CBD treatment (300 mg/day) 12 . Interestingly, these investigations all used study products containing single extracted compounds (CBD only), which exhibit bell-shaped dose-response curves with limited dosage range for therapeutic response 13 . ...
... Treatment response analyses revealed rapid onset of clinically significant reductions in anxiety with most patients achieving and maintaining treatment response after 1 week and all patients achieving and maintaining treatment response by week 3. This rapid response has been observed in previous clinical trials of cannabinoid-based products 12 , and is a marked improvement over the typical time course (up to 12 weeks) often required for full treatment response using conventional pharmacotherapy 2 . ...
... Interestingly, in the current trial, treatment response was observed at a much lower dosage (~30 mg/day) than a previous trial using a single extracted CBD isolate (~300 mg/day) 12 . This difference may be related to the entourage effect, a term used to describe the potentially enhanced effects of cannabinoids when a variety of metabolites and closely related compounds (e.g., cannabinoids, terpenoids, flavonoids) work together synergistically 15 . ...
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Background Evidence suggests cannabidiol (CBD) has anxiolytic properties, indicating potential for novel treatment strategies. However, few clinical trials of CBD-based products have been conducted, and none thus far have examined the impact of these products on cognition. Methods For the open-label stage of clinical trial NCT02548559, autoregressive linear modeling assessed efficacy and tolerability of four-weeks of 1 mL t.i.d. treatment with a full-spectrum, high-CBD sublingual solution (9.97 mg/mL CBD, 0.23 mg/mL Δ−9-tetrahydrocannabinol) in 14 outpatients with moderate-to-severe anxiety, defined as ≥16 on the Beck Anxiety Inventory (BAI) or ≥11 on the Overall Anxiety Severity and Impairment Scale (OASIS). Results Findings suggest significant improvement on primary outcomes measuring anxiety and secondary outcomes assessing mood, sleep, quality of life, and cognition (specifically executive function) following treatment. Anxiety is significantly reduced at week 4 relative to baseline (BAI: 95% CI = [−21.03, −11.40], p < 0.001, OASIS: 95% CI = [−9.79, −6.07], p < 0.001). Clinically significant treatment response (≥15% symptom reduction) is achieved and maintained as early as week 1 in most patients (BAI = 78.6%, OASIS = 92.7%); cumulative frequency of treatment responders reached 100% by week 3. The study drug is well-tolerated, with high adherence/patient retention and no reported intoxication or serious adverse events. Minor side effects, including sleepiness/fatigue, increased energy, and dry mouth are infrequently endorsed. Conclusions Results provide preliminary evidence supporting efficacy and tolerability of a full-spectrum, high-CBD product for anxiety. Patients quickly achieve and maintain symptom reduction with few side effects. A definitive assessment of the impact of this novel treatment on clinical symptoms and cognition will be ascertained in the ongoing double-blind, placebo-controlled stage.
... The ISI uses a 5-point Likert scale of 0-4 to rate each item (0 = no problem; 4 = very severe problem), yielding a total score ranging from 0 to 28. The total score is interpreted as follows: absence of insomnia (0-7); sub-threshold insomnia (8)(9)(10)(11)(12)(13)(14); moderate insomnia (15)(16)(17)(18)(19)(20)(21); and severe insomnia (22)(23)(24)(25)(26)(27)(28). ...
... Previous smaller studies have demonstrated improvements in patient reported outcomes over shorter periods of time and with mixed cannabis delivery systems including inhaled and oromucosal medications [7,23], and for specific clinical conditions in pain [24,25], anxiety [26,27], cancer [28,29], and sleep [30]. This is the first comprehensive analysis of this magnitude and length of time for oral MC daily dosages prescribed in a cannabis naïve cohort. ...
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Introduction Oral medicinal cannabis (MC) has been increasingly prescribed for a wide range of clinical conditions since 2016. Despite an exponential rise in prescriptions and publications, high quality clinical efficacy and safety studies are lacking. The outcomes of a large Australian clinical electronic registry cohort are presented. Methods A prospective cannabis-naïve patient cohort prescribed oral MC participated in an ongoing longitudinal registry at a network of specialised clinics. Patient MC dose, safety and validated outcome data were collected regularly over two years and analysed. Results 3,961 patients (mean age 56.07 years [SD 19.08], 51.0% female) with multimorbidity (mean diagnoses 5.14 [SD 4.08]) and polypharmacy (mean 6.26 medications [SD 4.61]) were included in this analysis. Clinical indications were for: chronic pain (71.9%), psychiatric (15.4%), neurological (2.1%), and other diagnoses (10.7%). Median total oral daily dose was 10mg for Δ9-tetrahydrocannabinol (THC) and 22.5mg for cannabidiol (CBD). A stable dose was observed for over two years. 37.3% experienced treatment related adverse events. These were graded mild (67%), moderate (31%), severe (<2%, n = 23) and two (0.1%) serious adverse events. Statistically significant improvements at a p value of <0.001 across all outcomes were sustained for over two years, including: clinical global impression (CGI-E, +39%: CGI-I, +52%; p<0.001), pain interference and severity (BPI, 26.1% and 22.2%; p<0.001), mental health (DASS-21, depression 24.5%, anxiety 25.5%, stress 27.7%; p<0.001), insomnia (ISI, 35.0%; p<0.001), and health status (RAND SF36: physical function, 34.4%: emotional well-being, 37.3%; p<0.001). Mean number of concomitant medications did not significantly change over 2 years (p = 0.481). Conclusions Oral MC was demonstrated to be safe and well-tolerated for a sustained period in a large complex cohort of cannabis-naïve, multimorbid patients with polypharmacy. There was significant improvement (p<0.001) across all measured clinical outcomes over two years. Results are subject to limitations of Real World Data (RWD) for causation and generalisability. Future high quality randomised controlled trials are awaited.
... Numerous publications are proving the beneficial effects of using CBD in individuals suffering from anxiety [101][102][103][104][105][106][107][108][109][110]. A double-blind randomized clinical trial investigated the beneficial effect of orally administered CBD on 24 patients with social anxiety, who had to undergo a simulated public speaking test, compared to 11 healthy individuals [101]. ...
... Indeed, CBD is very well tolerated, and produces adverse effects only at low incidence [45,46]. In clinical trials, the most common adverse effects reported after CBD administration included somnolence, sedation, fatigue, diarrhea, vomiting, and nausea [47,48]. It is worth mentioning that serious adverse effects following CBD treatment were observed in clinical trials with epilepsy, including severe somnolence, lethargy, increased hepatic transaminases, rash, and pneumonia. ...
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Pharmacological agents limiting secondary tissue loss and improving functional outcomes after stroke are still limited. Cannabidiol (CBD), the major non-psychoactive component of Cannabis sativa, has been proposed as a neuroprotective agent against experimental cerebral ischemia. The effects of CBD mostly relate to the modulation of neuroinflammation, including glial activation. To investigate the effects of CBD on glial cells after focal ischemia in vivo, we performed time-lapse imaging of microglia and astroglial Ca2+ signaling in the somatosensory cortex in the subacute phase of stroke by in vivo two-photon laser-scanning microscopy using transgenic mice with microglial EGFP expression and astrocyte-specific expression of the genetically encoded Ca2+ sensor GCaMP3. CBD (10 mg/kg, intraperitoneally) prevented ischemia-induced neurological impairment, reducing the neurological deficit score from 2.0 ± 1.2 to 0.8 ± 0.8, and protected against neurodegeneration, as shown by the reduction (more than 70%) in Fluoro-Jade C staining (18.8 ± 7.5 to 5.3 ± 0.3). CBD reduced ischemia-induced microglial activation assessed by changes in soma area and total branch length, and exerted a balancing effect on astroglial Ca2+ signals. Our findings indicate that the neuroprotective effects of CBD may occur in the subacute phase of ischemia, and reinforce its strong anti-inflammatory property. Nevertheless, its mechanism of action on glial cells still requires further studies.
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Chapter
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Background: The most efficacious treatments for social anxiety disorder (SAD) are the SSRIs and cognitive therapy (CT). Combined treatment is advocated for SAD but has not been evaluated in randomized trials using CT and SSRI. Our aim was to evaluate whether one treatment is more effective than the other and whether combined treatment is more effective than the single treatments. Methods: A total of 102 patients were randomly assigned to paroxetine, CT, the combination of CT and paroxetine, or pill placebo. The medication treatment lasted 26 weeks. Of the 102 patients, 54% fulfilled the criteria for an additional diagnosis of avoidant personality disorder. Outcomes were measured at posttreatment and 12-month follow-up assessments. Results: CT was superior to paroxetine alone and to pill placebo at the end of treatment, but it was not superior to the combination treatment. At the 12-month follow-up, the CT group maintained benefits and was significantly better than placebo and paroxetine alone, whereas there were no significant differences among combination treatment, paroxetine alone, and placebo. Recovery rates at 12 months were much higher in the CT group (68%) compared to 40% in the combination group, 24% in the paroxetine group, and 4% in the pill placebo group. Conclusions: CT was the most effective treatment for SAD at both posttreatment and follow-up compared to paroxetine and better than combined treatment at the 12-month follow-up on the Liebowitz Social Anxiety Scale. Combined treatment provided no advantage over single treatments; rather there was less effect of the combined treatment compared to CT alone.
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Cannabidiol (CBD), a Cannabis sativa constituent, is a pharmacologically broad-spectrum drug that in recent years has drawn increasing interest as a treatment for a range of neuropsychiatric disorders. The purpose of the current review is to determine CBD's potential as a treatment for anxiety-related disorders, by assessing evidence from preclinical, human experimental, clinical, and epidemiological studies. We found that existing preclinical evidence strongly supports CBD as a treatment for generalized anxiety disorder, panic disorder, social anxiety disorder, obsessive-compulsive disorder, and post-traumatic stress disorder when administered acutely; however, few studies have investigated chronic CBD dosing. Likewise, evidence from human studies supports an anxiolytic role of CBD, but is currently limited to acute dosing, also with few studies in clinical populations. Overall, current evidence indicates CBD has considerable potential as a treatment for multiple anxiety disorders, with need for further study of chronic and therapeutic effects in relevant clinical populations.
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Cannabis and cannabinoid drugs are widely used to treat disease or alleviate symptoms, but their efficacy for specific indications is not clear. To conduct a systematic review of the benefits and adverse events (AEs) of cannabinoids. Twenty-eight databases from inception to April 2015. Randomized clinical trials of cannabinoids for the following indications: nausea and vomiting due to chemotherapy, appetite stimulation in HIV/AIDS, chronic pain, spasticity due to multiple sclerosis or paraplegia, depression, anxiety disorder, sleep disorder, psychosis, glaucoma, or Tourette syndrome. Study quality was assessed using the Cochrane risk of bias tool. All review stages were conducted independently by 2 reviewers. Where possible, data were pooled using random-effects meta-analysis. Patient-relevant/disease-specific outcomes, activities of daily living, quality of life, global impression of change, and AEs. A total of 79 trials (6462 participants) were included; 4 were judged at low risk of bias. Most trials showed improvement in symptoms associated with cannabinoids but these associations did not reach statistical significance in all trials. Compared with placebo, cannabinoids were associated with a greater average number of patients showing a complete nausea and vomiting response (47% vs 20%; odds ratio [OR], 3.82 [95% CI, 1.55-9.42]; 3 trials), reduction in pain (37% vs 31%; OR, 1.41 [95% CI, 0.99-2.00]; 8 trials), a greater average reduction in numerical rating scale pain assessment (on a 0-10-point scale; weighted mean difference [WMD], -0.46 [95% CI, -0.80 to -0.11]; 6 trials), and average reduction in the Ashworth spasticity scale (WMD, -0.36 [95% CI, -0.69 to -0.05]; 7 trials). There was an increased risk of short-term AEs with cannabinoids, including serious AEs. Common AEs included dizziness, dry mouth, nausea, fatigue, somnolence, euphoria, vomiting, disorientation, drowsiness, confusion, loss of balance, and hallucination. There was moderate-quality evidence to support the use of cannabinoids for the treatment of chronic pain and spasticity. There was low-quality evidence suggesting that cannabinoids were associated with improvements in nausea and vomiting due to chemotherapy, weight gain in HIV infection, sleep disorders, and Tourette syndrome. Cannabinoids were associated with an increased risk of short-term AEs.
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Objective: Research in both animals and humans indicates that cannabidiol (CBD) has antipsychotic properties. The authors assessed the safety and effectiveness of CBD in patients with schizophrenia. Method: In an exploratory double-blind parallel-group trial, patients with schizophrenia were randomized in a 1:1 ratio to receive CBD (1000 mg/day; N=43) or placebo (N=45) alongside their existing antipsychotic medication. Participants were assessed before and after treatment using the Positive and Negative Syndrome Scale (PANSS), the Brief Assessment of Cognition in Schizophrenia (BACS), the Global Assessment of Functioning scale (GAF), and the improvement and severity scales of the Clinical Global Impressions Scale (CGI-I and CGI-S). Results: After 6 weeks of treatment, compared with the placebo group, the CBD group had lower levels of positive psychotic symptoms (PANSS: treatment difference=-1.4, 95% CI=-2.5, -0.2) and were more likely to have been rated as improved (CGI-I: treatment difference=-0.5, 95% CI=-0.8, -0.1) and as not severely unwell (CGI-S: treatment difference=-0.3, 95% CI=-0.5, 0.0) by the treating clinician. Patients who received CBD also showed greater improvements that fell short of statistical significance in cognitive performance (BACS: treatment difference=1.31, 95% CI=-0.10, 2.72) and in overall functioning (GAF: treatment difference=3.0, 95% CI=-0.4, 6.4). CBD was well tolerated, and rates of adverse events were similar between the CBD and placebo groups. Conclusions: These findings suggest that CBD has beneficial effects in patients with schizophrenia. As CBD's effects do not appear to depend on dopamine receptor antagonism, this agent may represent a new class of treatment for the disorder.
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Anxiety disorders constitute the largest group of mental disorders in most western societies and are a leading cause of disability. The essential features of anxiety disorders are excessive and enduring fear, anxiety or avoidance of perceived threats, and can also include panic attacks. Although the neurobiology of individual anxiety disorders is largely unknown, some generalizations have been identified for most disorders, such as alterations in the limbic system, dysfunction of the hypothalamic-pituitary-adrenal axis and genetic factors. In addition, general risk factors for anxiety disorders include female sex and a family history of anxiety, although disorder-specific risk factors have also been identified. The diagnostic criteria for anxiety disorders varies for the individual disorders, but are generally similar across the two most common classification systems: The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) and the International Classification of Diseases, Tenth Edition (ICD-10). Despite their public health significance, the vast majority of anxiety disorders remain undetected and untreated by health care systems, even in economically advanced countries. If untreated, these disorders are usually chronic with waxing and waning symptoms. Impairments associated with anxiety disorders range from limitations in role functioning to severe disabilities, such as the patient being unable to leave their home.
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Background: Almost a third of patients with epilepsy have a treatment-resistant form, which is associated with severe morbidity and increased mortality. Cannabis-based treatments for epilepsy have generated much interest, but scientific data are scarce. We aimed to establish whether addition of cannabidiol to existing anti-epileptic regimens would be safe, tolerated, and efficacious in children and young adults with treatment-resistant epilepsy. Methods: In this open-label trial, patients (aged 1-30 years) with severe, intractable, childhood-onset, treatment-resistant epilepsy, who were receiving stable doses of antiepileptic drugs before study entry, were enrolled in an expanded-access programme at 11 epilepsy centres across the USA. Patients were given oral cannabidiol at 2-5 mg/kg per day, up-titrated until intolerance or to a maximum dose of 25 mg/kg or 50 mg/kg per day (dependent on study site). The primary objective was to establish the safety and tolerability of cannabidiol and the primary efficacy endpoint was median percentage change in the mean monthly frequency of motor seizures at 12 weeks. The efficacy analysis was by modified intention to treat. Comparisons of the percentage change in frequency of motor seizures were done with a Mann-Whitney U test. Results: Between Jan 15, 2014, and Jan 15, 2015, 214 patients were enrolled; 162 (76%) patients who had at least 12 weeks of follow-up after the first dose of cannabidiol were included in the safety and tolerability analysis, and 137 (64%) patients were included in the efficacy analysis. In the safety group, 33 (20%) patients had Dravet syndrome and 31 (19%) patients had Lennox-Gastaut syndrome. The remaining patients had intractable epilepsies of different causes and type. Adverse events were reported in 128 (79%) of the 162 patients within the safety group. Adverse events reported in more than 10% of patients were somnolence (n=41 [25%]), decreased appetite (n=31 [19%]), diarrhoea (n=31 [19%]), fatigue (n=21 [13%]), and convulsion (n=18 [11%]). Five (3%) patients discontinued treatment because of an adverse event. Serious adverse events were reported in 48 (30%) patients, including one death-a sudden unexpected death in epilepsy regarded as unrelated to study drug. 20 (12%) patients had severe adverse events possibly related to cannabidiol use, the most common of which was status epilepticus (n=9 [6%]). The median monthly frequency of motor seizures was 30·0 (IQR 11·0-96·0) at baseline and 15·8 (5·6-57·6) over the 12 week treatment period. The median reduction in monthly motor seizures was 36·5% (IQR 0-64·7). Interpretation: Our findings suggest that cannabidiol might reduce seizure frequency and might have an adequate safety profile in children and young adults with highly treatment-resistant epilepsy. Randomised controlled trials are warranted to characterise the safety profile and true efficacy of this compound. Funding: GW Pharmaceuticals, Epilepsy Therapy Project of the Epilepsy Foundation, Finding A Cure for Epilepsy and Seizures.
Article
The comorbidity of current and lifetime DSM-IV anxiety and mood disorders was examined in 1,127 outpatients who were assessed with the Anxiety Disorders Interview Schedule for DSM-IV :Lifetime version (ADIS-IV-L). The current and lifetime prevalence of additional Axis I disorders in principal anxiety and mood disorders was found to be 57% and 81%, respectively. The principal diagnostic categories associated with the highest comorbidity rates were mood disorders, posttraumatic stress disorder (PTSD), and generalized anxiety disorder (GAD). A high rate of lifetime comorbidity was found between the anxiety and mood disorders; the lifetime association with mood disorders was particularly strong for PTSD, GAD, obsessive-compulsive disorder, and social phobia. The findings are discussed in regard to their implications for the classification of emotional disorders.
Article
• While other anxiety disorders have recently become the subjects of increasing investigation, social phobia remains, except among behavior therapists, relatively unstudied. As a result, major uncertainties exist concerning classification, prevalence, severity, etiology, assessment, and treatment of social phobia. Existing findings do suggest that in its own right and as a comparison for other anxiety disorders, social phobia should prove a fertile area for psychobiological and clinical investigation.