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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,
UnitedStates
Reviewed by:
Francisco Silveira Guimaraes,
University of São Paulo, Brazil
Sagnik Bhattacharyya,
King’s College London,
UnitedKingdom
*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
NobuoMasataka*
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 efcacy 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 300mg CBD or placebo (n=20) daily for 4weeks. 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
signicantly decreased anxiety measured by both scales. The results indicate that CBD
could bea 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 eects 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 etal., 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 eects 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 eects 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, eects, 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 signicant 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 eective
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 eective for SAD if it is executed, it is also true that
people with the disorder quite oen 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 ecacy 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 signicant decrease aer 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 ecacy of CBD as at
least an adjunctive option for intervention in people with SAD.
While SAD has been classied 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 ecacy 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 eectiveness of psychological
treatments (De Gregorio etal., 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 ecacy 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 aer 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 signicantly 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
Masataka Cannabidiol and Social Anxiety
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 etal., 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 etal., 1994; First etal., 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 3weeks showing stable FNE scores (Watson and Friend, 1969;
the primary outcome measure). Subsequently, aer 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
aer 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.
Aer the completion of the intervention, at the follow-up,
the clinical psychologists who had been responsible for the
intervention visited the participants briey at their home once
a week to check for any eect 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 aernoon, 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 eects in healthy
subjects exposed to a simulated public speaking test (Zuardi
etal., 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 dierent 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 aernoon 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 aer the completion of the study revealed that
none of them noticed the dierence 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 eect was statistically
signicant 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
signicant (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 eect was statistically signicant 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 signicant (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 dierence 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 signicant 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 signicant difference from pretreatment measurement.
Masataka Cannabidiol and Social Anxiety
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 signicantly dierent from one another
in the preintervention measurement (p = 0.66).
At the follow-up conducted aer the completion of the
intervention, none of the participants had any signicant
health complaint, although no systematic evaluation of side
eects 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 eects 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 etal., 1993; Blessing etal., 2015). A pioneering
study that investigated the eects on SAD patients showed that
CBD reduces anticipatory anxiety (Crippa etal., 2011). Moreover,
CBD was found to exert a signicant eect 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 eect 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 eective
(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 beuntreated. 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 eective option for reducing the barriers facing
SAD patients in need of treatment.
In all, the results of the current study provide evidence for
anxiolytic eects 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 beperformed 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 eects 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
draed 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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