Systematic literature review of human studies assessing the efficacy of cannabidiol for social anxiety

Abstract

1. Introduction

Social Anxiety Disorder (SAD) is characterized by clinically significant fear of one or more specific social situations in which an individual may feel scrutinized, judged, or humiliated (American Psychiatric Association [APA], 2013). Critically, the anxiety related to these events also manifests in anticipatory anxiety and post-event processing: worry or dread surrounding the upcoming situation, even far beforehand, and rumination over their performance afterwards (APA, 2013; Clark and Wells, 1995). Consequently, individuals with SAD often develop avoidance behaviors to mitigate their discomfort (APA, 2013), leading them to appear shy or socially withdrawn, which can be mistaken as disinterest by others (Clark and Wells, 1995). This creates a cycle of distress in which the individual is consistently perceiving themselves as inferior and engaging in maladaptive coping strategies to avoid anxiety-inducing social situations (Rachman et al., 2000).

The lifetime prevalence of SAD in the United States is 7% annually; it is nearly twice as common among women and has a median onset age of 13 years (APA, 2013). SAD is associated with decreased quality of life, lower socioeconomic status, and reduced vocational productivity (APA, 2013). Despite the persistent impairments in social functioning that impact other aspects of life, only 50% of individuals seek treatment after experiencing symptoms for 15–20 years (APA, 2013). Of those who pursue clinical care, only 30% of individuals experience symptom remission within one year (APA, 2013). Therefore, improved access to effective treatment is imperative.

Several treatment options already exist. Cognitive-behavioral therapy (CBT) is a particularly effective psychosocial intervention for the treatment of SAD (Goldin et al., 2014; Nordahl et al., 2016; Rodebaugh et al., 2004), and first-line pharmacotherapies include selective serotonin reuptake inhibitors (SSRI) and selective norepinephrine reuptake inhibitors (SNRI) (Blanco et al., 2002; Garakani et al., 2020; National Collaborating Centre for Mental Health [NCCMH], 2013). While tricyclic antidepressants (TCA) and monoamine oxidase inhibitors (MAOI) remain in use as second-line options, the newer SSRIs and SNRIs have increased tolerability and fewer contraindications (Blanco et al., 2002; Garakani et al., 2020; NCCMH, 2013). Benzodiazepines are also still widely used and act much more rapidly (minutes versus weeks) but can lead to tolerance, abuse, and dependence, in addition to causing sedation and cognitive and motor impairments. Therefore, they are preferred for adjunctive short-term use with SSRIs, SNRIs, and/or psychosocial treatment (Balon and Starcevic, 2020; Garakani et al., 2020; Stewart, 2005). Atypical antipsychotics and beta-blockers have also been used off-label to augment antidepressants, regulating mood and autonomic activity; the latter may benefit individuals with SAD in performance situations as they are often hyper-aware of their bodily states (Davidson, 2006; Katzman et al., 2014). Overall, although there are a variety of existing treatment options for SAD, the large majority of affected individuals do not experience remission within one year (APA, 2013). Therefore, there is an urgent need for novel pharmacotherapeutic options to improve SAD treatment outcomes.

Emerging evidence suggests that cannabidiol (CBD), a phytocannabinoid in the cannabis plant, may be a promising treatment option for individuals with SAD. CBD is a non-intoxicating cannabinoid that has low abuse potential and considerable tolerability across a wide range of doses (Bergamaschi et al., 2011b; Larsen and Shahinas, 2020). Preclinical studies have demonstrated anxiolytic effects of CBD in models of SAD and suggest that CBD acts on various neural regions implicated in the disorder (Campos et al., 2013; Campos and Guimaraes, 2009; Gomes et al., 2011). Notably, CBD may have some key advantages over existing treatments; preliminary evidence suggests it can improve acute anxiety without psychoactive or sedative side effects, while chronic administration may have enduring benefits for improving symptoms over time (Bergamaschi et al., 2011b). Therefore, the current review will synthesize emerging evidence for CBD’s efficacy in ameliorating symptoms of social anxiety and highlight remaining gaps in the literature to pave the way for future evidence-based work in this area. To this end, we will first review CBD’s diverse mechanisms of action, human neuroimaging findings in SAD, and neuroimaging literature suggesting that CBD alters the function of neural regions implicated in SAD. Finally, we will systematically review existing studies that directly assess the effect of CBD administration on social anxiety symptoms in healthy volunteers and individuals with SAD.

2. Methods

A systematic literature search of Medline, Embase, and Psycinfo was conducted on June 25th, 2021, with 6 search terms encompassing the following parameters: social anxiety disorder (OR social anxiety, social phobia, sad) and cannabidiol (OR cbd). This produced 78 studies, and three additional studies were identified from other sources (see Fig. 1 for PRISMA flowchart). Studies were included in the current review if they utilized original data examining the effects of CBD administration on social anxiety symptoms. Studies were excluded if they a) did not include original data (i.e., conference abstract only, review papers), or b) did not assess social anxiety symptoms. Additionally, included studies were assessed for risk of bias using the revised Cochrane risk-of-bias tool for randomized trials (RoB 2) (Sterne et al., 2019).

Fig. 1.

PRISMA Flowchart. Overview of the study selection process.

3. Results

Seven studies were identified for inclusion (see Fig. 1 for PRISMA flowchart), including 4 studies examining the effects of CBD on experimentally-induced social anxiety among healthy volunteers (summarized in Table 1A) and 3 studies assessing the impact of CBD on social anxiety symptoms among individuals with SAD (summarized in Table 1B). Together, these studies include data from n = 278 individuals (n = 71 individuals with SAD; n = 207 healthy volunteers). Notably, female participants were underrepresented (n = 100 female participants vs. n = 178 male participants), despite data that SAD is twice as prevalent among women. The bias assessment identified 5 articles with some concerns of bias (Bergamaschi et al., 2011a; Crippa et al., 2011; Linares et al., 2019; Zuardi et al., 1993, 2017) and 2 articles with a high risk of bias (Arndt and de Wit, 2017; Masataka, 2019) (see Tables 1A and ​and1B1B).

4. Discussion

SAD is a debilitating anxiety disorder characterized by persistent and intense fear of specific social situations leading to compensatory avoidance behaviors, which is associated with substantially decreased quality of life. While a variety of evidence-based treatment options exist, a minority of patients experience symptom remission following 1-year of treatment, and existing pharmacotherapies are limited by a delayed course of action for SSRIs/SNRIs, and high abuse liability and problematic side effects in the case of benzodiazepines. CBD has emerged a promising treatment candidate for SAD and preliminary neuroimaging data suggests that CBD acts on the same brain regions known to be altered in SAD. Additionally, CBD may have key advantages over existing treatments, including a rapid course of action, reduced abuse liability and potential for drug interactions with alcohol and opioids, as well as reduced sedative and cognitive side effects. However, few studies to date have directly examined the efficacy of CBD for SAD. Therefore, the current systematic review examined the preliminary extant literature addressing the efficacy of CBD for SAD in human participants in order to synthesize current findings and highlight important areas for future research.

Overall, the literature reviewed supports the anxiolytic effect of CBD administration, both among healthy volunteers undergoing experimental social anxiety paradigms, as well as individuals with SAD. Within healthy volunteers, a reduction in anxiety was observed in experimental public speaking tasks (Zuardi et al., 1993) in an inverted U-shaped dose-response curve (Linares et al., 2019; Zuardi et al., 2017). Notably, significant anxiolytic effects of CBD occurred without the concomitant sedation observed with benzodiazepine treatment (Linares et al., 2019; Zuardi et al., 1993, 2017). In individuals with SAD, social anxiety symptoms were ameliorated by CBD administration in a public speaking paradigm (Bergamaschi et al., 2011a), a SPECT scan (Crippa et al., 2011), and a longitudinal study involving one month of daily CBD treatment (Masataka, 2019). Again, studies including SAD patients also observed significant improvements in anxiety without cognitive or sedative side effects (Bergamaschi et al., 2011a; Crippa et al., 2011).

With regard to the magnitude of CBD’s anxiolytic effects, studies in healthy volunteers have reported that pre-stress subjective anxiety ratings were approximately 2–27% lower in the CBD condition versus placebo, ratings during the stress induction were approximately 10–12% lower, and post-stress rating were approximately 16–52% lower for CBD relative to placebo (Zuardi et al., 1993, 2017). Among individuals with SAD, studies involving acute CBD administration reported that pre-stress ratings were approximately 18–45% lower in the CBD condition relative to placebo, ratings were approximately 18–44% lower during stress induction, and 27–78% lower following the stressor (Bergamaschi et al., 2011a; Crippa et al., 2011). For the one study assessing chronic CBD administration, individuals in the CBD condition reported symptom reductions of approximately 25% and 16% (depending on the outcome measure) following one month of treatment, relative to 0% and 4%, respectively, for individuals in the placebo condition (Masataka, 2019).

Although systematic side effect assessments were not conducted in the studies reviewed here, data suggest that CBD administration is well-tolerated (Bergamaschi et al., 2011b; Taylor et al., 2018). A recent meta-analysis of CBD’s adverse effects (AEs) following 1–14 weeks of treatment for various indications reported sedation, decreased appetite, diarrhea, and somnolence as the most common side effects (Chesney et al., 2020). Notably, AEs were reported more frequently among individuals taking higher CBD doses and among individuals in treatment for epilepsy (Chesney et al., 2020), likely due to drug-drug interactions with antiepileptic drugs (Gaston et al., 2017; Geffrey et al., 2015; Morrison et al., 2019). In the non-epilepsy studies, solely diarrhea was more frequent with CBD treatment versus placebo (Chesney et al., 2020). Anxiolytic effects were observed with considerably lower, acute doses of CBD (Bergamaschi et al., 2011a; Crippa et al., 2011; Linares et al., 2019; Zuardi et al., 1993, 2017) relative to doses administered for other indications (Chesney et al., 2020), likely mitigating potential dose-related AEs. Nonetheless, it is essential that possible interactions with SSRIs/SNRIs and benzodiazepines are thoroughly assessed prior to CBD being used in the treatment of SAD.

The existing literature also provides important preliminary data to evaluate optimal CBD dosing. While administration of 100–900mg CBD was examined, extant studies suggest 300mg may be the most effective anxiolytic dose (Linares et al., 2019; Masataka, 2019; Zuardi et al., 1993, 2017), likely due to the inverted U-shaped dose-response curve identified in preclinical (Campos et al., 2013; Campos and Guimaraes, 2009; Gomes et al., 2011) and clinical (Linares et al., 2019; Zuardi et al., 2017) studies. Relative to placebo, 300mg CBD significantly attenuated anxiety both when administered acutely (Linares et al., 2019; Zuardi et al., 1993, 2017) and chronically (Masataka, 2019), among healthy volunteers (Zuardi et al., 1993, 2017) and individuals with SAD (Bergamaschi et al., 2011a). However, whereas several studies compared multiple CBD doses in healthy volunteers (Linares et al., 2019; Zuardi et al., 1993, 2017), existing studies including patient populations have only examined a single dose (600mg (Bergamaschi et al., 2011a), 400mg (Crippa et al., 2011), and 300mg (Masataka, 2019)). Therefore, future studies directly comparing different CBD doses among patients with SAD are urgently needed.

Collectively, these data suggest that CBD administration may have key benefits over existing pharmacotherapies for SAD (Blanco et al., 2002). In particular, CBD appears to reduce social anxiety symptoms quickly without impairing cognitive or physical functioning. The rapid course of action can present an advantage over the several-week-long latency period of SSRIs and SNRIs, and the lack of functionally impairing side effects is a notable advantage over benzodiazepines. Moreover, unlike benzodiazepines, CBD has a low abuse potential and lacks the potential for fatal interactions with alcohol and opioids (Bergamaschi et al., 2011b; Jones et al., 2014; Stewart, 2005; Tori et al., 2020). Since CBD is not associated with these risks, it may be especially appealing to individuals with SAD that are younger, older, or those with comorbid substance use disorders.

While the majority of studies were judged to have some concerns with regard to their overall risk of bias, this was largely driven by the fact that studies did not include a preregistered analysis plan. Risk of bias across other domains (randomization process, deviations from intended interventions, missing outcome data, and measurement of the outcome, as well as a sixth domain regarding crossover effects, for crossover studies only) was assessed to be low in all but two studies. Masataka (2019) was deemed high risk with regard to missing outcome data that disproportionately affected the experimental group, where three participants dropped out due to an adverse taste associated with the CBD solution (see Supplement S1). Additionally, the Arndt and de Wit (2017) study was delineated as high risk, having an insufficient washout period (1 week) to mitigate crossover effects of the tasks across trials. Therefore, the majority of studies had a low risk of bias across most domains, whereas Masataka (2019) and Arndt and de Wit (2017) were found to have potential bias attributed to missing outcome data and crossover effects, respectively (see Supplement S1).

Although the studies converged in observing acute anxiolytic effects of CBD administration, there was substantial variability in the timing between CBD administration and testing, ranging from 90 to 160 min (Bergamaschi et al., 2011a; Crippa et al., 2011; Linares et al., 2019; Zuardi et al., 1993, 2017). In experimental public speaking paradigms, differences in this span may have led to significantly reduced anxiety relative to placebo during the speech (Bergamaschi et al., 2011a; Linares et al., 2019) versus post-speech (Zuardi et al., 1993, 2017) phases of the task. Individuals with SAD experience elevated social anxiety symptoms during a stressor, as well as persistent post-stress anxiety due to negatively biased post-event processing (Clark and Wells, 1995; Rachman et al., 2000). Several studies reviewed demonstrated that CBD ameliorated post-stress anxiety (Crippa et al., 2011; Zuardi et al., 1993, 2017) and negative self-evaluations (Bergamaschi et al., 2011a). Therefore, it has the potential to improve anxiety symptoms both during and following stressful events, aiding in diminishing rumination and maladaptive avoidance behaviors. However, it is essential that future studies systematically evaluate the optimal timing of administration and duration of CBD’s anxiolytic effects, as well as assessing varying doses in individuals with SAD.

In contrast to the majority of studies reviewed, Arndt and de Wit (2017) did not detect anxiolytic effects of CBD (300, 600, 900mg). The discrepancy in these results may be attributable to practice effects from repeated task administration, potential tolerance to CBD, or reduced CBD exposure due to drug administration when participants were fasted. Participants in the current study completed each task on four different occasions one week apart, which may have led the tasks to become less salient over time. Additionally, participants in this study had a much higher level of current cannabis use relative to subjects in the other studies reviewed. Specifically, 14 participants in the current study reported using cannabis an average of five times per month. Although it is impossible to know the CBD content of the cannabis used, this raises the possibility that these participants could have some level of tolerance to CBD exposure. Finally, participants agreed to fast prior to CBD administration (although they were given a granola bar at baseline), which may have limited their CBD exposure, as pharmacokinetic analyses have shown significantly greater CBD absorption in fed versus fasted states (Taylor et al., 2018). Future studies should assess whether CBD attenuates anxiety on tasks aside from public speaking paradigms among individuals with SAD to evaluate the specificity of CBD’s anxiolytic effects in this patient population.

While the majority of the reviewed literature investigated acute CBD administration (Arndt and de Wit, 2017; Bergamaschi et al., 2011a; Crippa et al., 2011; Linares et al., 2019; Zuardi et al., 1993; Zuardi et al., 2017), only one chronic administration study in individuals with SAD has been undertaken (Masataka, 2019). Over one month, 300mg CBD was given daily to participants and markedly reduced their social anxiety symptoms relative to placebo. Although the authors did not systematically evaluate cognitive or sedative side effects, no adverse effects were reported during or after the intervention (Masataka, 2019). Furthermore, the CBD group was significantly more likely to seek further treatment (medication and CBT) than the placebo group (Masataka, 2019), suggesting that chronic CBD administration can aid in removing barriers to additional treatment by decreasing symptoms. More chronic administration studies in individuals with SAD are thus needed to support these findings and carefully investigate potential side effects of long-term use.

Although nearly twice as many women than men are diagnosed with SAD (APA, 2013), women have been underrepresented in the current literature, and no studies have examined sex differences in the efficacy of CBD for treating social anxiety. This is particularly essential given pharmacokinetic data suggesting that women receive greater exposure from the same dose of CBD (Nadulski et al., 2005), and known sex differences in the effects of existing pharmacotherapies for SAD. For example, benzodiazepines are prescribed twice as often to women (Olfson et al., 2015), despite data suggesting women experience more adverse effects than men (Zucker and Prendergast, 2020) and concerning their abuse potential (Stewart, 2005). Therefore, it is critical that future studies include both male and female participants with SAD and assess sex differences in the efficacy, dosing, and side effect profile of CBD administration.

Overall, the preliminary extant human literature supports the potential efficacy of CBD for social anxiety. Existing data suggest that acute administration of CBD significantly attenuates social anxiety, without significant sedation or cognitive impairment. However, additional research is needed to determine optimal dosing among individuals with SAD, assess the timecourse of CBD’s acute effects, examine the efficacy and side effect profile of chronic CBD administration, assess sex differences in the use of CBD for social anxiety, as well as investigate CBD’s mechanisms of action.

Supplementary Material

Acknowledgements

Footnotes

References