Cannabinoid as a Treatment for Social Anxiety Disorder

2Over the past few years, marijuana and its many compounds have been becoming increasing popular around the world. One compound in particular, cannabinoid (CBD), a non-psychoactive compound of tetrahydrocannabinol (THC), has been of great interest as a potential treatment for numerous medical diseases. As recent as 2018, cannabinoid has been approved as an alternative anticonvulsant medications for treatment refractory seizures (Epidiolex, 2018). The success of using this drug as a treatment for this neurological disorder has lead to further research of this product for other symptoms and disorders from pain and nausea/vomiting, to a variety of psychiatric disorders.

New research on CBD being an effective treatment for anxiety, particularly social anxiety disorder (SAD) is promising. SAD is characterized by excessive fears of scrutiny, embarrassment, and humiliation in social or performance situations, leading to significant distress or impairment in functioning (American Psychiatric Association, 2018). This condition is estimated to affect between 3-7% of the US adult population and, if untreated, can be associated with the development of major depression, substance abuse, along with extensive functional impairment, and reduced quality of life (Ruscio et al., 2008).

As the popularity of this drug increases, more patients may be tempted to try this easily accessible supplement for their mental health problems. For future medical providers, who will no doubt receive inquiries for this drug, it would be good to be able to reply with scientific, evidence-based responsed. In this literature review, we will discuss the latest research surrounding CBD and develop a better understanding if CBD is as a safe and effective for treating adults age 18-65 with SAD.

These next few studies examine the effect of CBD on experimentally induced anxiety. As SAD anxiety is often acute and induced by stressful social situations, acute anxiety induced by experimental situations is a good equivalent. These studies all measure CBD's effect on acute anxiety induced from stressful experimental situations.

This first study investigates the action of CBD on participants undergoing a stress-inducing neuroimaging procedure. The single-photon emission computed tomography, or SPECT, measures the limbic and paralimbic brain, areas that are known to be associated with anxiety (Crippa et al., 2011). In a double-blind placebo, 10 participants diagnosed SAD were given either CBD or a placebo and then underwent the procedure. In the next session, the same procedure was performed, with patients who received CBD in the first trial now receiving a placebo and vice versa. Participant's anxiety was also measured throughout using subjective questionnaires.

The results of the trials showed a significant decrease in participant's subjective anxiety (p<0.001) and reduced regional cerebral blood flow (rCBF) in overlapping but distinct limbic and paralimbic areas (p??‰<??‰0.001). Because the rCBF was overlapping and not exactly consistent with areas associated with anxiety, this study failed to find a correlation between the anxiolytic effects of CBD on neuroimaging. However, this study did demonstrate a reduction in presumed anticipatory anxiety associated with undergoing SPECT procedures. The next study examined the effects of CBD on healthy participants and participants with SAD undergoing a simulated public speaking test (SPST) (Bergamaschi et al., 2011). A previous 2008 study found that during a SPST, participants with SAD have higher anxiety levels, greater cognitive impairment, discomfort, and decreased alertness compared with the control group (Crippa et al.). During the study, participant with SAD or healthy controls received either CBD or a placebo in a double-blind randomized design. The participants then performed a SPST. Subjective and physiological measurements of anxiety were measured throughout the study Based on the measurements of subjective anxiety, the group with SAD who did not receive CBD had higher anxiety, cognitive impairment, discomfort, and diminished alert levels than the SAD CBD group.

The study concluded that in participants with SAD, CBD reduced subjective anxiety symptoms resulting in a similar response to the SPST as healthy controls, yet no significant differences were noted among the physiological measures of anxiety. In another 2013 study, a Pavlovian fear and learning mechanism was used to induce conditioned fear on participants by shocking them with a colored box and electric shocks ((Das et al., 2013). This study sought to examine CBD on Pavlovian fear and learning mechanisms as they are an important component to anxiety disorders (Watson & Rayner, 1920). Once participants established fear of the box, the researchers tested how long it took to un-condition that fear or for that fear to go through extinction. The participants were divided into three groups, one group receiving CBD before fear extinction, one receiving CBD after fear extinction, and one not receiving CBD at all. Throughout the study, anxiety, current mood, and physical symptoms were assessed with various subjective questionnaires, skin conductance response, and shock expectancy following extinction. The results of this study found that CBD had no acute effects on fear extinction. However, CBD given to the post-extinction group enhanced consolidation of extinction as measured by shock expectancy. The study also found that CBD given either pre or post-extinction reduced restoration of autonomic contextual responding. These preliminary findings show promising evidence that CBD may be an effective adjunct to extinction-based therapies for anxiety disorders. Now that we have examined studies that that show a positive correlation between CBD and reduced anxiety in SAD and healthy volunteers, we will now look at some studies that come to different conclusions. Some studies have concluded that CBD has no effect on baseline anxiety in healthy volunteers. A 2012, double blind, crossover, placebo-controlled trial looked at the effects CBD compared to THC and a placebo on 16 healthy volunteers (Martin-Santos et al.). The drugs and placebo were administered in consecutive sessions in a one-month interval. Symptoms of anxiety were measured using physiological measurements and symptoms ratings at the 1, 2, and 3-hour intervals. The data was analyzed and the researches concluded that there were no differences between the CBD and placebo on any symptomatic or physiological variables. However, unlike previous studies discussed, participants were not placed in simulated anxiety-inducing situations. Though the study may have found no effect of CBD on baseline anxiety, had these volunteers been placed in acutely stressful situations, maybe CBD would have had an anxiolytic effect. Another more recent study found similar results. This study was looking into the effects of THC and CBD, both alone and combined on subject's ability to process emotional affects - deficits in which are characteristic of mood disorders like depression or anxiety (Hindocha et al. 2015). Participants involved varied in at-home cannabis use and had various types of schizotypy. In a 4-way, double-blind, placebo-controlled crossover design, participants inhaled either THC, CBD, both THC and CBD, or a placebo and completed an emotional facial affect recognition task and a visual analogue scale of how stoned participants felt, was completed. The study concluded that CBD did not influence feelings of being stoned and improved recognition of emotional facial affects and weakens the impairment induced by THC. However, the study also investigated the correlation between self-report measures with performance on the emotional processing task across CBD administration, to see whether baseline psychological wellbeing was associated with performance accuracy. However, no statistically significant correlation was found, with p's >0.05 after analysis.

This demonstrates an opposite correlation from the earlier study where CBD improved cognitive impairment, discomfort, and diminished alert levels all associated with diminished performance accuracy (Bergamaschi et al., 2011). Again, CBD's effect was only tested on these participant's baseline anxiety, and not its effect on participants in anxiety augmented scenarios. Though CBD may not show as promising evidence as a treatment for long-term anxiety like generalize anxiety disorder, it does show efficacy as treatment for acute anxiety like in social anxiety disorder.

Various studies have established clinical evidence for CBD's efficacy for SAD. We will now examine how CBD compares to other treatments for SAD. Current medical therapies for this disorder include drugs like selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOI), and benzodiazepines (Stein, 2018). These medications are not without side effects and adverse health outcomes. Also, unlike CBD, in the case of many of these medications (ex: SSRI's) a patient may have to take the medication for several weeks before they feel the effect of the medication (Taylor et al. 2006). A systemic review analyzed recent studies on CBD, both preclinical animal studies and clinical studies on humans (Blessing et al., 2015). The study noted that there was substantial evidence that CBD showed comparable efficacy to ipsapirone (a 5-HT1AR agonist) or diazepam (a benzodiazepine), other treatments for SAD.

The downside to all of these studies include small sample size, sample bias, and lack of serum CBD levels to correlate with subjective and physiologic measures of anxiety. Though there are many pre-clinical animal studies confirming its effectiveness for treating many mental health disorders, there are few clinical trials that have concluded its efficacy and many of which demonstrate mixed results (Blessing et. al., 2015). Unfortunately with today's regulatory and sociopolitical climate, research on marijuana and its many components is significantly limited (Farach et al., 2012). Until it becomes easier for research on CBD to be performed, including recruiting large enough sample sizes to sufficiently identify comprehensive treatment effects, there may not be adequate evidence to support CBD as an effective treatment for anxiety.

Though it may be hard in the current climate to definitely prove that CBD is effective for SAD, CBD is still a product that is currently available over the counter to everyone. For people who have heard about the proposed power of the drug and want to try it, are there any risks in taking it? In this next portion of the paper, the safety profile and side effects of CBD will be discussed.

A 2011 literature review examines the safety and side effect profile of CBD and concluded that based on recent advances in CBD administration, controlled CBD may be safe in humans and animals (Bergamaschi et al.). The study looked at the effect of CBD on in vitro studies animals find CBD to have no effect on embryonic development, increased food intake, development of catalepsy, and no effect on motor changes. Additionally, in animal models, the review found that CBD had no effect on many physiological parameters including blood pressure, heart rate, body temperature, glucose levels and did not induce ataxia, tremors, vomiting, and many other negative physical effects.

In human studies, even at a wide range of doses, CBD was not found to cause adverse side effects in acute or chronic studies. CBD does not interfere with heart rate, blood pressure, or performance in a verbal paired associated learning test (Zuardi et al., 1982). Chronic studies even found it may be an effective treatment for refractory cases of schizophrenia, bipolar affective disorder, Parkinson's disease, and cannabis addiction (Bergamaschi et al.). The systemic review did note that in several in vitro and in vivo studies CBD had to the potential to interact with hepatic drug metabolism, decreased capacity of fertilization, and decrease activity of some drug transporters. The review concluded with a statement that CBD, even at relatively high doses and with chronic use, is well tolerated in humans. The review does admit that further research is needed to determine accuracy of the reported side effects and that constant monitoring of the drug is required when used for clinical use.

As previously mentioned, CBD is FDA approved as prescription as adjuvant therapy for seizure disorder (Epidiolex, 2018). Clinical trials of the drug found that potential side effects of this drug include central nervous system depression (drowsiness, lethargy, sedation, etc.), skin rash, weight loss, decreased appetite, anemia, increase serum alanine aminotransferase and transaminases, infection, and asthenia. Though the only contraindication to this medication involves a hypersensitivity reaction to CBD, there are other warnings that patients must be aware of before taking this medication. For example, CBD may cause CNS depression, which may be hazardous if driving or operating heavy machinery. Also, the increase in liver transaminases have caused a few patients to become hospitalized. Though patients who are most often have a significant increase in hepatic transaminases have a high baseline transaminase, use other seizure medication that are hepatotoxic, and take a high dose of CBD.

Though there is evidence that CBD in general has a good safety profile, people should still be cautious when taking it, even when the CBD they are taking is prescribed from a doctor and FDA approved. Unfortunately, the popularity of this miracle cure is not affected by the lack of solid scientific confirmation and largely unknown safety profile. There are abundant of producers and sellers of CBD that are active in the market distributing CBD as a supplement without regulation (Hazekamp, 2018). There are growing concerns over the legality, quality, and safety of this new over the counter drug.

A 2017 study investigated the content of 46 different samples of CBD (Hazekamp). The samples came from various sources, some home-made and some were purchased from an online webstore, some had labels describing the contents, some did not. The researchers then analyzed the components of the CBD oil and compared it, when possible, to the contents advertised on the label. The study found that not only did the CBD content widely vary from the advertised about, 15% of the samples contained no CBD at all while 57% of the samples also contained > 1% THC. Though many of the samples, analyzed advertised a high THC content, the researchers where unclear whether CBD consumers were always aware of this.

Additionally, the study found there was a high level of non-decarboxylated cannabinoids, a precursor to CBD, in many samples. These non-carboxylated cannabinoids are converted to CBD after proper heating, yet research on the efficacy and safety of these precursors is significantly limited. This is not an isolated stud, many other studies have developed similar conclusions about questionable CBD content of many products on the market. Since 2015, the FDA has issued an annual warning letter about CBD drugs on the market that do not contain the levels of CBD they claimed (2015/2016 warning letters and test results for cannabidiol-related products).

CBD therefore may be an effective therapy for SAD, if CBD truly does have the assumed anxiolytic properties confirmed in animal trials and the few clinical trials. If the side effect profile of the drug is indeed safe, it may be a good alternative to current medications used for this drug. However, current clinical evidence for this medication is mixed, and while many case reports and animal studies show positive evidence of CBD's efficacy, provider's should still be cautious recommending CBD to patients. Additionally, CBD is not without side effects and risks even when the product is FDA approved. Current products available to consumers have unknown CBD content that is not subjected to any regulatory body. Before this new medication can be recommended to patients for SAD, more research must be done.

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