cbd oil for agoraphobia

How CBD can help for Agoraphobia

Let’s look at how CBD can help for Agoraphobia.

Have you ever felt so embarrassed by something that you felt you could not leave your home in weeks? Are you afraid of being a victim of a crime every time you leave home? Do you avoid certain events or places that you used to go to because you suffered a panic attack? You may have agoraphobia and CBD can help you.

CBD helps soothe the mind so you do not feel an overwhelming level of discomfort

Because agoraphobia is considered a complex panic disorder, CBD oil can help with symptoms. By reducing hyperactivity in some regions of the brain, CBD helps soothe the mind so you do not feel an overwhelming level of discomfort when you want to go somewhere that can trigger panic attacks.

Many people think that agoraphobia is a fear of open spaces. But there is much more to this mess than that. Agoraphobia is the fear of places or situations that can cause panic, embarrassment or impotence. Someone who is agoraphobic may begin to feel the symptoms of a panic attack when they are in a stressful situation from which they can not escape. Or if they return to a place that has given them a panic attack before. Agoraphobia is when you let your fears dictate where you go every day.

Cannabidiol

Has shown in studies its potential to regulate the endocannabinoid system. This includes regulating the response to fear, which is what triggers panic attacks. CBD has been able to reduce the activity of the amygdala, which is what causes the fight or flight response that causes panic, as well as the insular one that is hyperactive in patients with anxiety.

CBD Oil for Panic Attacks – February 2022

A panic attack is characterized by a sudden, intense fear even when there is no apparent cause. It can trigger severe physical reactions in an individual, such as rapid heartbeat, dizziness, muscle tension, trembling, and shortness of breath (7) .

Most individuals have one or two panic attacks throughout their life, with the problem going away when a stressful situation ends. People who have recurrent episodes and are in constant fear may have a condition known as panic disorder (8) .

According to the Anxiety and Depression Association of America, panic disorders affect six million adults in the United States (9) . Panic disorder is one of the five major types of anxiety disorders (10) .

Treating panic disorder usually involves a combination of psychological and pharmacological interventions. Benzodiazepines (BDZs) and selective serotonin reuptake inhibitors ( SSRIs ) are typically utilized due to their more favorable adverse effect profiles over other treatments (11) .

In 2014, a new class of drugs known as azapirones was examined for panic disorder . Experts believe that this new medication causes less drowsiness and physical impairment than BDZs (12) .

Azapirones are considered anxiolytic because of their ability to reduce anxiety, which is prevalent in panic attacks. Hydroxyzine, a partial serotonin agonist, has also gained recent popularity as an alternative.

CBD’s potential to help with panic disorder may be attributed to its anti-anxiety effects (13) . CBD is a non-psychoactive compound obtained from the Cannabis sativa plant.

A 2015 study published by the journal Neurotherapeutics presented evidence supporting CBD as a potential treatment for neuropsychiatric conditions, such as panic disorder (14) .

The authors of the study assessed several results from clinical trials concerning the potential benefits of CBD as a treatment for anxiety.

In the animal model studies, they learned that systemically administered CBD reduced rapid heart rate and blood pressure . The researchers also reported a decrease in the anxiety-causing effects of stress in the subjects (15) .

By the end of the review, the authors concluded that CBD could be a possible treatment for anxiety disorders based on its potential anti-anxiety and anti-panic (panicolytic) actions.

In 2017, another study that reviewed the anti-panic capability of cannabidiol was published in the journal Current Neuropharmacology .

The reviewers analyzed both experimental animal and human studies on the presumed panicolytic properties of CBD (16) .

In the human trials, one study showed that a 300 mg dose of CBD lowered anxiety in healthy volunteers. The results were assessed after the subjects took a simulated public speaking test.

In another trial, patients with social anxiety disorders were observed to have higher anxiety levels , cognitive impairment, and increased alertness during a speech performance.

After receiving 600 mg of CBD, the subjects were found to be significantly less anxious (17) .

The study noted that the lab results from these clinical trials had encouraged new approaches in studying the potential effects of CBD on panic disorder .

In the animal model studies, an acute administration of CBD reduced the expression of panic-related behaviors in mice. This anti-panic effect was again seen in CBD-administered rats when their escape response was noticeably reduced in an elevated maze trial.

These findings in both human and animal studies support the concept that cannabidiol exhibits anti-panic properties.

By the end of the review, the authors concluded that CBD presents a better alternative to the first-line treatment for panic disorder . They found that the compound does not induce dependence and tolerance upon consumption.

They also emphasized that more clinical trials on panic disorder patients are needed to fully demonstrate CBD’s effectiveness in treating this condition (18) .

How CBD Oil Works to Help with Panic Attacks

Cannabidiol is thought to interact with a part of the body known as the endocannabinoid system (ECS). The ECS is a unique system that is believed to maintain homeostasis or biological balance in response to changes in the environment (19) .

Physiological functions, such as mood, cognition, and chronic pain perception, are some aspects that are regulated by the ECS. Experts believe that it is able to modulate these functions because of its numerous receptors (20) .

CBD has been suggested to activate 5-HT1A serotonin receptors in several regions of the brain (21) . This specific type of receptor is said to contribute to the mechanism of action of anti-anxiety and antidepressant drugs (22) .

Besides serotonin, CBD is also believed to engage other chemical structures, like the CB1 and CB2 cannabinoid receptors of the ECS (23) . Both receptors have been linked to the strong involvement of the ECS in neuropsychiatric disorders, particularly with anxiety and depression (24) .

These findings have led researchers to hypothesize that the anti-panic effects of CBD may be a result of its interaction with various receptors in the body (25) .

The Pros and Cons of CBD Oil for Panic Attacks

The Pros
  • CBD could be used to alleviate the symptoms of panic attacks . Several studies have shown that CBD has properties that can reduce rapid heart rate, blood pressure , and anxiety.
  • Cannabidiol reportedly interacts with various receptors in the body, such as the serotonin and cannabinoid receptors. Both of these chemical structures have been associated with anxiety, which is a common trait of panic disorder .
  • CBD is a non-psychoactive compound of cannabis plants . It does not cause a “high” upon consumption, unlike its counterpart, tetrahydrocannabinol ( THC ).
  • Purchasing and consuming cannabidiol is allowed in most places in the United States , such as in Colorado . In areas where CBD is legally sold, people can get CBD products even without a prescription from a physician.
  • According to a study, CBD does not alter psychomotor and psychological functions upon intake. Even high doses reaching as much as 1,500 mg of CBD per day have been reported to be well-tolerated in humans (26) .
The Cons
  • Although some studies on CBD use and panic attacks were conducted on humans, many assumptions have been based on animal models. More clinical trials on human subjects are necessary to assess the efficacy of CBD in treating panic disorder .
  • There are no CBD products approved by the United States Food and Drug Administration ( FDA ) for alleviating panic disorder symptoms. The only accepted CBD product is Epidiolex, a medication prescribed to treat seizures associated with two rare forms of epilepsy (27) .
  • People taking certain medications may be at risk of experiencing drug interactions when consuming CBD. C annabidiol may alter the way a drug works, leading to adverse reactions (28) .
  • Currently, CBD is prone to inaccurate labeling, particularly for products sold online and in some dispensaries (29) Buying CBD through these channels puts users at risk of consuming more or less of the compound than expected.

How CBD Oil Compares to Alternative Treatments for Panic Attacks

There are various self-help measures and therapies that could be useful in anxiety issues , such as panic disorder . These alternative therapies may be applied alone or in conjunction with other conventional treatments.

Chamomile, lavender, and lemon balm are herbal therapies that could help with anxiety-related disorders (30) .

A preliminary study of chamomile in humans revealed that the plant has anti-anxiety and antidepressant properties (31) .

Lavender is also believed to have anxiolytic effects that could benefit people with panic disorder . As an essential oil, it is often used in aromatherapy, which may exert psychological effects beneficial to people with anxiety (32) .

Meanwhile, preliminary research data on lemon balm has shown that it could reduce some of the symptoms of anxiety (33) .

There are CBD brands nowadays that are selling CBD products infused with these herbs.

Cannabidiol and chamomile are often found in teas, which users can drink for relaxation. The combination is also available as tinctures and is advertised to help with sleep.

Chamomile is known as a mild sedative to calm nerves and help with sleep problems (34) , while CBD was shown to improve sleep in subjects during a clinical trial (35) .

CBD and lavender are usually sold together as drops that users can apply sublingually or under the tongue. There are also CBD rubs containing lavender that are said to help soothe discomfort.

CBD and lemon balm are available as gummies, teas, tinctures , and ointments. The infusion is advertised to promote calmness and alleviate anxiety.

How to Choose the Best CBD Oil for Panic Attacks

Currently, three forms of CBD are available: full-spectrum , broad-spectrum , and CBD isolates .

The most popular among them is full-spectrum CBD. This variant has all of the natural compounds present in Cannabis sativa plants.

Full-spectrum CBD oil contains chemical compounds, such as terpenes , flavonoids, and even THC . Quality full-spectrum hemp extract has a high cannabidiol content and only small amounts of the other compounds.

CBD oil that contains all of the chemical compounds of cannabis is known for its “ entourage effect .” CO2 extraction is one way to obtain full-spectrum CBD.

The next type of CBD is known as broad-spectrum . This CBD variant contains almost the same phytocannabinoids as that of full-spectrum but without the THC .

Some people choose broad-spectrum CBD over full-spectrum because they do not wish to consume the psychoactive THC compound.

CBD isolate is the third type of cannabidiol product and is usually sold in crystalline or powdered form. A cannabidiol isolate is the purest type of CBD in the market.

During the extraction process of CBD isolates , all of the other compounds are removed, leaving only pure CBD .

Whichever type of CBD one chooses, buyers must purchase only the best quality product available to maximize CBD’s health benefits .

Choose only the best CBD oil for panic attacks by following these tips:

  • Look for the certificate of analysis (COA) or the third-party lab report of the CBD product selected. This document is especially important since it indicates that the item has undergone thorough lab testing and contains precisely the specifications listed on its label.
  • Read up on product and shop reviews if buying from an online store. If purchasing from a physical dispensary, check if it has proper authorization to sell CBD.
  • Buy only CBD derived from organic hemp . The hemp plant is the most reliable source of high-quality cannabidiol .
  • Ensure that the legalities involving CBD are followed in the state where it is going to be bought and used.
  • Consult a health care professional, preferably someone experienced in medical cannabis, before deciding to use CBD for the symptoms of panic disorder .

Additional Tips to Get the Best CBD Oil Products

  1. Avoid buying from CBD companies that claim to sell cannabidiol derived from the seeds and stalks of hemp plants . The reason for this is simple: non-GMO industrial hemp stalks have very little CBD, while its seeds do not have cannabidiol .
  2. It is vital that interested buyers first assess the quality of CBD edibles, such as gummies, before purchasing. Be wary of brands that sell CBD snacks that contain sub-standard or artificial ingredients.
  3. Feel free to contact CBD brands for inquiries or questions regarding their products. It is best to choose another CBD company if they fail to respond appropriately.

CBD Dosage for Panic Attacks

There is no approved CBD product for treating panic attacks . Therefore, users do not have an official guide that can help them know the proper dosage for panic disorder .

However, some individuals rely on several factors that they believe can help determine the right dose of CBD. The two most commonly cited are the body weight of the user and the amount of CBD available in each product.

Information from past clinical trials may also provide people with an idea of a suitable dosing range fit for human consumption.

In a report published by the World Health Organization in 2017, the agency mentioned that they analyzed a study where human subjects were given as much as 600 mg of CBD. They found that despite this high dose in their treatment, the participants did not have any adverse reactions after (36) .

The report also noted that CBD has a generally favorable safety profile.

An even higher dose of CBD intake has been recorded with no harmful side effects observed. Chronic use of CBD oil , reaching as high as 1,500 mg per day, is likewise reported to be safe for humans (37) .

How to Take CBD Oil for Panic Attacks

A straightforward approach to consuming CBD oil for panic attacks is to take the compound in the form of edibles or capsules. Popular edibles, such as CBD gummies , brownies, and tablets, are great for beginners due to how easy they are to take.

CBD tinctures or drops allow users to apply CBD oil under the tongue. Applying CBD in this manner is a suitable method for those who want to control their CBD dosage.

These CBD tinctures have droppers that make it very easy to measure the right amount of cannabidiol one needs to take.

CBD topicals could also be beneficial for people with panic disorders since these products can be applied in massage therapies for relaxation. Many CBD companies sell CBD products as salves, balms, lotions, and creams.

Meanwhile, some users may choose to inhale CBD through flavored or unflavored vaping products. However, people who are suffering from lung disorders may not be ideal candidates for CBD vape s, as these may worsen their conditions (38) .

Seek medical advice from a physician before deciding to purchase any product made with cannabidiol .

Getting help from a doctor who is experienced with cannabis use is highly recommended.

What is Anxiety?

Anxiety is an emotional response characterized by worried thoughts, tension, and physical changes, such as increased blood pressure .

It is normal to feel anxious sometimes. However, anxiety that does not go away, especially when it starts to affect day-to-day life, could be a sign of an anxiety disorder.

Anxiety disorders are the most prevalent mental illness in the United States and are said to affect about 40 million adults or 18.1% of the population yearly (39) .

The following are the most common signs of anxiety:

  • Feeling tense, restless, or nervous
  • Having a sense of impending danger
  • Experiencing an increased heart rate
  • Rapid breathing or hyperventilating
  • Trembling
  • Sweating
  • Feeling tired or weak
  • Having trouble thinking or concentrating on anything
  • Having problems sleeping
  • Finding it difficult to control worry
  • Feeling the urge to avoid situations that could trigger anxiety

Many factors can cause anxiety disorders, such as genetics, ongoing stress, physical health concerns, or traumatic events (40) .

It is essential to consult a doctor concerning anxiety symptoms . Medical experts can diagnose anxiety disorders and help people manage their anxiety problems.

Types of Anxiety Disorders

Several types of anxiety disorders exist today. These are generalized anxiety disorder , panic disorder , and various phobia-related problems.

Generalized Anxiety Disorder (GAD)

People who have generalized anxiety disorders are known to be excessively worrisome. These individuals usually worry about social interactions, work, personal health, and day-to-day life circumstances.

GAD symptoms typically include:

  • The feeling of being on-edge all the time
  • Having a hard time concentrating
  • Being easily fatigued
  • Irritability
  • Experiencing muscle tension
  • Problems with sleep, such as difficulty in staying or falling asleep

Panic Disorder

Individuals with panic disorder experience repeated panic attacks . An attack can happen without warning or can be triggered by situations involving fear.

A person having a panic attack may experience:

  • Sweating
  • Shaking or trembling
  • Accelerated heart rate or heart palpitations
  • Feelings of impending danger
  • Sensations of smothering, choking, or shortness of breath
  • Feelings of having no control

People who have panic disorder often worry when the next panic attack may happen. They try to prevent future panic attacks by avoiding situations, places, or behaviors associated with the experience.

Phobia-Related Disorders

A phobia is the feeling of an intense fear of specific situations or objects. Although it is reasonable to feel anxious in some scenarios, the kind of fear that people with phobias have is unrealistic.

A person with a phobia may:

  • Excessively worry about encountering the feared situation or object
  • Actively take steps to avoid what they fear
  • Feel sudden and intense anxiousness upon encountering the feared situation or object

Phobia-related disorders also have their subtypes.

Specific phobias, or simply called phobias, is when a person fears a particular type of object or situation. Some examples of specific phobias include the fear of heights, blood, flying, injections, and insects.

Patients with social anxiety disorders are those with a generally intense fear or anxiety toward social interactions. They worry that behaviors or actions linked with their condition are negatively looked upon by other people, which leads to embarrassment.

A person who has agoraphobia has an intense fear of two or more of these situations:

  • Being in open spaces
  • Using public transportation
  • Standing in a crowd
  • Being alone outside of their home
  • Being in enclosed spaces

Those with agoraphobia usually avoid these scenarios, partly because they believe it might be difficult for them to leave in case they have panic-like reactions.

Conventional Treatments and Therapies for Anxiety Disorders

Patients with anxiety disorders are generally recommended to undergo psychotherapy, take prescribed medications, or both (41) .

There are several methods believed to alleviate anxiety, which is why people should work with their medical provider to select the proper treatments for their needs.

CBD at this early stage may be considered a useful adjunct, or additional, treatment method in addition to already established, safe, and readily available treatments. Always talk to your healthcare provider first before taking CBD for any reason or if you are concerned about your mood.

Cognitive Behavioral Therapy

Cognitive behavioral therapy (CBT) is a type of psychotherapy that is said to help people deal with their anxiety disorders. This approach teaches individuals to think, behave, and react to anxiety-producing situations and objects differently.

Two subtypes of CBT are exposure therapy and cognitive therapy. These two are used alone or in combination to treat social anxiety disorder .

Exposure therapy aims to help individuals confront their underlying fears so they can resume activities that they have been avoiding. The goal of cognitive therapy is to identify, challenge, and remove unhelpful thoughts of anxiety disorders.

CBT could potentially be done in groups with other patients or individually. Doctors often assign “homework” for participants to accomplish between their sessions.

Anti-Anxiety Medications

Anxiolytic medications reduce anxiety symptoms , panic attacks , or feelings of extreme fear in a person. Benzodiazepines are the most common anti-anxiety drugs.

Using benzodiazepines, however, have both advantages and disadvantages.

One of the advantages it offers is its effectiveness in relieving anxiety while taking effect faster than antidepressant medications. Its disadvantage, however, is that users become dependent, requiring them to take higher doses to achieve the same result.

Doctors try to avoid such problems by prescribing benzodiazepines to patients for only a short time. This practice is particularly helpful for those who have a history of substance abuse or can quickly become dependent on medications.

A person who suddenly stops taking benzodiazepines may experience withdrawal symptoms, a return of anxiety, or even death. These risks are why medical professionals tell patients to slowly and safely decrease dosage when deciding to stop taking the drug.

Antidepressants

Although primarily used for treating depression, antidepressants may also help with anxiety disorders. This type of medication could change the way the brain uses certain chemicals that control stress or mood.

However, a person may have to try several antidepressant drugs to find the one that can improve their symptoms the most. Medications that have been helpful for a close family member in the past are usually considered.

For those who have already started taking antidepressants, do not stop unless advised by a doctor. Abruptly stopping the use of antidepressants can lead to withdrawal symptoms.

Antidepressant medications, such as selective serotonin reuptake inhibitors , are the most common first-line treatments used for anxiety. Tricyclic antidepressants are the less commonly-used drugs to treat anxiety disorders.

Beta-Blockers

Doctors may also consider the use of beta-blockers to relieve the physical symptoms of anxiety, such as rapid heartbeat and trembling. These prescription medications may help individuals keep their symptoms under control.

Joining Support Groups for Anxiety Disorders

People suffering from anxiety disorders may benefit from support groups where they can share their problems and achievements with others who have similar conditions.

The following are the perceived advantages of joining anxiety support groups:

  • Showing to others that they are not alone
  • Helping people with anxiety disorders develop new social skills
  • Allowing participants to open up and talk about their situation
  • Sharing new strategies to cope with their condition
  • Strengthening resolve to stick with a prescribed treatment plan
  • Sharing practical advice and skills

Participants in these support groups often form bonds based on the commonality of their daily experiences. People learn from one another, obtain relief, have fun, and are inspired by each other’s journey.

It is not uncommon to see people who have already recovered from their disorder but are still attending these support groups to help others.

Online chat rooms could also prove to be useful. However, any advice obtained from the web should be considered carefully.

It is always important for users to check with a doctor before following online recommendations.

Conclusion

A panic attack is a situation where a person experiences sudden and intense fear even if there is no real danger nearby. Most people experience panic attacks once or twice in their lifetime.

Individuals who continuously have episodes of panic attacks and are always fearful may have a condition known as panic disorder . The Anxiety and Depression Association of America stated that six million adults in the United States are affected by panic disorder .

The conventional treatment for panic disorder usually involves a combination of psychological and pharmacological interventions. Anti-anxiety and antidepressant medications, as well as CBT, are considered first-line treatments for alleviating the symptoms of this mental health disorder.

Cannabidiol , more popularly known as CBD, could be a potential treatment for panic attacks due to its supposed effects in decreasing anxiety. CBD, unlike THC , is a non-psychoactive compound derived from cannabis plants .

Several studies have shown that cannabidiol is capable of reducing the symptoms associated with panic attacks . Clinical trials on both animal and human studies provide evidence that CBD exhibits anti-panic properties.

CBD is believed to interact with a system known as the endocannabinoid system or ECS. The ECS is said to maintain the biological balance in the body when responding to environmental changes.

Taking cannabidiol has been suggested to activate specific receptors in the brain and body to bring about its supposed anti-anxiety and anti-panic effects.

CBD comes in three forms and undergoes a unique extraction method .

Although CBD use may appear to be a better alternative than standard medications, there is still a lack of knowledge about its overall efficacy in treating panic disorder in humans. The FDA has also not approved any CBD product as a form of treatment for panic attacks .

Before deciding to take CBD hemp oil , users should first seek medical advice from a doctor to avoid complications.

Cannabidiol enhancement of exposure therapy in treatment refractory patients with phobias: study protocol of a randomized controlled trial

Phobic anxiety disorders are among the most prevalent psychiatric disorders and are burdensome in terms of loss of quality of life and work productivity. Evidence-based treatments are relatively successful in the majority of patients, especially exposure therapy. However, a substantial subset of patients fails to achieve or stay in remission. Preclinical and genetic research have yielded evidence that the cannabinoid system is involved in the extinction of fear, presumed to underlie the beneficial effects of exposure therapy in phobic disorders. A cannabinoid constituent that may enhance endocannabinoid signaling is cannabidiol (CBD), a non-psychoactive component of cannabis. Hence, the addition of CBD to exposure therapy is expected to strengthen effects of treatment. To determine the added benefit of CBD on exposure therapy, we conduct a randomized controlled trial, in which patients in whom previous treatment as usual has not yielded sufficient response receive either CBD or placebo preceding 8 exposure sessions in a double-blind fashion. A subsidiary aim is to explore which (combination of) clinical, behavioral and genetic profiles of patients are related to treatment response.

Methods/design

This is an 8-week multicenter, randomized, double-blind, placebo-controlled trial. Seventy-two patients with social phobia or panic disorder with agoraphobia with incomplete response to earlier treatment will be included from outpatient clinics in the Netherlands. Patients are randomized to augmentation of exposure therapy with 300 mg CBD or placebo. The study medication is administered orally, 2 h preceding each of the eight 90 min exposure sessions. Measurements will take place at baseline, first administration of medication, every session, mid-treatment, last administration of medication, post-treatment and at 3 and 6 months’ follow-up. The primary outcome measure is the score on the Fear Questionnaire (FQ). In addition, determinants of the expected treatment enhancing effect of CBD will be explored.

Discussion

This is the first trial to investigate whether the addition of CBD to exposure therapy is effective in reducing phobic symptoms in treatment refractory patients with social phobia or panic disorder with agoraphobia.

Trial registration

Netherlands Trial Register NTR5100. Registered 13 March 2015. Protocol version: issue date 17 Jan 2018, protocol amendment number 7.

Background

Phobic disorders (e.g. social anxiety disorder, panic disorder with agoraphobia) are among the most prevalent disorders according to the World Health Organization’s World Mental Health Survey Initiative [1]. These and other anxiety disorders have major impact on health, individual suffering and societal costs [2]. The estimated societal costs in Europe as a result of anxiety disorders were 74.4 billion Euros in 2010, affecting more than 69 million Europeans [3]. Anxiety disorders often co-occur with other mental health disorders [4, 5], and are associated with an increased risk of suicide [6]. Spontaneous recovery from these disorders is uncommon; if left untreated, phobias typically follow a chronic course, with low remission and high relapse rates [7].

The current evidence-based treatment entails exposure with response prevention therapy, either alone or in combination with serotonin reuptake inhibitors (SSRIs). Exposure therapy is relatively successful, with improvement in up to 60% of patients. However, only 30 to 50% of phobic patients achieves full remission [8]. Likewise, treatment with SSRIs is relatively effective, however, many patients experience relapse after discontinuing SSRI treatment [9, 10], while the effects of successful exposure treatment seem to be more sustainable [11]. Considering the high prevalence of anxiety disorders and the large number of patients for whom the anxiety symptoms remain refractory after (repeated) gold-standard treatments, new approaches to the treatment of anxiety are urgently needed [12, 13]. Preclinical as well as clinical studies have pointed to the relevance of utilizing fear learning paradigms for a deeper understanding of the neurocircuitry and neurochemistry of the fear system involved in anxiety disorders [14]. Specifically, patients with anxiety disorders show stronger fear responses during extinction than comparison subjects [15], and poor fear extinction is predictive of poor outcome in exposure therapy [16].

A potential novel target for the facilitation of fear extinction has been derived from preclinical research. The crucial involvement of the cannabinoid system in fear extinction was first shown by Marsicano et al. [17]. The results show that (genetic or pharmacological) blockage of transmission at the cannabinoid receptor 1 (CB1) inhibits extinction of fear in mice. This is not surprising given the fact the CB1 receptors are richly expressed in memory-related brain areas such as hippocampus and prefrontal cortex, and as such can modulate (fear) memory [18]. In the last 15 years many studies have extended this finding using both animal and human subjects (for reviews see [12] or [19]). Animal research has shown that facilitation of the endocannabinoid system (ECS) enhances extinction, whereas blocking or deletion of CB1 receptors impairs extinction. In healthy human subjects we have demonstrated that genetic variation in a CB1 polymorphism significantly affected extinction learning [20]. Furthermore, the administration of cannabinoids in humans has shown to strengthen extinction and protect against reinstatement of fear [21,22,23]. In summary, previous research clearly points to the ECS as a promising candidate for extinction enhancement. Until now, studies in humans have mainly investigated the effects of delta-9-tetrahydrocannabinol (THC), which has been shown to decrease physiological measures of fear during extinction [24] and recall [21]. However, THC is not suitable for phobic patients given the diversity of psychoactive effects caused by THC, among which the high that recreational users of cannabis seek.

In the meantime, studies have demonstrated the potential benefit of another important ingredient of cannabis: cannabidiol (CBD, for a review see [25]). CBD interacts with several receptors in the brain including cannabinoid receptors 1 and 2, transient receptor potential vanilloid type 1 (TRVP1) and serotonin 1A (5-HT1A) receptor, and inhibits or in other ways negatively affects the function of the enzyme that degrades endogenously released cannabinoid neurotransmitters (fatty acid amine hydrolase; FAAH [26]). In line with FAAH’s function in degrading anandamide [27], inhibition of FAAH has been shown to increase levels of anandamide. Preclinical research indicates that CBD enhances fear extinction and reconsolidation, and co-administrating CB1 antagonists block such effects suggesting that they are exerted via modulation of the ECS [28, 29]. Extinction of conditioned fear is proposed to underlie the effect of exposure therapy [14]. Hence, the finding that CBD specifically affects (the consolidation of) extinction suggests a potential use of CBD in augmenting the effect of exposure therapy. This leads to the hypothesis that administration of CBD during sessions of exposure therapy is expected to specifically enhance the extinction of pathological fears. The advantage of this application is that CBD needs to be administered occasionally, i.e. preceding exposure sessions only.

We aim to take this previous research to the next level by conducting the first randomized controlled trial with CBD versus 7, administered in a double-blind fashion, for the augmentation of exposure treatment in patients with social phobia or panic disorder with agoraphobia. Also, we aim to specifically target patients who have already received one of the gold-standard treatments without responding sufficiently or having relapsed, because this group needs additional approaches most.

The main study aim is to test whether administration of CBD as an augmentation step in exposure therapy can strengthen treatment outcome in patients with phobic disorders who have previously failed to respond satisfactorily to evidence-based treatment. Clinical measurements are used to investigate whether the effect of CBD on exposure is quicker, stronger, or longer-lasting than regular exposure therapy only. Additionally, there are various exploratory subsidiary aims in this study. First, a fear conditioning and extinction task is applied at baseline. This task has shown enhanced fear responses in patients with anxiety disorders as opposed to healthy comparison subjects [30]. This task also revealed different extinction trajectories, with patients being overrepresented in a poor extinction profile [16]. These profiles have also shown to be sensitive to differences between patients who will benefit from exposure treatment and those who will not. A re-extinction assessment is done after the first medication administration. The aim of this task is to explore a) whether patients with a specific profile can particularly benefit from CBD augmentation during exposure, and b) the acute effects of CBD intake on fear extinction. Second, we aim to explore the interactions between specific genetic variation and CBD administration on treatment effect. We are particularly interested in studying whether variants within the cannabinoid receptor 1 gene are involved in a differential response to CBD augmented exposure therapy, including rs2180619 identified in our previous study in healthy individuals associated with impaired spontaneous extinction of conditioned fear [20]. Additionally, impact of genetic polymorphisms within the FAAH gene [31] and genetic polymorphisms identified as being related to treatment response in anxiety disorders [32] will be explored. Similarly, clinical predictors of treatment response will be assessed to determine which sort of patients might benefit most from this augmented treatment. Lastly, we aim to assess cost-effectiveness of CBD enhancement of exposure treatment.

Methods

Study design

The study encompasses a multi-site randomized, double-blind, placebo-controlled fixed dose clinical trial for patients with treatment resistant social phobia or panic disorder with agoraphobia. Either placebo (N = 36) or 300 mg cannabidiol (N = 36) will be administered 8 times as an adjunct to 8 weekly 90 min sessions consisting of standardized exposure therapy. The study has been approved by the Medical Ethics Committee of the University Medical Centre Utrecht. Written informed consent will be obtained from all participants. The enrollment of the first participant was on 15 February 2016, recruitment is ongoing at the time of submission. Figure 1 displays a flowchart of the study.

Flowchart of the study design. Data is collected both during T0-T6 measurements and therapy sessions, see Table 1 for a complete overview