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Cbd oil for anxiety pdf

Highs and Lows: CBD Oil for Anxiety Disorders

Almost half of all CBD users in the US use CBD to help relieve anxiety and stress. This new medication offers a potential alternative for Australian patients who experience side effects or lack of efficacy from traditional medicines prescribed for anxiety.

Quick Summary: The Highlights

  • Current evidence indicates that cannabidiol (CBD) oil has considerable potential as a treatment option for multiple anxiety disorders.
  • Studies show CBD oil is safe and well tolerated for short-term use, even at high doses.
  • CBD oil does not cause a high that is generally associated with recreational cannabis use.
  • If your regular doctor is unwilling to prescribe, you can do our quick eligibility test and book in directly with one of our doctors.

The ABCs of CBD: What Is It?

Cannabidiol (CBD) belongs to a class of molecules called cannabinoids. These are chemicals found in cannabis (marijuana and hemp) plants. 1 CBD oil contains CBD dissolved in a carrier oil. 2

How Does It Work?

The endocannabinoid system (ECS) is a complex cell-signalling system, identified in the early 1990s by researchers investigating THC (delta-9-tetrahydrocannabinol), a common cannabinoid. The system is active in your body, even if you don’t use cannabis. The ECS consists of cannabinoid receptors found throughout your body.

Our brain contains the highest number of cannabinoid receptors in the human body. CBD modulates how our brain cells behave by controlling the release of neurotransmitters (the body’s chemical messengers).

CBD can also activate non-cannabinoid receptors, such as serotonin receptors. Low levels of brain serotonin, a neurotransmitter, is associated with depression and anxiety. CBD may help the brain use serotonin more effectively in some people, although this is not yet fully understood. 3

How Is CBD Different to THC?

More than 100 different types of cannabinoids have been found in the leaves and flowers of the cannabis plant. The two most common cannabinoids used in medicinal cannabis products are CBD and THC.

While from the same class of molecules, CBD and THC work differently to one another. 4

THC may be used to reduce symptoms of nausea, vomiting, pain and muscle spasticity as well as improve sleep and appetite. In some people who take too much, THC may cause a high that is generally associated with recreational cannabis use. 5

CBD does not cause a high and may reduce the unwanted side effects of THC. 5

Evidence Snapshot: What Does the Research Say?

While more research is needed to better understand how and why CBD works in the treatment of anxiety disorders, it is relatively safe. 6 CBD could be an option for those patients who have not experienced benefits from traditional medication or have experienced side effects from these medications.

Generalised Anxiety

Current evidence indicates CBD has considerable potential as a short-term treatment for multiple anxiety disorders. Further studies are needed for to determine its use for long-term treatment. 7

Table 1 (below) summarises the evidence from short-term psychological studies of CBD oil for anxiety disorders. CBD was initially found to reverse the anxiety effects of THC when used together.

However, it had no effect on anxiety when used alone at the dosages given in these studies. 8,9 At higher dosages, CBD reduced anxiety associated with a simulated public speaking test in healthy adults, as well as in adults with social anxiety disorder.

It showed a comparable effectiveness to ipsapirone (a 5-HT1A agonist) or diazepam (a benzodiazepine). 10,11

CBD also reduced anxiety in patients undergoing a single-photon emission computed tomography (SPECT) imaging procedure, in both healthy adults and adults with social anxiety disorder. 12

Table 1: Evidence from short-term psychological studies of CBD oil for anxiety disorders

Study Measure of anxiety Results
Karniol et al. 8 Anxiety and pulse rate after taking THC Decrease subjective anxiety and pulse rate
Zuardi et al. 9 STAI after taking THC Decrease in STAI scores
Zuardi et al. 10 VAMS, STAI and blood pressure following simulated public speaking test Decrease in STAI scores, VAMS scores and blood pressure
Crippa et al. 12 VAMS Decrease in VAMS scores
Bhattacharyya et al. 13 STAI and VAMS Decrease in STAI scores and VAMS scores
Bergamaschi et al. 11 VAMS, SSPS-N, cognitive impairment, SCR and heart rate Decrease in VAMS scores, SSPS-N scores and cognitive impairment; no effect on SCR or heart rate
Hindocha et al. 14 Baseline VAS anxiety No significant effect

SCR = skin conductance response; SSPS-N = negative self-evaluation subscale; STAI = Spielberger’s state trait anxiety inventory; THC = delta-9-tetrahydrocannabinol; VAMS = visual analogue mood scale

Neuroimaging studies have demonstrated modified blood flow in specific areas of the brain associated with anxiety. 12,15

CBD was also found to be effective in reducing anxiety symptoms in patients with anxiety disorders and post-traumatic stress disorder when used in combination with other pharmacological treatment and psychotherapies. 16,17

Anxiety and Depression

A study shows that CBD improve patients’ overall quality of life after 3 weeks of treatment for various conditions. Patients who received CBD for anxiety or depression specifically experienced improvements in their ability to perform daily tasks as well as a reduction in pain and anxiety or depression symptoms. 18

Post-traumatic Stress Disorder and Phobia Therapy

Studies suggest CBD decreased the severity of patients’ post-traumatic stress disorder symptoms when given alongside routine psychiatric care 16 or when given with THC. 19 When taken together with THC, an “entourage effect” occurs. This is where THC enhances the effects of CBD, while CBD counters the adverse effects of THC. 20

A study has demonstrated CBD can enhance the effects of exposure therapy. This is a kind of phobia therapy that helps patients separate certain cues with a fear response. 21

Which Anxiety Disorders Can CBD Oil Help Treat?

Existing pre-clinical evidence strongly supports CBD oil as short-term treatment for the following anxiety disorders: 7

  • generalised anxiety disorder
  • panic disorder
  • social anxiety disorder
  • obsessive compulsive disorder
  • post-traumatic stress disorder.

What Is CBD Oil’s Place in Anxiety Treatment Pathways?

Anxiety is the most common mental health condition in Australia, with 1 in 4 people (1 in 3 women and 1 in 5 men) experiencing anxiety at some stage in their life. 22 There are many ways to manage anxiety. The sooner people with anxiety get support, the sooner they are likely to recover.

Currently, the main pharmacological treatments for anxiety disorders include selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, monoamine oxidase inhibitors, tricyclics, partial 5-hydroxytryptamine 1A (5-HT1A) receptor agonists, and benzodiazepines. 23 These medicines tend to have adverse effects and a low rate of effectiveness (in about 40 to 60% of patients). 24

Anxiety disorders may also be treated using psychological approaches, such as cognitive behavioural therapy. 24 However, these therapies can be costly and limited to specific situations. 25

CBD oil is not considered first line treatment for anxiety disorders, but may be a suitable alternative when other treatments have been unsuccessful. Evidence supports the use of CBD oil as an effective monotherapy or complementary therapy for treating anxiety disorders. 26

The therapeutic effects of CBD oil for the treatment of anxiety include the reduction of: 27

  • muscular tension
  • restlessness
  • fatigue
  • problems in concentration
  • social anxiety.

Benefits vs. Risk

CBD oil can be a good alternative when other medicines aren’t working. It is well tolerated, has minimal side effects and has lots of research data strongly supporting its anxiolytic effects. 10,11

Currently, CBD oil is only available on the Pharmaceutical Benefits Scheme (PBS) for treatment of Dravet syndrome, also known as severe myoclonic epilepsy in infancy (SMEI). 28

Out of pocket costs may be high for indications not covered on the PBS. On average, patients who are using CBD oil for anxiety disorders will need to pay between $4–10 per day for their medicine.

How Do I Take CBD for Anxiety?

You can take CBD products in several ways: 29

  • by using a spray into your mouth or under your tongue (orally or sublingually)
  • by swallowing oils, liquid capsules or tablets (orally)
  • by vaporising CBD flower – heating the flower and inhaling the vapour using a flower vaporizer device
  • by vaporising CBD extract cartridges through a metered dosage device

Smoking CBD oil or flower is not recommended as it increases the risk of cancer, stroke, heart disease and other serious health conditions. 29

Taking CBD oil orally allows you to easily measure the exact dose. When taken orally, the effects of CBD begin working within 30 minutes to 2 hours. Vaping CBD results in more immediate effects. 30

You may choose to take CBD oil in the morning to relieve anxiety throughout the day, or just before a stressful event, such as giving a speech.

CBD for Anxiety Dosing

A recent review found that different studies don’t have a consensus on a single universal dosage of CBD oil that everyone should take for treatment of anxiety disorders. Rather, it highlighted that different people respond to different dosages of CBD oil. Most studies used dosages between 20 to 1,500mg per day. 6

A 2018 study found that 300mg of CBD, given 90 minutes before a simulated public speaking test, significantly reduced speakers’ anxiety. Those who received a lower dose (150mg) and higher dose (600mg) saw little benefit. 31 These results highlight how dosages can be variable and a higher dosage does not necessarily mean it is more effective.

A 2019 study tested CBD oil in lower doses (25 to 75mg/day) and found that anxiety decreased within the first month and remained low for most patients. 17

The dosage of CBD oil you should take depends on a range of factors, including:

  • your weight
  • the condition being treated
  • the concentration of CBD in the product.

However, few commercially available CBD products contain enough CBD to replicate the therapeutic effects seen in clinical trials. 32

It is important that you speak with your doctor about the appropriate dosage and any potential risks before starting CBD oil. Generally, it Is best to start with a smaller dosage and gradually increase until the desired effect is reached (known as titrating the dosage).

Unless your doctor recommends a specific dose, start by taking 10 to 20mg a day for a week to ensure you can tolerate it and that you don’t experience any unwanted adverse effects. If the desired effect is not achieved, try increasing in increments of 5mg each week until the desired effect is reached. 33 Table 2 (below) summarises the successful dosages that studies have evaluated for anxiety relief specifically.

Table 2: Successful dosages of CBD oil evaluated for anxiety relief

Dosage Condition being treated
600mg 11 Social anxiety disorder before a simulated public speaking test
300mg 31 Anxiety before a simulated public speaking test
25 to 75mg 17 Generalised anxiety and/or sleep problems
33 to 49mg per day 16 Post-traumatic stress disorder, in addition to routine psychiatric treatment

Figure 1: Successful dosages of CBD oil evaluated for anxiety relief

CBD Oil Dosing Research

More studies with standardised approaches to dosing are needed to determine the appropriate dosing strategy for CBD oil and its place in therapy. 26

Calculating CBD Oil Dosage for Anxiety

CBD oil usually comes in a dropper bottle. The packaging may specify how much CBD is in a single drop. This will allow you to determine how many drops you need.

Sometimes, it might be difficult to calculate how much CBD is in one drop because the packaging specifies the total amount of CBD in the entire bottle, not how much is in a single drop. As a rule of thumb, one drop (not the full dropper) is about 0.05mL.

For example, a 15mL bottle of CBD oil contains 300 drops. If the strength of the formulation is 30mg/mL, each drop contains 1.5mg of CBD.

When Should CBD Oil Be Taken?

You can take CBD oil with or without food. However, taking it with food (particularly a high fat, high calorie meal) can increase the level of CBD in your blood 34 and make it more effective. Because of this, you need to be consistent when you take CBD oil. Consistent dosing will minimise variability in the way the medicine works.

Is It Possible to Take Too Much CBD?

Studies have shown that dosages of up to 5,000mg a day are safe and well-tolerated. 35 However, it is important to remember that more research is needed to understand the potential long-term effects of CBD oil at these dosages.

Is CBD Oil for Anxiety Safe to Take?

Side Effects

Like all medicines, CBD oil can have side effects. The extent of these effects vary with the type of product and between individuals. In general, the side effects of CBD products are less than those for THC products. 5 A recent review shows that extensive research has found CBD oil to be relatively safe. 6

Known side effects of CBD include: 5

  • fatigue and sedation
  • dizziness (vertigo)
  • nausea and vomiting
  • fever
  • decreased or increased appetite
  • dry mouth

Continuous use of CBD oil is safe and well tolerated. 6,11 Studies show that CBD oil is well tolerated even at high doses (up to 5,000mg). 35

Contact your doctor if you experience any medicine-related side effect or adverse event.

Withdrawal and Dependence

Withdrawal symptoms from CBD oil is not associated with discontinuation and it may be stopped without gradually reducing. 35

CBD oil demonstrates no potential for abuse or dependence. 36,37

Interactions

CBD oil blocks CYP3A4, an enzyme responsible for breaking down many medicines. This can increase the level of medicines in your system, resulting in unwanted or harmful side effects. There is potential for CBD oil to be associated with drug interactions through blocking this enzyme, but it is not yet clear whether these effects occur at CBD oil’s usual dosage ranges. 27

High dosages of CBD oil may increase plasma concentrations of certain epilepsy medicines such as clobazam and topiramate, while abnormal liver function test results were noted in patients taking CBD oil together with valproate. Although the observed level changes of the epilepsy medicines remained within the accepted therapeutic dosages, the study emphasises on the importance of monitoring serum antiepileptic drug levels and liver function tests during treatment with CBD oil. 38

A recent comprehensive review found that there have been reports of CBD oil interacting with epilepsy medicines, antidepressants, opioid analgesics and THC, as well as several other common medicines such as paracetamol, and substances including alcohol. 39

It is important that you speak with your doctor about any vitamins, supplements, prescription and over-the-counter medicines you are taking before starting or stopping CBD oil.

What should patients and caregivers know?

  • CBD oil does not cause a high as it does not contain THC.
  • Assess your sensitivity to CBD oil. Your individual ability to tolerate CBD oil can play a role in determining how much you need. Unless your doctor recommends a specific dose, start with a low dose and gradually increase until you achieve the desired effect.
  • Although CBD oil may help with your anxiety, do not stop any medicines you are already using without talking to your doctor first. Suddenly stopping your prescription medicines may cause you to experience withdrawal symptoms.
  • As CBD oil is not intoxicating, there are no restrictions around driving when taking products that contain only CBD. However, take care when taking products containing both CBD and THC as it is illegal to drive while you are taking THC products. 29

What Are the Next Steps?

In most states in Australia, most GPs and specialists can prescribe CBD oil. However, they will need to apply under the special access scheme.

If your doctor is unwilling to apply on your behalf or uncomfortable prescribing medical cannabis, they can refer you to our clinic. We do virtual consultations nationwide and in-person at our flagship clinic in Sydney.

Click here for a quick online eligibility test to see if you qualify.

You can also call us at (02) 9098 9128 or email us at [email protected] and we can advise if medical cannabis could be an option for your condition.

Cannabis, a cause for anxiety? A critical appraisal of the anxiogenic and anxiolytic properties

Cannabis has been documented for use in alleviating anxiety. However, certain research has also shown that it can produce feelings of anxiety, panic, paranoia and psychosis. In humans, Δ 9 -tetrahydrocannabinol (THC) has been associated with an anxiogenic response, while anxiolytic activity has been attributed mainly to cannabidiol (CBD). In animal studies, the effects of THC are highly dose-dependent, and biphasic effects of cannabinoids on anxiety-related responses have been extensively documented. A more precise assessment is required of both the anxiolytic and anxiogenic potentials of phytocannabinoids, with an aim towards the development of the ‘holy grail’ in cannabis research, a medicinally-active formulation which may assist in the treatment of anxiety or mood disorders without eliciting any anxiogenic effects.

Objectives

To systematically review studies assessing cannabinoid interventions (e.g. THC or CBD or whole cannabis interventions) both in animals and humans, as well as recent epidemiological studies reporting on anxiolytic or anxiogenic effects from cannabis consumption.

Method

The articles selected for this review were identified up to January 2020 through searches in the electronic databases OVID MEDLINE, Cochrane Central Register of Controlled Trials, PubMed, and PsycINFO.

Results

Acute doses of CBD were found to reduce anxiety both in animals and humans, without having an anxiogenic effect at higher doses. Epidemiological studies tend to support an anxiolytic effect from the consumption of either CBD or THC, as well as whole plant cannabis. Conversely, the available human clinical studies demonstrate a common anxiogenic response to THC (especially at higher doses).

Conclusion

Based on current data, cannabinoid therapies (containing primarily CBD) may provide a more suitable treatment for people with pre-existing anxiety or as a potential adjunctive role in managing anxiety or stress-related disorders. However, further research is needed to explore other cannabinoids and phytochemical constituents present in cannabis (e.g. terpenes) as anxiolytic interventions. Future clinical trials involving patients with anxiety disorders are warranted due to the small number of available human studies.

Background

Cannabis spp. have over 500 phytochemicals documented, including well over 100 cannabinoids, which are unique to the genus [1, 2]. Until recently, cannabis and its components were largely restricted under international legislation due to the perceived lack of medical value and the substantial risk of misuse [2]. As a result, the pharmacology of most of the cannabinoids are largely unknown. However, one of the more potent psychoactive compounds, Δ 9 -tetrahydrocannabinol (THC), has been extensively isolated, synthesised and studied [3] since it was first isolated in 1964 [4]. Along with the emergence of literature on this compound, there has been a corresponding increase in the use of cannabis for medical purposes, with the most frequently stated reasons for its use being for the management of pain, anxiety and depression [5].

Cannabis remains the most commonly consumed illicit drug around the world [6], whilst clinical research is nascent, yet rapidly emerging. Research is urgently required due to the large variety of cannabis preparations that are available on both the licit and illicit drug markets (depending on jurisdictions) [1]. Furthermore, both community and laboratory-based studies have demonstrated that the relative quantities of cannabinoids in the plant may directly affect its pharmacological activity when consumed. For example, when taken together with THC, CBD may potentially offset some of the adverse effects of THC, such as memory impairment and paranoia [7, 8]. It has been demonstrated in rodents that high doses of CBD are able to negate some of the anxiogenic response created by THC [9].

Recreational use of cannabis is commonly reported to lead to a feeling of euphoria accompanied by a decrease in anxiety and an increase in sociability [10]. Conversely, it is also frequently reported that cannabis can produce feelings of anxiety, panic, paranoia and psychosis [3, 11,12,13,14,15,16]. It has also been demonstrated that changes in sociability depends on prior exposure and use of cannabis [17]. So why may this contradictory finding be present? Studies have indicated that the two predominant compounds in cannabis: CBD and THC, appear to have opposing actions, with the reported anxiolytic effect attributed to CBD and anxiogenic outcomes being attributed to the THC [18]. Nevertheless, a number of more recent publications have shown that this outcome of THC is dosage-dependent, with lower dosages having the opposite effect.

There is extensive research supporting the biphasic nature of cannabinoids in both anxiety [19,20,21,22,23,24,25] (Fig. 1) and behavioral responses including motor activity [26,27,28,29,30] and aggression [31]. Different doses of THC have been found to be biphasic in reward and motor activity [32], and memory and cognition [31, 33]. Whilst the majority of these studies have been conducted on rodents, human studies (covered in detail later) have also provided promising results. Several reports have also found that in animals [34,35,36,37], as well as in humans [37], THC acts differently according to whether it is administered by itself or concurrently with other cannabinoids or terpenes. It has been discussed in the literature that CBD, due to its anxiolytic properties, may have a protective effect against certain negative psychological effects from THC [7, 8]. Research has also shown that it may also be capable of antagonising at least some of the adverse effects related to THC [1, 38]. Recent research has indicated that when low-dose CBD (4 mg) is combined with THC the intoxicating effects of THC were enhanced, while high doses of CBD (400 mg) decreased the same effects [38]. Furthermore, the plethora of chemical constituents found in whole cannabis have been found to be more active than single, purified phytocannabinoids [4, 39]. This being said, cannabis terpenoids as potential synergistic contributors to the effects of phytocannabinoids has not yet been explored in sufficient detail [39].

Summary of biphasic anxiolytic/anxiogenic effects of cannabis

The plant’s anxiety-modulating action has largely been attributed to a biphasic interaction with the CB1 receptor. Rey et al. (2012) [40] found that the anxiolytic effects of low doses occur when they interact with the CB1 receptor on cortical glutamatergic terminals. Conversely, interaction with the CB1 receptor on the GABAergic terminals is responsible for anxiogenesis, something which takes place when higher doses are administered. Further, the use of a CB1 receptor antagonist has been found to fully reverse the effects of THC [41]. However, other non-CB1 receptors are also believed to be involved including serotonin 5-HT1A receptors [42] and the opioid system [20, 43, 44]. There has also been research in recent years to determine the neural site at which these interactions take place. These studies have largely involved injecting THC into various parts of the brain in animal models and observing any anxiolytic or anxiogenic effect [41]; or by observing the effects of oral doses on the brains of individuals under the influence of THC using functional magnetic resonance imaging (fMRI) [45]. Not surprisingly, it has also been found that an individual’s history of cannabis use plays a role in the response of an individual to cannabis intake [46], something which has been observed in both animal [20, 42, 43, 47] and human models [48].

Whilst other papers have reviewed the association of cannabis with anxiety prevalence [49], or explored the underlying potential anxiolytic or anxiogenic mechanisms of action [20, 41,42,43,44,45], or covered the current human clinical trial evidence in the area [16], no comprehensive integrated paper exists to date which critically appraises both the potential anxiolytic and anxiogenic effects of the plant across these research domains. This review seeks to fill this void by compiling a broad overview of the scientific literature on both the anxiolytic and angiogenic properties of both whole plant cannabis and isolates (e.g. THC, CBD, and other phytocannabinoids and terpenes) in both animals and humans. This systematic review covers animal models, epidemiological data and human clinical trials, concluding with a perspective for industry, clinicians, and the public about current recommendations for medicinal cannabis formulations which may provide anxiolytic activity with lesser risk of anxiogenic effects.

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Method

To provide a comprehensive review of the area, both animal and human studies were sought for inclusion. In order to include as many relevant sources as possible, there were no exclusions based on types of animals or models (testing anxiety or mood paradigms) used in the studies. Human studies included in the review involved either epidemiological studies exploring the cross-sectional or longitudinal association between cannabis use and anxiety, or interventional studies using whole cannabis extracts or isolates (botanically-derived only) for any anxiety disorder, or to test an acute anxiogenic or anxiolytic effect. Synthetic cannabinoid analogues were excluded from this review.

Articles were identified using the electronic databases of OVID MEDLINE, Cochrane Central Register of Controlled Trials, PubMed, and PsycINFO up to January 2020, and only included articles in English. No time limits were set. Intervention studies (animal or human) could involve either acute or chronic administration of cannabis-based treatment. Studies testing major cannabinoids or whole plant interventions were included. Where the composition was unknown, studies where THC was administered via cigarette or inhaler were excluded for the clinical trial portion of this review. In addition, reference lists were searched for additional references. The main database search was split into three systematic search streams: animal models; epidemiological data; human clinical trials (see Fig. 2). An additional limit was set for epidemiological studies over the past five years (2016-2020), due to the breadth of current data. The term ‘significant’ was used for a p value of < 0.05.

Process of identification and screening of articles for inclusion

The following search terms were used to locate animal models as well as epidemiological and intervention studies:

“delta 9 thc OR THC OR tetrahydrocannabinol OR delta 9 tetrahydrocannabinol OR delta 9-THC OR D9-THC OR Delta [9] -THC OR Δ9-THC OR CBD OR canna* OR terpenes AND “anxi* OR anxiety disorder* OR anxiolytic* OR anti-anxiety OR anxiogenic OR social phobia OR social anxiety OR panic disorder OR post-traumatic stress disorder OR PTSD.

Our search revealed a total of 1095 studies with 66 being relevant for a full review of the articles for potential inclusion. A final review revealed a total of 35 studies eligible for inclusion (17 preclinical, 8 human, and 10 epidemiological).

Results

Epidemiological data

Our review of the data revealed 10 studies involving cannabis users consuming whole cannabis preparations or extracts for anxiety (see Tables 1, 2). Included in our review were cross-sectional studies with no demographic limitations. Three studies in particular demonstrated that such use is prevalent, with more than half of the participants in each survey confirming using cannabis for anxiety [50,51,52]. Further, these studies indicate that there is also a significant proportion of people who replaced some or all prescription medication with cannabis use [53, 54]. The majority of participants were recruited online, particularly through social media or through medicinal cannabis suppliers.

The three cross-sectional studies found that respondents reported that they used cannabis medicinally for anxiety, second only to pain [50, 52, 55], with close to half of all survey participants stating they use cannabis for anxiety [50,51,52, 56]. In a study of 1429 participants, Sexton et al. (2016) [50] found that over half (59.8%) of medical users reported using cannabis as an alternative to pharmaceutical prescriptions [50]. Similarly, a US study of 2774 participants found this to be 46% of users [53]. Additionally, one study of 2032 people found that nearly half of the respondents had substituted an anxiety medication prescribed to them by their physician, with medical cannabis [56], and 61% indicated that cannabis had completely replaced their prescribed medication. Likewise, another study consisting of 1513 participants found similar results, with 71.8% indicating that they had reduced their intake of anti-anxiety medications [54] (Table 2).

In a review of 5085 responses recorded in a smart-phone application, it was found that users of the app reported significantly lower anxiety levels following cannabis use [57] (Table 2). Further, only 2.1% experienced exacerbated symptoms, while only 4.4% reported no change in anxiety symptoms. An Australian study of 1748 participants found that fewer than 1% of respondents felt that the treated symptom, including anxiety, had worsened compared to 71 to 92% who felt it had improved [51]. Such results were further confirmed by Turna et al. (2019) [56] where 92% of the 2032 respondents reported that cannabis improved their anxiety symptoms. Despite this response, the scores of self-reported questionnaires indicate that symptoms remained moderately severe.

In a 3-year longitudinal survey of cannabis use by patients with a primary anxiety disorder diagnosis (N = 3723), it was found that remission rates from anxiety disorders were higher among cannabis nonusers (Table 2). However, these differences were not statistically significant in adjusted models [58]. Discrepancies in responses are further highlighted as men reported experiencing greater headache/migraine relief from medical cannabis than women, despite a larger proportion of women reporting using it for this reason. Of note also is that women were significantly more likely than men to report using cannabis to treat anxiety [59]. A summary caveat concerns that the epidemiological data should be considered within the limitation of survey respondents being a ‘captive’ sample who had an active interest in cannabis use.

Animal studies

Our initial search returned 1095 articles, with a further nine studies found through handsearching of the references. A total of 17 preclinical studies were found to be relevant for inclusion (Tables 3 and 4). The focus of the research concerned primarily CBD and/or THC.

With respect to CBD, both Schier et al. (2012) [60] and Blessing et al. (2015) [61] concluded that when it was administered acutely, anxiolytic-like effects were only present at low doses, yet has the advantage of not producing anxiogenic effects at higher dose (see Table 3). Schier et al. (2012) [60] also noted that chronic doses produced mixed results, with both anxiolytic-like and anxiogenic-like outcomes being observed. Lee et al. (2017) [62] observed predominantly anxiolytic-like responses in the studies analysed, which applied to both acute and chronic administration. Iffland & Grotenhermen (2017) [63] concluded that CBD may only be anxiolytic where stress had been induced before CBD administration.

There was also some variance in the results. For example, Valjient et al. (2002) [21] observed that only the highest dose of 5.0 mg/kg had an anxiogenic-like effect, and lowest dose of 0.03 mg/kg had an anxiolytic-like effect in male CD-1 mice. Conversely, Fokos et al. (2010) [64] observed the opposite in male Sprague–Dawley rats with the low dose of 0.5 mg/kg producing an anxiogenic-like effect and the high dose of 1 mg/kg producing an anxiolytic-like effect. In McLendon et al.’s (1976) [65] study of male Rhesus monkeys, all doses from 0.2 mg/kg to 1 mg/kg produced an anxiolytic-like response. Conversely, Rock et al. (2017) [66] observed an anxiogenic-like response for both dosages of 1.0 mg/kg and 10 mg/kg in male Sprague–Dawley rats.

This variance may partly be due to different animals being studied. While McLendon et al. (1976) [65] used monkeys in their study, this was the only study found to do so, with the rest of the reviewed studies using rodents. Studies also differed in design, including types of test employed, the size of the apparatus used, dosages administered, and the route of administration.

Elevated plus-maze (EPM)

Braida et al. (2007) [42] injected male Sprague–Dawley rats with a THC dosage of either 0.015, 0.075 or 0.75 mg/kg and then placed them in the EPM. It was found that THC exhibited a dosage-dependent effect with the highest dosage of THC corresponding to the maximum anxiolytic effect. Another approach involved male Sprague–Dawley rats being administered dosages ranging from 0.075 to 1.5 mg/kg [67]. It was found that even with the addition of a higher dosage compared to the previous study, the maximum anxiolytic effect was still found to occur when the rats were administered 0.75 mg/kg THC, which supports the idea that depending on the dose THC can produce both anxiolytic and anxiogenic responses. The study by Schramm-Sapyta et al. (2007) [68] was unique in that rats were used in their EPM instead of mice. These male CD rats were also divided into two age groups: adolescent and adult. The rats were injected with either 0.5 or 2.5 mg/kg THC. They concluded that while there was a significant effect of drug dose on the percentage of time spent in the open arms, there was no significant effect of age on this outcome. At the lower dose of 0.5 mg/kg though, THC was less anxiogenic in adolescents than in adult rats.

The next study sought to determine the brain regions involved in producing anxiogenic or anxiolytic effects by injecting THC ranging from 0.001 mg to 0.01 mg directly into various parts of the rat brain [41]. The results indicated that in certain regions, different dosages produce opposite effects. For example, when injected into the ventral hippocampus, the lower dose of 0.005 mg produced a significant anxiolytic-like effect, which switches to an anxiogenic-like response when 0.01 mg was injected. In contrast, low doses had no effect when injected into the prefrontal cortex, whereas the higher dose of 0.01 mg produced an anxiolytic like response and 0.025 mg produced an anxiogenic-like outcome. When injected into the basolateral amygdala, 0.001 mg THC induced a significant anxiogenic-like response whereas higher THC doses did not affect anxiety behavior.

In an alternative to the typical rat-model studies above, one study utilised male C57BL/6 JArc mice [69]. When CBD was administered acutely, there was no change in the percentage of time in the open arms or ratio of open-arm entries was observed. Neither was any change in the total number of EPM arm entries. In contrast, Schleicher et al. (2019) [70] found that in male and female C57BL/6J mice who were injected with 20 mg/kg CBD for 6 weeks there was a significant decrease in the time spent in the open arms [70]. Conversely Zieba et al. (2019) [71] found that acute administration of CBD increased time in open arms of EPM in male Fmr1 KO mice. The same mice were all given both doses with at least three days between tests. When given the higher dose (20 mg/kg), they were found to spend a longer amount of time in open arms compared to when they received the lower dose (5 mg/kg) (p < 0.005 and p < 0.05, respectively) [71].

In Long et al.’s (2010) [69] study of chronic administration, male C57BL/6JArc mice received 21 consecutive daily intraperitoneal injections of either THC (0.3, 1.0, 3.0 or 10.0 mg/kg) or CBD (1.0, 5.0, 10.0, 50.0 mg/kg). While there was a trend (p = 0.08) towards an effect of THC on time spent in the inner open arm, there was no effect on the open arm entry ratio. When CBD was administered, there was no effect on the open-arm entry ratio or percentage of time spent on open arms [69]. However, there was a similar trend (p = 0.09). towards an effect of CBD on time spent in the open arm section closest to the center zone of the EPM.

Like Schleicher et al. (2019) [70], Kasten et al. (2019) [72] also used C57Bl/6 J mice, but also included both sexes, and both adults and adolescents in their observations. The mice were injected with THC (1.0, 5.0 or 10.0 mg/kg), CBD (5.0, 10.0 or 20.0 mg/kg), and THC + CBD (10 mg/kg and 20 mg/kg respectively). Although there were no trends consistent across all categories, they did observe that while there was no significant effect of age there was a significant dose-related reduction in the time spent in open arms and open arm entries. Conversely it was observed that there was no interaction between the dose of CBD and the time spent on the open arms.

Another method saw male Sprague–Dawley exposed to either 10 days of chronic unpredictable stress or no stressor [64]. After this period, they were injected with either a low (0.5 mg/kg) or a high (1.0 mg/kg) dosage of THC, then being placed in an EPM. It was observed that in unstressed animals, the rats that were administered either 0.5 mg/kg or 1 mg/kg THC showed anxiolytic-like effects. In stressed animals, however, only the high dosage of THC induced an anxiolytic-like response, whereas the low dosage induced anxiogenic effects. These results directly contradict both the idea that THC is anxiolytic at low dosages, and anxiogenic at high dosages at least when stress is applied.

Light-dark (LD) box

Although the aim of the Valjent et al. (2002) [21] study was to determine the effect of THC and nicotine administered together, we were able to utilise their results in this review, as THC was first administered alone. This involved the acute administration of either 0.03, 0.1, 0.3, 1, 2.5 or 5 mg/kg to determine at what dosage THC would produce a clear anxiolytic-like response. It was found that anxiolysis occurred at a dosage of 0.3 mg/kg. This markedly changed to an anxiogenic effect when 5.0 mg/kg was administered and there was no change in the response relative to vehicle for all other dosages given. These findings were further confirmed when in the same year the low dosage of 0.3 mg/kg THC was again given to male CD1 mice and once again an anxiolytic-like response was observed [20]. This was done based on the conclusions of the previous study, and with the intention to induce this anxiolytic-like response. Alternative dosages of 0.3, 1, 3 or 10 mg/kg were also employed [69]. The timeframe also differed, with these given in 21 daily injections. This study implies that there is a clear correlation between increasing dosages of THC and time spent in the dark area of the LD box.

In contrast to the other studies, Schramm-Sapyta et al. (2007) [68] looked at acute THC administration in adolescent and adult male CD rats. The rats received either 0.5 or 2.5 mg/kg THC. It was observed that the time in the light compartment was significantly reduced proportionally to increasing dose by THC in both adolescents and adults. Conversely, Rock et al. (2017) [73] studied the effect of THC chronic administration on male Sprague–Dawley rats using dosages of 1.0 and 10 mg/kg. At the dosages chosen, THC decreased the amount of time spent in the light chamber of the LD box on days one and 21, suggesting an anxiogenic-like effect both acutely as well as chronically. Furthermore, at a dose of 10 mg/kg only, THC increased the latency to enter the light box, but only on Day 1. This latency to enter was increased with the addition of a prior stressor. Long et al. (2010) [69] found that THC given at a high dose of 10 mg/kg to male C57BL/6JArc mice significantly decreased the time spent in the light compartment. Contrarily, it was observed that when the low dose of 1 mg/kg CBD was administered this resulted in a significant increase in the time spent in the light compartment. However, when 20 mg/kg CBD was given over a period of 6 weeks, no change in anxiety related behaviour was observed [70].

Open field (OF) test

Long et al. (2010) [69] tested mice injected with THC in an OF test. The ratio of central to total distance travelled (distance ratio) and the time spent in the central zone were taken as measures of anxiety. It was noted that when the maximum dosage of 10 mg/kg was given, there was a significant decrease in the time spent in the central area and a decrease in the distance ratio. This was consistently demonstrated when THC was given daily over 21 days, with a significantly decreased overall distance travelled on day 15 and on day 21, the latter of which was also observed when doses of 1 mg/kg and 3 mg/kg were given.

Kasten et al. (2019) [72] found that 5 and 10 mg/kg doses of THC in adult mice reduced total locomotion. In the 5 mg/kg adult group this was significantly correlated with reduced time in the centre of the open field indicating an anxiogenic-like response. When 10 mg/kg CBD was given, reduced activity in the adult group was also observed, but this was not significantly correlated with anxiety-like metrics. In support of this Long et al. (2010) [69] observed that acute doses of CBD (1 and 50 mg/kg) produced an anxiolytic-like effect and Schleicher et al. (2019) [70], who injected male and female C57BL/6 J mice over a period of time, found that anxiety behaviour in the open field test was not affected. In contrast, Zieba et al. (2019) [71] found that in their male Fmr1 KO mice acute CBD treatment had no impact on anxiety related parameters in the open field test [71]. However, they did find that CBD given chronically at 50 mg/kg increased the time spent in the central zone of the OF test on day 15.

Social interaction

The social interaction test for rodents was first introduced by File and Hyde (1978) [74]. In this study experimental manipulation was used to increase anxiety and this was observed to result in a decrease in social interaction. This test has continued to be used as it is sensitive to both anxiolytic and anxiogenic effects [75] and is an accepted measure of anxiety-like behaviours.

Test male C57BL/6JArc mice and those who had received 0.3, 1, 3 or 10 mg/kg THC were placed in opposite corners of a grey perspex arena to test social interaction [69]. Mice were allowed to explore freely for 10 min during which time the authors recorded manually the frequency and total duration of the active socio-positive behaviours undertaken by the mouse who had received the dosage of THC. It was found that while THC decreased the combined frequency of the socio-positive behaviours, the total duration of all these behaviours remained the same. However, the duration was decreased at 10 mg/kg THC, indicating an anxiogenic-like response at this higher dose.

Malone et al. (2009) [9], pre-treated male Sprague–Dawley rats with either vehicle, 5.0 or 20 mg/kg CBD. These rats were then administered either vehicle, 1.0, 3.0 or 10 mg/kg THC. A significant CBD-THC interaction was observed, as well as a significant effect of CBD on the total time spent interacting. The overall trend was that rats treated with a combination of a low dose of CBD and THC interacted less than rats treated with just the THC. However, when the dose of CBD was increased, these rats interacted more than those treated with just the THC. This outcome suggests that while CBD is able to negate some of the anxiogenic response of THC, higher doses of CBD are needed to achieve this.

Cardiac conditioned response (CCR)

McLendon et al. (1976) [65] used pairing one of two tones with the delivery of a peripheral electric shock in male Rhesus monkeys to establish the cardiac conditioned response (CCR). The conditioned response is considered to be part of the complex of physiological and behavioural changes characteristic of anxiety and has been used to study anxiety in human [65, 76]. The effect of various dosages of 0.2, 0.5 or 1.0 mg/kg intravenous THC was given. The results revealed that THC blocked the CCR in a dosage dependent manner and this was consistent across trials and across animals. At the lowest dosage tested of 0.2 mg/kg a slight attenuation was consistently noticed with a reduction in the conditioned response of 5 to 6 beats per minute observed. At the next highest dosage of 0.5 mg/kg a reduction of 10 to 15 beats per minute was noted for each animal and at the highest dosage of 1 mg/kg, there was a resultant complete block of the CCR in every case.

As detailed in Table 4, our search revealed a range of studies of cannabinoids (primarily THC) in anxiety models beginning in 1976. Research over this period of 40 + years has revealed conclusions that are inconsistent. Generally, the results indicate that at lower dosages an anxiolytic response for THC is observed, with the opposite being true of higher doses (however as indicate above across differing animal modes, this finding is not always consistent).

Human studies

Of the initial 1095 articles detected in our initial search, 26 full text articles were assessed for eligibility. Of these, 17 met our initial inclusion criteria and an additional five were identified through handsearching of references. Of these, eight were found to meet inclusion criteria and are included in this review.

Acute human clinical trials

The anxiogenic properties of isolated THC has have been firmly established in humans and as demonstrated in Table 5, and no human studies provided any evidence of anxiolytic effects. However, the dosages administered varied widely in the studies described ranging from 2.5 mg [48, 77] to 30 mg [78]. In addition there were two studies which utilised mg/kg [79, 80]. While these two studies are able to be compared more easily with the animal studies, this difference in measurement means that they are not comparable to the other studies as the masses of the participants are not provided.

Evidence of THC’s potential anxiolytic effects in humans, was first published in 2004. The study sample size consisted of 22 healthy individuals who had previously used cannabis, but had never been diagnosed with a cannabis abuse disorder [77]. In a 3-day, double-blind, randomised procedure, 22 volunteers received 2.5 or 5 mg of THC. They were asked to score their feelings using the Visual Analog Scale for anxiety (VAS-A) [81]. The results showed a statistically significant increase in VAS-A scores of ‘anxious’. This was observed to occur in a dosage-dependent manner, yet there were no statistically significant changes in the VAS-A scores for panic.

In a follow up US study, the same methodology was applied to people who were frequent users of cannabis [48]. The researchers aimed to determine if this frequent use offers protection from or tolerance to the effects of THC. Thirty frequent users were compared to 22 healthy volunteers, who acted as the control. Once again, a correlation between the dosage given and the VAS scores for anxiety was observed with VAS anxiety scores transiently increasing in both groups. It was noted that those who frequently smoked cannabis displayed significantly smaller increases in anxiety than controls.

Converse to the anxiogenic effects of THC, CBD appears to have the opposite effect. In Bergamaschi et al. (2011) [82], participants with social anxiety disorder (SAD) and an additional 12 controls were blindly allocated to receive CBD or placebo 1.5 h before a simulation public speaking test. The Visual Analogue Mood Scale (VAMS), Negative Self-Statement scale, and physiological measures were taken at six time points during the test. CBD administration resulted in significantly reduced anxiety, cognitive impairment and discomfort, and significantly decreased hyper-alertness in anticipatory speech. Further, Crippa et al. (2011) [83], observed regional cerebral blood flow activity in the brain of participants with SAD who were given CBD or placebo. CBD was found to modulate blood flow in the left parahippocampal gyrus, hippocampus, and inferior temporal gyrus, and right posterior cingulate gyrus. In addition, participants who received CBD reported significantly lower subjective anxiety than those who received a placebo.

Another two studies utilised Spielberger’s State-Trait Anxiety Inventory (STAI) to measure anxiety [18, 84]. In the first, participants participated in five experimental sessions where they received 0.5 mg/kg THC with the STAI being conducted at the start of the first and last experimental session [80]. In the second study this was done at baseline and 1,2, and 3 h post administration with 10 mg THC [84]. In both cases, an increased STAI score was noted. Further, it was found that both the STAI and the VAMS scores were significantly increased following THC intake relative to intake of a placebo. When CBD was administered alongside THC, this anxiogenic effect appeared to be reduced [18]. When CBD was given by itself, there was no change in the STAI score compared to the baseline. However, a possible reduction in anxiety was evidenced in the results of the VAMS anxiety and tranquilization subscale [84] Compared with placebo, CBD administration did not significantly change any of the subject ratings.

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Another similar study, used a differing assessment, the Subjective Drug Effects Questionnaire (SDEQ) [79]. Ten frequent and 10 occasional cannabis users received doses of 0.2, 0.4, and 0.6 mg/kg THC. THC was found to have a profound anxiogenic effect, with participants stating that they felt increasingly more tense, jittery and less in control as the dose was increased. Karniol et al. (1974) [78] also reported a strong anxiogenic reaction as a result of THC administration with subjects expressing that the feeling of anxiety sometimes reached a near panic state. Further, four of the five subjects gave this feeling as the maximum grade possible in this study. In this case, 30 mg of THC was administered. This study also administered various doses of CBD (15.0, 30.0, 60.0 mg) to participants. Anxiety was reported by only two of the 15 subjects. When CBD was administered with THC, the anxiogenic effects of the latter were reduced.

Discussion

Data synthesis

The overall pattern of human clinical data supports consistent anxiogenic effects from THC, while CBD shows a consistent anxiolytic effect. In combination with CBD, the anxiogenic effect of THC has been shown to be decreased. However, further investigation is needed to categorically affirm this effect. Based on this data, it would imply that cannabis preparations higher in CBD and lower in THC cannabis would be most successful in treating anxiety. However, some survey data does not support this, with a preference for high THC cannabis being of greater interest to consumers for addressing affective symptoms. Further to this, only a very small percentage in surveys reported severe or intolerable side effects of using cannabis for their symptoms [51]; and in general, whole cannabis tends to have a much higher THC:CBD ratio. The epidemiological data is in contrast to the findings of the clinical trials.

These discrepancies could be due to the fact that while a substantial number of patients cross-sectionally report using cannabis and related products to treat anxiety symptoms or disorders, it has not been firmly established whether this anxiety occurred before or as a result of the cannabis usage [16, 85]. As epidemiological research largely relies on anonymous surveys, the composition of the cannabis being used is unable to be confirmed. It is known however, that between 1995 and 2015 there has been a 212% increase in THC content in the marijuana flower [86]. It is also known that plants producing high levels of THC are incapable of producing much CBD [86]. Thus, recent studies looking at whole cannabis consumption in theory should provide a relatively reliable source of information regarding the anxiogenic and/or anxiolytic properties of THC. Our review also highlights the lack of data from jurisdictions where cannabis is not legal, as most of the included studies are based on surveys by those living in certain states in the US or Canada where medicinal use is legal. An important consideration to note when assessing the epidemiological data is that many studies are based on self-reported effects from participants who are purposively using cannabis for their anxiety, and thus due to the sample bias, conclusions must be tempered.

In respect to the animal model research, there is strong evidence suggesting that an anxiolytic effect occurs after the administration of a small acute dose of CBD [60, 61, 63]. Results however differed depending on whether CBD was acutely or chronically administered, as well as the animal model used. This was demonstrated by Rubino et al. (2007) [67] and Schleicher et al. (2019) [70], who both observed no change in anxiety behaviour in the open field test, but significant changes in behavior in the elevated plus maze.

As the present data indicates, no clear conclusion can be drawn from the preclinical studies of acute administration of THC. This could in part be due to the types of animal model being utilised. For example, Onaivi et al. (1990) [19] found that in an elevated plus maze, THC induced both in rats and in mice, an increased aversion to the open arms of the elevated plus maze; but this effect was approximately three times greater in rats than in mice. Thus, while the two predominant tests for rodents are the elevated plus maze and the light–dark box, the results are difficult to compare as rats and mice may react differently to the test paradigm. This suggests that physiological parameters such as the cardiac conditioned response used by McLendon et al. (1976) [65] might be a more accurate measure as it relies much less on human observation.

In humans, research has also shown that the anxiogenic effects of THC are greater among infrequent or non-users relative to frequent users [16], and high potency THC in cannabis products in particular, are thought to induce the development of psychotic-like symptoms or overt psychosis in vulnerable individuals. Similarly, intoxication by low-dose CBD has been found to be particularly prominent in infrequent cannabis users [38]. Further, it has been observed in early 1970s research that individuals who were anxious before receiving it became less anxious under the influence of cannabis (note that potentially far lower THC preparations would have been used). Conversely, non-anxious persons became more anxious [87]. In an animal model, Long et al. (2010) [69] found that differences were observed amongst mice depending on the day in which they were tested, which suggests that the length of time over which the treatment is given also effects the anxiolytic and anxiogenic properties. Kasten et al. (2019) [72] also observed inconsistencies across the groups investigated, with adolescent male mice performing differently to adult male mice, which in turn performed differently to adolescent female and adult female mice. This clearly shows that age, sex and background of exposure may have an impact on how an animal or human reacts to THC or CBD inoculation, something which was found by Cuttler et al’s. (2016) [59] epidemiological survey, where different results were reported depending on the sex of the person responding.

Differences in methodologies and limitations of data provided across the studies reviewed, further reduces our ability to draw strong conclusions. This includes the irregularities in doses given, where some studies used mg/kg and others mg only, and different administration methods being used. Most acute studies using THC employ an oral or inhalation route of administration [77]. Oral administration delays the onset of effects by 30 min to two hours, produces lower peak plasma levels, and prolongs the action of the THC compared to the inhaled or intravenous route [88, 89].

In summary, the human clinical studies using acute THC consistently produced an anxiogenic effect, while studies using CBD and epidemiological studies of whole plant cannabis in anxiety disorders showed an anxiolytic effect. This is surprising as the doses of CBD that have been shown to have therapeutic effects are far lower than what is commonly found in cannabis plant matter, such as that which is being used by the majority of participants surveyed in the epidemiological studies [38]. Furthermore, these findings have not been reliably replicated in animal studies, and further larger human RCTs are required for stronger validation.

Development of optimal anxiolytic cannabinoid therapies

Pharmacological treatment of anxiety relies on our understanding of the neurobiological interactions responsible [90]. While there are various different targets, the endocannabinoid system has, in recent years, increasingly been attributed with the control of stress, anxiety and fear. Endocannabinoids appear to modulate this system as well as the dopamine system, and hypothalamo-pituitary-adrenocortical axis [46, 91].

Though several classes of synthetic CB receptor agonists have been developed, these alternatives are high-potency CB1 receptor activators which elicit pronounced psychotropic effects, something which has seen them recently revoked across most Western countries. THC on the other hand, is a partial agonist at the CB1 receptor [38, 90], while CBD acts with low-affinity on the CB1 and CB2 receptors [38]. Cannabis, as a substrate of the CB1 and CB2 receptors in the endocannabinoid system, is therefore a prime substance for investigation.

However, research has been limited given the controversial legal history surrounding cannabis. Policies are rapidly evolving, and access to cannabis and cannabinoid products is increasing worldwide [38], with it now being decriminalised or permitted for medical purposes in many countries [92]. In Australia however, this change only took place in 2016. Prior to this it was considered a schedule 9 drug and so research into its medical use has been highly restricted [93]. As such this is still an emerging field.

With ongoing clinical research into the use of cannabis for anxiety, it is likely that optimised cannabinoid ratios of THC and CBD will eventually be better understood. Various software programs in use by the general public (e.g. Strainprint Technologies, Releaf etc.) may also be of value to researchers tackling this challenge. Apps such as these are able to track patient symptoms and collect data on the specific cannabis dosage form, cannabinoid ratios and particular cannabis products used for certain diseases, conditions or symptomatic relief.

These two constituents may only be part of the story, and continuing research into the pharmacological activity of the cannabinoids themselves may reveal that THC and CBD are not the only cannabinoids of clinical interest in anxiety. Notwithstanding the academic appetite for cannabinoid research, an often-overlooked phytochemical class, such as the terpenes/terpenoids, has also shown significant anxiolytic action. D-limonene and linalool, whilst not exclusively found in cannabis, have demonstrated anxiolytic activity; the former via the 5HT1A receptor [4, 94, 95]. As such, specific chemovars of cannabis with higher expression of these terpenes may be of greater clinical interest, particularly when paired with higher CBD concentrations. With such a complex chemistry extent in the Cannabis genus, it is plausible that many phytochemicals could be contributing to anxiolytic activity, likely interacting with numerous receptor types.  Further, as previously mentioned, some research has shown that the adverse effects of THC, may be dose dependent and are potentially decreased by low doses of CBD [38]. Hence, further research into these interactions would contribute greatly to this area.

Lastly, each individual using cannabis is also unique, making the study of pharmacogenomics an important aspect of ongoing cannabis research [96]. Variability in cannabinoid receptor genes, transporter genes and pharmacokinetic drug metabolism [97], such as that observed in the Cytochrome P450 system, are important factors for consideration. Further investigation of single nucleotide polymorphisms (SNPs), in particular of fatty acid amide hydrolase (FAAH), may potentially affect individual responses to CBD, and is another worthy research pathway in the future [96].

Conclusion

The results of this review suggest that there is tentative support based on epidemiological surveys and clinical studies showing that whole cannabis and CBD may have a beneficial role in anxiety disorders (for certain candidates in this population). In contrast, for isolated THC, acute human studies consistently show an anxiogenic effect. However, animal studies show that there may be potential for THC to be used as an anxiolytic, if given at the right dose for the patient, and that this may require gradual titration to ameliorate initial anxiogenic effects. Further to this, such an approach may be assisted via the co-administration of CBD, other cannabinoids or terpenes found in the cannabis plant which have yet to be studied substantially.

Further human studies are needed to establish consistency in the results, therapeutic thresholds, and dosage required for cannabinoid therapies to produce an anxiolytic effect in humans, and further research on cannabinoids and terpenes may yield a more optimised anxiolytic formulation.

Cannabidiol as a Potential Treatment for Anxiety Disorders

Cannabidiol (CBD), a Cannabis sativa constituent, is a pharmacologically broad-spectrum drug that in recent years has drawn increasing interest as a treatment for a range of neuropsychiatric disorders. The purpose of the current review is to determine CBD’s potential as a treatment for anxiety-related disorders, by assessing evidence from preclinical, human experimental, clinical, and epidemiological studies. We found that existing preclinical evidence strongly supports CBD as a treatment for generalized anxiety disorder, panic disorder, social anxiety disorder, obsessive–compulsive disorder, and post-traumatic stress disorder when administered acutely; however, few studies have investigated chronic CBD dosing. Likewise, evidence from human studies supports an anxiolytic role of CBD, but is currently limited to acute dosing, also with few studies in clinical populations. Overall, current evidence indicates CBD has considerable potential as a treatment for multiple anxiety disorders, with need for further study of chronic and therapeutic effects in relevant clinical populations.

Electronic supplementary material

The online version of this article (doi:10.1007/s13311-015-0387-1) contains supplementary material, which is available to authorized users.

Keywords: Cannabidiol, Endocannabinoids, Anxiety, Generalized anxiety disorder, Post-traumatic stress disorder

Introduction

Fear and anxiety are adaptive responses essential to coping with threats to survival. Yet excessive or persistent fear may be maladaptive, leading to disability. Symptoms arising from excessive fear and anxiety occur in a number of neuropsychiatric disorders, including generalized anxiety disorder (GAD), panic disorder (PD), post-traumatic stress disorder (PTSD), social anxiety disorder (SAD), and obsessive–compulsive disorder (OCD). Notably, PTSD and OCD are no longer classified as anxiety disorders in the recent revision of the Diagnostic and Statistical Manual of Mental Disorders-5; however, excessive anxiety is central to the symptomatology of both disorders. These anxiety-related disorders are associated with a diminished sense of well-being, elevated rates of unemployment and relationship breakdown, and elevated suicide risk [1–3]. Together, they have a lifetime prevalence in the USA of 29 % [4], the highest of any mental disorder, and constitute an immense social and economic burden [5, 6].

Currently available pharmacological treatments include serotonin reuptake inhibitors, serotonin–norepinephrine reuptake inhibitors, benzodiazepines, monoamine oxidase inhibitors, tricyclic antidepressant drugs, and partial 5-hydroxytryptamine (5-HT)1A receptor agonists. Anticonvulsants and atypical antipsychotics are also used to treat PTSD. These medications are associated with limited response rates and residual symptoms, particularly in PTSD, and adverse effects may also limit tolerability and adherence [7–10]. The substantial burden of anxiety-related disorders and the limitations of current treatments place a high priority on developing novel pharmaceutical treatments.

Cannabidiol (CBD) is a phytocannabinoid constituent of Cannabis sativa that lacks the psychoactive effects of ∆ 9- tetrahydrocannabinol (THC). CBD has broad therapeutic properties across a range of neuropsychiatric disorders, stemming from diverse central nervous system actions [11, 12]. In recent years, CBD has attracted increasing interest as a potential anxiolytic treatment [13–15]. The purpose of this review is to assess evidence from current preclinical, clinical, and epidemiological studies pertaining to the potential risks and benefits of CBD as a treatment for anxiety disorders.

Methods

A search of MEDLINE (PubMed), PsycINFO, Web of Science Scopus, and the Cochrane Library databases was conducted for English-language papers published up to 1 January 2015, using the search terms “cannabidiol” and “anxiety” or “fear” or “stress” or “anxiety disorder” or “generalized anxiety disorder” or “social anxiety disorder” or “social phobia” or “post-traumatic stress disorder” or “panic disorder” or “obsessive compulsive disorder”. In total, 49 primary preclinical, clinical, or epidemiological studies were included. Neuroimaging studies that documented results from anxiety-related tasks, or resting neural activity, were included. Epidemiological or clinical studies that assessed CBD’s effects on anxiety symptoms, or the potential protective effects of CBD on anxiety symptoms induced by cannabis use (where the CBD content of cannabis is inferred via a higher CBD:THC ratio), were included.

CBD Pharmacology Relevant to Anxiety

General Pharmacology and Therapeutic Profile

Cannabis sativa, a species of the Cannabis genus of flowering plants, is one of the most frequently used illicit recreational substances in Western culture. The 2 major phyto- cannabinoid constituents with central nervous system activity are THC, responsible for the euphoric and mind-altering effects, and CBD, which lacks these psychoactive effects. Preclinical and clinical studies show CBD possesses a wide range of therapeutic properties, including antipsychotic, analgesic, neuroprotective, anticonvulsant, antiemetic, antioxidant, anti-inflammatory, antiarthritic, and antineoplastic properties (see [11, 12, 16–19] for reviews). A review of potential side effects in humans found that CBD was well tolerated across a wide dose range, up to 1500 mg/day (orally), with no reported psychomotor slowing, negative mood effects, or vital sign abnormalities noted [20].

CBD has a broad pharmacological profile, including interactions with several receptors known to regulate fear and anxiety-related behaviors, specifically the cannabinoid type 1 receptor (CB1R), the serotonin 5-HT1A receptor, and the transient receptor potential (TRP) vanilloid type 1 (TRPV1) receptor [11, 12, 19, 21]. In addition, CBD may also regulate, directly or indirectly, the peroxisome proliferator-activated receptor-γ, the orphan G-protein-coupled receptor 55, the equilibrative nucleoside transporter, the adenosine transporter, additional TRP channels, and glycine receptors [11, 12, 19, 21]. In the current review of primary studies, the following receptor-specific actions were found to have been investigated as potential mediators of CBD’s anxiolytic action: CB1R, TRPV1 receptors, and 5-HT1A receptors. Pharmacology relevant to these actions is detailed below.

The Endocannabinoid System

Following cloning of the endogenous receptor for THC, namely the CB1R, endogenous CB1R ligands, or “endocannabinoids” (eCBs) were discovered, namely anandamide (AEA) and 2-arachidonoylglycerol (reviewed in [22]). The CB1R is an inhibitory Gi/o protein-coupled receptor that is mainly localized to nerve terminals, and is expressed on both γ-aminobutryic acid-ergic and glutamatergic neurons. eCBs are fatty acid derivatives that are synthesized on demand in response to neuronal depolarization and Ca 2+ influx, via cleavage of membrane phospholipids. The primary mechanism by which eCBs regulate synaptic function is retrograde signaling, wherein eCBs produced by depolarization of the postsynaptic neuron activate presynaptic CB1Rs, leading to inhibition of neurotransmitter release [23]. The “eCB system” includes AEA and 2-arachidonoylglycerol; their respective degradative enzymes fatty acid amide hydroxylase (FAAH) and monoacylglycerol lipase; the CB1R and related CB2 receptor (the latter expressed mainly in the periphery); as well as several other receptors activated by eCBs, including the TRPV1 receptor, peroxisome proliferator-activated receptor-γ, and G protein-coupled 55 receptor, which functionally interact with CB1R signaling (reviewed in [21, 24]). Interactions with the TRPV1 receptor, in particular, appear to be critical in regulating the extent to which eCB release leads to inhibition or facilitation of presynaptic neurotransmitter release [25]. The TRPV1 receptor is a postsynaptic cation channel that underlies sensation of noxious heat in the periphery, with capsacin (hot chili) as an exogenous ligand. TRPV1 receptors are also expressed in the brain, including the amygdala, periaqueductal grey, hippocampus, and other areas [26, 27].

The eCB system regulates diverse physiological functions, including caloric energy balance and immune function [28]. The eCB system is also integral to regulation of emotional behavior, being essential to forms of synaptic plasticity that determine learning and response to emotionally salient, particularly highly aversive events [29, 30]. Activation of CB1Rs produces anxiolytic effects in various models of unconditioned fear, relevant to multiple anxiety disorder symptom domains (reviewed in [30–33]). Regarding conditioned fear, the effect of CB1R activation is complex: CB1R activation may enhance or reduce fear expression, depending on brain locus and the eCB ligand [34]; however, CB1R activation potently enhances fear extinction [35], and can prevent fear reconsolidation. Genetic manipulations that impede CB1R activation are anxiogenic [35], and individuals with eCB system gene polymorphisms that reduce eCB tone—for example, FAAH gene polymorphisms—exhibit physiological, psychological, and neuroimaging features consistent with impaired fear regulation [36]. Reduction of AEA–CB1R signaling in the amygdala mediates the anxiogenic effects of corticotropin-releasing hormone [37], and CB1R activation is essential to negative feedback of the neuroendocrine stress response, and protects against the adverse effects of chronic stress [38, 39]. Finally, chronic stress impairs eCB signaling in the hippocampus and amygdala, leading to anxiety [40, 41], and people with PTSD show elevated CB1R availability and reduced peripheral AEA, suggestive of reduced eCB tone [42].

Accordingly, CB1R activation has been suggested as a target for anxiolytic drug development [15, 43, 44]. Proposed agents for enhancing CB1R activation include THC, which is a potent and direct agonist; synthetic CB1R agonists; FAAH inhibitors and other agents that increase eCB availability, as well as nonpsychoactive cannabis phytocannabinoids, including CBD. While CBD has low affinity for the CB1R, it functions as an indirect agonist, potentially via augmentation of CB1R constitutional activity, or via increasing AEA through FAAH inhibition (reviewed in [21]).

Several complexities of the eCB system may impact upon the potential of CBD and other CB1R-activating agents to serve as anxiolytic drugs. First, CB1R agonists, including THC and AEA, have a biphasic effect: low doses are anxiolytic, but higher doses are ineffective or anxiogenic, in both preclinical models in and humans (reviewed in [33, 45]). This biphasic profile may stem from the capacity of CB1R agonists to also activate TRPV1 receptors when administered at a high, but not low dose, as demonstrated for AEA [46]. Activation of TRPV1 receptors is predominantly anxiogenic, and thus a critical balance of eCB levels, determining CB1 versus TRPV1 activation, is proposed to govern emotional behavior [27, 47]. CBD acts as a TRPV1 agonist at high concentrations, potentially by interfering with AEA inactivation [48]. In addition to dose-dependent activation of TRPV1 channels, the anxiogenic versus anxiolytic balance of CB1R agonists also depends on dynamic factors, including environmental stressors [33, 49].

5-HT1A Receptors

The 5-HT1A receptor (5-HT1AR) is an established anxiolytic target. Buspirone and other 5-HT1AR agonists are approved for the treatment of GAD, with fair response rates [50]. In preclinical studies, 5-HT1AR agonists are anxiolytic in animal models of general anxiety [51], prevent the adverse effects of stress [52], and enhance fear extinction [53]. Both pre- and postsynaptic 5-HT1ARs are coupled to various members of the Gi/o protein family. They are expressed on serotonergic neurons in the raphe, where they exert autoinhibitory function, and various other brain areas involved in fear and anxiety [54, 55]. Mechanisms underlying the anxiolytic effects of 5-HT1AR activation are complex, varying between both brain region, and pre- versus postsynaptic locus, and are not fully established [56]. While in vitro studies suggest CBD acts as a direct 5-HT1AR agonist [57], in vivo studies are more consistent with CBD acting as an allosteric modulator, or facilitator of 5-HT1A signaling [58].

Preclinical Evaluations

Generalized Anxiety Models

Relevant studies in animal models are summarized in chronological order in Table ​ Table1. 1 . CBD has been studied in a wide range of animal models of general anxiety, including the elevated plus maze (EPM), the Vogel-conflict test (VCT), and the elevated T maze (ETM). See Table ​ Table1 1 for the anxiolytic effect specific to each paradigm. Initial studies of CBD in these models showed conflicting results: high (100 mg/kg) doses were ineffective, while low (10 mg/kg) doses were anxiolytic [59, 60]. When tested over a wide range of doses in further studies, the anxiolytic effects of CBD presented a bell-shaped dose–response curve, with anxiolytic effects observed at moderate but not higher doses [61, 90]. All further studies of acute systemic CBD without prior stress showed anxiolytic effects or no effect [62, 65], the latter study involving intracerebroventricular rather than the intraperitoneal route. No anxiogenic effects of acute systemic CBD dosing in models of general anxiety have yet been reported. As yet, few studies have examined chronic dosing effects of CBD in models of generalized anxiety. Campos et al. [66] showed that in rat, CBD treatment for 21 days attenuated inhibitory avoidance acquisition [83]. Long et al. [69] showed that, in mouse, CBD produced moderate anxiolytic effects in some paradigms, with no effects in others.

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Table 1

Study Animal Route Dose Model Effect Receptor Involvement
Silveira Filho et al. [59] WR i.p. 100 mg/kg,
acute
GSCT No effect NA
Zuardi et al. [60] WR i.p. 10 mg/kg,
acute
CER Anxiolytic NA
Onaivi et al. [61] ICR mice i.p. 0.01, 0.10, 0.50, 1.00, 2.50, 5.00, 10.00, 50.00, 100.00 mg/kg, acute EPM Anxiolytic Effects ↓ by IP flumazenil, unchanged by naloxone
Guimaraes et al. [61] WR i.p. 2.5, 5.0, 10.0 and 20.0 mg/kg, acute EPM Anxiolytic NA
Moreira et al. [62] WR i.p. 2.5, 5.0 and 10.0 mg/kg, acute VCT Anxiolytic Effect unchanged by IP flumazenil
Resstel et al. [63] WR i.p. 10 mg/kg, acute CFC Anxiolytic NA
Campos et al. [64] WR dlPAG 15.0, 30.0, 60.0 nmol/0.2 μl, acute EPM Anxiolytic Both effects ↓ by intra-dlPAG WAY100635 but not intra-dlPAG AM251
VCT Anxiolytic
Bitencourt et al. [65] WR i.c.v. 2.0 μg/μl
5 min before extinction, acute
CFC
extinction
Anxiolytic Extinction effect ↓ by SR141716A but not capsazepine
EPM before and 24 h after CFC No effect before CFC
Anxiolytic following CFC
Campos et al. [66] WR dlPAG 30, 60 mg/kg, acute EPM Anxiolytic Intra-dlPAG capsazepine renders 60 mg/kg anxiolytic
Resstel et al. [67] WR i.p. 1, 10 or 20 mg/kg, acute RS Anxiolytic,
↓ Pressor
↓ Tachycardia
All effects ↓ by systemic WAY100635
EPM 24 h
following RS
Anxiolytic
Soares et al. [68] WR dlPAG 15, 30 or 60 nmol, acute ETM Anxiolytic
Panicolytic
All effects ↓ by intra-dlPAG WAY100635 but not AM251
PAG E-stim Panicolytic
Long et al. [69] C57BL/6 J mice i.p. 1, 5, 10, 50 mg/kg, chronic, daily/21 d EPM No effect NA
L-DT 1 mg/kg
anxiolytic
SI No effect
OF 50 mg/kg anxiolytic
Lemos et al. [70] WR i.p.
PL
IL
10 mg/kg IP, 30 nmol intra-PL and intra-IL, acute CFC IP and PL anxiolytic IL anxiogenic NA
Casarotto et al. [71] C57BL/6 J mice i.p. 15, 30, and 60 mg/kg, acute, or subchronic, daily/7 d MBT Anticompulsive Effect ↓ by IP AM251 but not WAY100635
Gomes et al. [72] WR BNST 15, 30, and 60 nmol, acute EPM Anxiolytic Both effects ↓ by intra BNST WAY100635
VCT Anxiolytic
Granjeiro et a l. [73] WR Intracisternal 15, 30, and 60 nmol, acute RS Anxiolytic, ↓Pressor ↓Tachycardia NA
EPM 24 h after RS Anxiolytic
Deiana et al. [74] SM i.p.
Oral
120 mg/kg, acute MBT Anticompulsive NA
Uribe-Marino et al. [75] SM i.p. 0.3, 3.0, 30.0 mg/kg, acute PS Panicolytic NA
Stern et al. [76] WR i.p. 3, 10, 30 mg/kg
immediately after retrieval, acute
Reconsolidation blockade Anxiolytic
1 and 7 d old fear memories disrupted
Effect ↓ by AM251 but not WAY100635
Campos et al. [77] WR i.p. 5 mg/kg, subchronic, daily/7 d EPM following PS Anxiolytic Effects ↓ by IP WAY100635
Hsiao et al. [78] WR CeA 1 μg/μl REM sleep time ↓ REM sleep suppression NA
EPM Anxiolytic
OF Anxiolytic
Gomes et al. [79] WR BNST 15, 30, 60 nmol, acute CFC Anxiolytic Both effects ↓ by intra-BNST WAY100635
El Batsh et al. [80] LE-H R i.p. 10 mg/kg, chronic,
daily/14 d
CFC Anxiogenic NA
Campos et al. [81] C57BL/6 mice i.p. 30 mg/kg 2 h after CUS,
chronic daily/14 d
EPM Anxiolytic Both effects ↓ by AM251
NSF Anxiolytic
Do Monte et al. [82] L-E HR IL 1 μg or 0.4 μg/0.2 μl 5 min before extinction daily/4 d Extinction of CFC Anxiolytic Effect ↓ by IP rimonabant
Campos et al. [83] Rat i.p. 5 mg/kg, chronic, daily/21 d ETM Anxiolytic
Panicolytic
Panicolytic effect ↓ by intra-dlPAG WAY100635
Almeida et al. [84] Rat i.p. 1, 5, 15 mg/kg, acute SI Anxiolytic NA
Gomes et al. [85] WR BNST 30 and 60 nmol, acute RS Anxiogenic
↑ Tachydardia
Effect ↓ by WAY100635
Twardowschy et al. [86] SM i.p. 3 mg/kg, acute PS Panicolytic Effects ↓ by IP WAY100635
Focaga et al. [87] WR PL 15, 30, 60 nmol, acute EPM Anxiogenic All effects ↓ by intra PL WAY100635
Anxiolytic EPM effect post-RS ↓ by IP metyrapone
EPM after RS Anxiolytic
CFC Anxiolytic
Nardo et al. [88] SM i.p. 30 mg/kg, acute MBT Anticompulsive NA
da Silva et al. [89] WR SNpr 5 μg/0.2 μl GABAA blockade in dlSC Panicolytic Both effects ↓ by AM251

Effective doses are in bold

Receptor specific agents: AM251 = cannabinoid receptor type 1 (CB1R) inverse agonist; WAY100635 = 5-hydroxytryptamine 1A antagonist; SR141716A = CB1R antagonist; rimonabant = CB1R antagonist; capsazepine = transient receptor potential vanilloid type 1 antagonist; naloxone = opioid antagonist; flumazenil = GABAA receptor antagonist

Anxiolytic effects in models used: CER = reduced fear response; CFC = reduced conditioned freezing; CFC extinction = reduced freezing following extinction training; EPM = reduced % time in open arm; ETM = decreased inhibitory avoidance; L-DT = increased % time in light; VCT = increased licks indicating reduced conflict; NSF = reduced latency to feed; OF = increased % time in center; SI = increased social interaction

Anticomplusive effects: MBT = reduced burying

Panicolytic effects: ETM = decreased escape; GABAA blockade in dlSC = defensive immobility, and explosive escape; PAG-E-Stim = increased threshold for escape; PS = reduced explosive escape

WR = Wistar rats; SM = Swiss mice; L-E HR = Long–Evans hooded rats; i.p. = intraperitoneal; dlPAG = dorsolateral periaqueductal gray; i.c.v. = intracerebroventricular; PL = prelimbic; IL = infralimbic; BNST = bed nucleus of the stria terminalis; CeA = amygdala central nucleus; SNpr = substantia nigra pars reticularis; CUS = chronic unpredictable stress; GSCT = Geller–Seifter conflict test; CER = conditioned emotional response; EPM = elevated plus maze; VCT = Vogel conflict test; CFC = contextual fear conditioning; RS = restraint stress; ETM = elevated T maze; PAG E-stim = electrical stimulation of the dlPAG; L-DT = light–dark test; SI = social interaction; OF = open field; MBT = marble-burying test; PS = predator stress; NSF = novelty suppressed feeding test; GABAA = γ-aminobutyric acid receptor A; dlSC = deep layers superior colliculus; REM = rapid eye movement; NA = not applicable

Anxiolytic effects of CBD in models of generalized anxiety have been linked to specific receptor mechanisms and brain regions. The midbrain dorsal periaqueductal gray (DPAG) is integral to anxiety, orchestrating autonomic and behavioral responses to threat [91], and DPAG stimulation in humans produces feelings of intense distress and dread [92]. Microinjection of CBD into the DPAG produced anxiolytic effects in the EPM, VGC, and ETM that were partially mediated by activation of 5-HT1ARs but not by CB1Rs [65, 68]. The bed nucleus of the stria terminalis (BNST) serves as a principal output structure of the amygdaloid complex to coordinate sustained fear responses, relevant to anxiety [93]. Anxiolytic effects of CBD in the EPM and VCT occurred upon microinjection into the BNST, where they depended on 5-HT1AR activation [79], and also upon microinjection into the central nucleus of the amygdala [78]. In the prelimbic cortex, which drives expression of fear responses via connections with the amygdala [94], CBD had more complex effects: in unstressed rats, CBD was anxiogenic in the EPM, partially via 5-HT1AR receptor activation; however, following acute restraint stress, CBD was anxiolytic [87]. Finally, the anxiolytic effects of systemic CBD partially depended on GABAA receptor activation in the EPM model but not in the VCT model [61, 62].

As noted, CBD has been found to have a bell-shaped response curve, with higher doses being ineffective. This may reflect activation of TRPV1 receptors at higher dose, as blockade of TRPV1 receptors in the DPAG rendered a previously ineffective high dose of CBD as anxiolytic in the EPM [66]. Given TRPV1 receptors have anxiogenic effects, this may indicate that at higher doses, CBD’s interaction with TRPV1 receptors to some extent impedes anxiolytic actions, although was notably not sufficient to produce anxiogenic effects.

Stress-induced Anxiety Models

Stress is an important contributor to anxiety disorders, and traumatic stress exposure is essential to the development of PTSD. Systemically administered CBD reduced acute increases in heart rate and blood pressure induced by restraint stress, as well as the delayed (24 h) anxiogenic effects of stress in the EPM, partially by 5-HT1AR activation [67, 73]. However intra-BNST microinjection of CBD augmented stress-induced heart rate increase, also partially via 5-HT1AR activation [85]. In a subchronic study, CBD administered daily 1 h after predator stress (a proposed model of PTSD) reduced the long-lasting anxiogenic effects of chronic predator stress, partially via 5-HT1AR activation [77]. In a chronic study, systemic CBD prevented increased anxiety produced by chronic unpredictable stress, in addition to increasing hippocampal AEA; these anxiolytic effects depended upon CB1R activation and hippocampal neurogenesis, as demonstrated by genetic ablation techniques [81]. Prior stress also appears to modulate CBD’s anxiogenic effects: microinjection of CBD into the prelimbic cortex of unstressed animals was anxiogenic in the EPM but following restraint stress was found to be anxiolytic [87]. Likewise, systemic CBD was anxiolytic in the EPM following but not prior to stress [65].

PD and Compulsive Behavior Models

CBD inhibited escape responses in the ETM and increased DPAG escape electrical threshold [68], both proposed models of panic attacks [95]. These effects partially depended on 5-HT1AR activation but were not affected by CB1R blockade. CBD was also panicolytic in the predator–prey model, which assesses explosive escape and defensive immobility in response to a boa constrictor snake, also partially via 5-HT1AR activation; however, more consistent with an anxiogenic effect, CBD was also noted to decrease time spent outside the burrow and increase defensive attention (not shown in Table ​ Table1) 1 ) [75, 86] . Finally, CBD, partially via CB1Rs, decreased defensive immobility and explosive escape caused by bicuculline-induced neuronal activation in the superior colliculus [89]. Anticompulsive effects of CBD were investigated in marble-burying behavior, conceptualized to model OCD [96]. Acute systemic CBD reduced marble-burying behavior for up to 7 days, with no attenuation in effect up to high (120 mg/kg) doses, and effect shown to depend on CB1Rs but not 5-HT1ARs [71, 74, 88].

Contextual Fear Conditioning, Fear Extinction, and Reconsolidation Blockade

Several studies assessed CBD using contextual fear conditioning. Briefly, this paradigm involves pairing a neutral context, the conditioned stimulus (CS), with an aversive unconditioned stimulus (US), a mild foot shock. After repeated pairings, the subject learns that the CS predicts the US, and subsequent CS presentation elicits freezing and other physiological responses. Systemic administration of CBD prior to CS re-exposure reduced conditioned cardiovascular responses [63], an effect reproduced by microinjection of CBD into the BNST, and partially mediated by 5-HT1AR activation [79]. Similarly, CBD in the prelimbic cortex reduced conditioned freezing [70], an effect prevented by 5-HT1AR blockade [87]. By contrast, CBD microinjection in the infralimbic cortex enhanced conditioned freezing [70]. Finally, El Batsh et al. [80] reported that repeated CBD doses over 21 days, that is chronic as opposed to acute treatment, facilitated conditioned freezing. In this study, CBD was administered prior to conditioning rather than prior to re-exposure as in acute studies, thus further directly comparable studies are required.

CBD has also been shown to enhance extinction of contextually conditioned fear responses. Extinction training involves repeated CS exposure in the absence of the US, leading to the formation of a new memory that inhibits fear responses and a decline in freezing over subsequent training sessions. Systemic CBD administration immediately before training markedly enhanced extinction, and this effect depended on CB1R activation, without involvement of TRPV1 receptors [65]. Further studies showed CB1Rs in the infralimbic cortex may be involved in this effect [82].

CBD also blocked reconsolidation of aversive memories in rat [76]. Briefly, fear memories, when reactivated by re-exposure (retrieval), enter into a labile state in which the memory trace may either be reconsolidated or extinguished [97], and this process may be pharmacologically modulated to achieve reconsolidation blockade or extinction. When administered immediately following retrieval, CBD prevented freezing to the conditioned context upon further re-exposure, and no reinstatement or spontaneous recovery was observed over 3 weeks, consistent with reconsolidation blockade rather than extinction [76]. This effect depended on CB1R activation but not 5-HT1AR activation [76].

Summary and Clinical Relevance

Overall, existing preclinical evidence strongly supports the potential of CBD as a treatment for anxiety disorders. CBD exhibits a broad range of actions, relevant to multiple symptom domains, including anxiolytic, panicolytic, and anticompulsive actions, as well as a decrease in autonomic arousal, a decrease in conditioned fear expression, enhancement of fear extinction, reconsolidation blockade, and prevention of the long-term anxiogenic effects of stress. Activation of 5-HT1ARs appears to mediate anxiolytic and panicolytic effects, in addition to reducing conditioned fear expression, although CB1R activation may play a limited role. By contrast, CB1R activation appears to mediate CBD’s anticompulsive effects, enhancement of fear extinction, reconsolidation blockade, and capacity to prevent the long-term anxiogenic consequences of stress, with involvement of hippocampal neurogenesis.

While CBD predominantly has acute anxiolytic effects, some species discrepancies are apparent. In addition, effects may be contingent on prior stress and vary according to brain region. A notable contrast between CBD and other agents that target the eCB system, including THC, direct CB1R agonists and FAAH inhibitors, is a lack of anxiogenic effects at a higher dose. Further receptor-specific studies may elucidate the receptor specific basis of this distinct dose response profile. Further studies are also required to establish the efficacy of CBD when administered in chronic dosing, as relatively few relevant studies exist, with mixed results, including both anxiolytic and anxiogenic outcomes.

Overall, preclinical evidence supports systemic CBD as an acute treatment of GAD, SAD, PD, OCD, and PTSD, and suggests that CBD has the advantage of not producing anxiogenic effects at higher dose, as distinct from other agents that enhance CB1R activation. In particular, results show potential for the treatment of multiple PTSD symptom domains, including reducing arousal and avoidance, preventing the long-term adverse effects of stress, as well as enhancing the extinction and blocking the reconsolidation of persistent fear memories.

Human Experimental and Clinical Studies

Evidence from Acute Psychological Studies

Relevant studies are summarized in Table ​ Table2. 2 . The anxiolytic effects of CBD in humans were first demonstrated in the context of reversing the anxiogenic effects of THC. CBD reduced THC-induced anxiety when administered simultaneously with this agent, but had no effect on baseline anxiety when administered alone [99, 100]. Further studies using higher doses supported a lack of anxiolytic effects at baseline [101, 107]. By contrast, CBD potently reduces experimentally induced anxiety or fear. CBD reduced anxiety associated with a simulated public speaking test in healthy subjects, and in subjects with SAD, showing a comparable efficacy to ipsapirone (a 5-HT1AR agonist) or diazepam [98, 105]. CBD also reduced the presumed anticipatory anxiety associated with undergoing a single-photon emission computed tomography (SPECT) imaging procedure, in both healthy and SAD subjects [102, 104]. Finally, CBD enhanced extinction of fear memories in healthy volunteers: specifically, inhaled CBD administered prior to or after extinction training in a contextual fear conditioning paradigm led to a trend-level enhancement in the reduction of skin conductance response during reinstatement, and a significant reduction in expectancy (of shock) ratings during reinstatement [106].

Table 2

Human psychological studies

Study Subjects,
design
CBD route,
dose
Measure Effect
Karniol et al. [99] HV,
DBP
Oral, 15, 30, 60 mg, alone or with THC,
acute, at 55, 95, 155, and 185 min
Anxiety and pulse rate after THC and at baseline ↓ THC-induced increases in subjective anxiety and pulse rate
No effect at baseline
Zuardi et al., [100] HV,
DBP
Oral 1 mg/kg alone or with THC, acute, 80 min STAI score after THC ↓ THC-induced increases in STAI scores
Zuardi et al. [98] HV,
DBP
Oral 300 mg,
acute, 80 min
VAMS, STAI and BP following SPST ↓ STAI scores
↓ VAMS scores
↓ BP
Martin-Santos et al. [101] HV,
DBP
Oral 600 mg,
acute, 1, 2, 3 h
Baseline anxiety and pulse rate No effect
Crippa et al. [102] 10 HV,
DBP
Oral 400 mg,
acute, 60 and 75 min
VAMS before SPECT
SPECT
↓ VAMS scores
Bhattacharyya et al. [103] 15 HV
DBP
Oral 600 mg,
acute, 1, 2, 3 h
STAI scores
VAMS scores
↓ STAI scores
↓ VAMS scores
Crippa et al. [104] SAD and HC
DBP
Oral 400 mg,
acute, 75 and 140 min
VAMS before SPECT
SPECT
↓ VAMS scores
Bergamaschi et al. [105] SAD and HC DBP Oral 600 mg, acute, 1, 2, 3 h VAMS, SSPS-N, cognitive impairment, SCR, HR after SPST ↓ VAMS, SSPS-N and cognitive impairment, no effect on SCR or HR
Das et al. [106] HV
DBP
Inhaled, 32 mg, acute, immediately following, before, after extinction SCR and shock expectancy following extinction CBD after extinction training produced trend level reduction in SCR and decreased shock expectancy
Hindocha et al. [107] Varying in schizotypy and cannabis use, DBP Inhaled, 16 mg, acute Baseline VAS anxiety No significant effect of CBD

HV = healthy volunteers; DBP = double-blind placebo; SAD = social anxiety disorder; HC = healthy controls; THC = Δ 9-tetrahydrocannabinol; STAI = Spielberger’s state trait anxiety inventory; VAMS = visual analog mood scale; BP = blood pressure; SPST = simulated public speaking test; SCR = skin conductance response; SPECT = single-photon emission computed tomography; SSPS-N = negative self-evaluation subscale; HR = heart rate; VAS = visual analog scale, CBD = cannabidiol

Evidence from Neuroimaging Studies

Relevant studies are summarized in Table ​ Table3. 3 . In a SPECT study of resting cerebral blood flow (rCBF) in normal subjects, CBD reduced rCBF in left medial temporal areas, including the amygdala and hippocampus, as well as the hypothalamus and left posterior cingulate gyrus, but increased rCBF in the left parahippocampal gyrus. These rCBF changes were not correlated with anxiolytic effects [102]. In a SPECT study, by the same authors, in patients with SAD, CBD reduced rCBF in overlapping, but distinct, limbic and paralimbic areas; again, with no correlations to anxiolytic effects [104].

Table 3

Study Subjects, design CBD route, dose, timing Measure Effect of CBD
Crippa et al. [102] 10 HV,
DBP
Oral 400 mg,
acute, 60 and 75 min
SPECT, resting (rCBF) ↓ rCBF in left medial temporal cluster, including amygdala and HPC, also ↓ rCBF in the HYP and posterior cingulate gyrus
↑ rCBF in left PHG
Borgwardt et al. [108] 15 HV,
DBP
Oral 600 mg,
acute, 1–2 h
fMRI during oddball and go/no-go task ↓ Activation in left insula, STG and MTG
Fusar-Poli et al. [109] 15 HV,
DBP
Oral 600 mg,
acute, 1–2 h
fMRI activation during fearful faces task ↓ Activation in left medial temporal region, including amygdala and anterior PHG, and in right ACC and PCC
Fusar-Poli et al. [110] 15 HV,
DBP
Oral 600 mg,
acute, 1–2 h
fMRI functional connectivity during fearful faces task ↓ Functional connectivity between L) AMY and ACC
Crippa et al. [104] SAD and HC
DBP
Oral 400 mg,
acute, 75 and 140 min
SPECT, resting (rCBF) ↓ rCBF in the left PHG, HPC and ITG.
↑ rCBF in the right posterior cingulate gyrus

CBD = cannabidiol; HV = healthy controls; DBP = double-blind placebo; SAD = social anxiety disorder; HC = healthy controls; SPECT = single-photo emission computed tomography; rCBF = regional cerebral blood flow; fMRI = functional magnetic resonance imaging; HPC = hippocampus; HYP = hypothalamus; PHG = parahippocampal gyrus; STG = superior temporal gyrus; MTG = medial temporal gyrus; ACC = anterior cingulate cortex; PCC = posterior cingulate cortex

In a series of placebo-controlled studies involving 15 healthy volunteers, Fusar-Poli et al. investigated the effects of CBD and THC on task-related blood-oxygen-level dependent functional magnetic resonance imaging activation, specifically the go/no-go and fearful faces tasks [109, 110]. The go/no-go task measures response inhibition, and is associated with activation of medial prefrontal, dorsolateral prefrontal, and parietal areas [111]. Response activation is diminished in PTSD and other anxiety disorders, and increased activation predicts response to treatment [112]. CBD produced no changes in predicted areas (relative to placebo) but reduced activation in the left insula, superior temporal gyrus, and transverse temporal gyrus. The fearful faces task activates the amygdala, and other medial temporal areas involved in emotion processing, and heightened amygdala response activation has been reported in anxiety disorders, including GAD and PTSD [113, 114]. CBD attenuated blood-oxygen-level dependent activation in the left amygdala, and the anterior and posterior cingulate cortex in response to intensely fearful faces, and also reduced amplitude in skin conductance fluctuation, which was highly correlated with amygdala activation [109]. Dynamic causal modeling analysis in this data set further showed CBD reduced forward functional connectivity between the amygdala and anterior cingulate cortex [110].

Evidence from Epidemiological and Chronic Studies

Epidemiological studies of various neuropsychiatric disorders indicate that a higher CBD content in chronically consumed cannabis may protect against adverse effects of THC, including psychotic symptoms, drug cravings, memory loss, and hippocampal gray matter loss [115–118] (reviewed in [119]). As THC acutely induces anxiety, this pattern may also be evident for chronic anxiety symptoms. Two studies were identified, including an uncontrolled retrospective study in civilian patients with PTSD patients [120], and a case study in a patient with severe sexual abuse-related PTSD [121], which showed that chronic cannabis use significantly reduces PTSD symptoms; however, these studies did not include data on the THC:CBD ratio. Thus, overall, no outcome data are currently available regarding the chronic effects of CBD in the treatment of anxiety symptoms, nor do any data exist regarding the potential protective effects of CBD on anxiety potentially induced by chronic THC use.

Summary and Clinical Relevance

Evidence from human studies strongly supports the potential for CBD as a treatment for anxiety disorders: at oral doses ranging from 300 to 600 mg, CBD reduces experimentally induced anxiety in healthy controls, without affecting baseline anxiety levels, and reduces anxiety in patients with SAD. Limited results in healthy subjects also support the efficacy of CBD in acutely enhancing fear extinction, suggesting potential for the treatment of PTSD, or for enhancing cognitive behavioral therapy. Neuroimaging findings provide evidence of neurobiological targets that may underlie CBD’s anxiolytic effects, including reduced amygdala activation and altered medial prefrontal amygdala connectivity, although current findings are limited by small sample sizes, and a lack of independent replication. Further studies are also required to establish whether chronic, in addition to acute CBD dosing is anxiolytic in human. Also, clinical findings are currently limited to SAD, whereas preclinical evidence suggests CBD’s potential to treat multiple symptom domains relevant to GAD, PD, and, particularly, PTSD.

Conclusions

Preclinical evidence conclusively demonstrates CBD’s efficacy in reducing anxiety behaviors relevant to multiple disorders, including PTSD, GAD, PD, OCD, and SAD, with a notable lack of anxiogenic effects. CBD’s anxiolytic actions appear to depend upon CB1Rs and 5-HT1ARs in several brain regions; however, investigation of additional receptor actions may reveal further mechanisms. Human experimental findings support preclinical findings, and also suggest a lack of anxiogenic effects, minimal sedative effects, and an excellent safety profile. Current preclinical and human findings mostly involve acute CBD dosing in healthy subjects, so further studies are required to establish whether chronic dosing of CBD has similar effects in relevant clinical populations. Overall, this review emphasizes the potential value and need for further study of CBD in the treatment of anxiety disorders.