cbd oil dose for panic attacks

Best CBD Oil for Panic Attacks

Studies looking into CBD’s potential to help regulate panic disorders is promising. We at CBD Clinicals have gathered the best CBD oils for anxiety and panic attacks on the market to help you make an informed purchase decision.

Spruce 750mg Lab Grade CBD Oil
  1. Peppermint flavor masks any unpleasant taste
  2. Contains 25mg of CBD per dropper full
  3. Bottle includes a graduated dropper for correct serving measurement

View Latest Prices

Best CBD Purity

NuLeaf Naturals 900mg Full Spectrum Hemp CBD Oil
  1. Natural remedy for various illnesses
  2. Product is full-spectrum whole-plant extract
  3. Contains naturally occurring synergistic cannabinoids and terpenes

View Latest Prices

Best High Potency

Spruce 2400mg Lab Grade CBD Oil
  1. Maximum possible potency
  2. Each dropper full contains 80mg of CBD
  3. Conveniently fits in a 30mL bottle

View Latest Prices

Avida Full Spectrum CBD Oil Tincture 500mg
  1. Proprietary full-spectrum
  2. Developed using advanced AVIDA CORE Spectrum Technology
  3. Highest naturally occurring Phyto-cannabinoids and Terpenes with THC (<0.3)

View Latest Prices

cbdMD CBD Oil Tincture Natural 1500mg
  1. Made using only CBD sourced from medical hemp
  2. Available in many flavours
  3. Safe for daily use

View Latest Prices

CBDistillery THC Free CBD Oil Tinctures
  1. Do not contain THC
  2. Available in different potencies and sizes
  3. Brand has special deals and offers

View Latest Prices

Best Customer Rated

cbdMD CBD Oil Tincture Natural 750mg
  1. THC-free
  2. Has plenty of flavours to choose from
  3. Totally vegan

View Latest Prices

Best For Beginners

NuLeaf Naturals 300mg Full Spectrum Hemp CBD Oil
  1. Lowest concentration for CBD beginners
  2. Fully organic and lab-tested
  3. Full-spectrum

View Latest Prices

Best Flavor Range

Hemp Bombs 750mg CBD Oil
  1. Has a wide range of flavours
  2. Safe to intake
  3. Get 20% off when you avail of their subscription

View Latest Prices

Best Allergy Friendly

Sunsoil CBD Oil Drops, Chocolate Mint Flavor
  1. Tastes great
  2. Uses hemp grown organically
  3. Laboratory tests done by a third party

View Latest Prices

Best CBD Oil for Panic Attacks 2022

    Editor’s Pick Best Organic Editor’s Pick Best Seller Best Natural Alternative Best THC-Free Best Customer Rated Best Starter Best Flavor Range Best Allergy Friendly

Compare the Best CBD Oil for Panic Attacks in 2021

Best CBD Oil for Panic Attacks

1. Spruce 750mg Lab Grade CBD Oil
cbdc overall score
CBDC Evaluation Table/Score
Overview

Each bottle of the 750mg CBD oil tincture contains 25mg of CBD per dropper full. The oil is peppermint flavor to mask any unpleasant tastes related to CBD.

2. NuLeaf Naturals 900mg Full Spectrum Hemp CBD Oil
cbdc overall score
CBDC Evaluation Table/Score
Overview

Natural remedy for various illnesses. NuLeaf Naturals’ CBD oil is a whole-plant extract containing a full spectrum of naturally occurring synergistic cannabinoids and terpenes.

3. Spruce 2400mg Lab Grade CBD Oil
cbdc overall score
CBDC Evaluation Table/Score
Overview

The largest bottle of CBD oil that Spruce offers contains 2,400mg of CBD. This is full-spectrum CBD oil, which is the maximum possible potency. Each high potency dropper full contains 80mg of CBD. There are no flavorings in it, which allows for the most CBD to fit in the 30ml bottle.

4. Avida Full Spectrum CBD Oil Tincture 500mg
cbdc overall score
CBDC Evaluation Table/Score
Overview

Avida Extracts Full Spectrum CBD oil is the latest iteration of the brand’s advanced Avida CORE Spectrum technology. They use a proprietary full spectrum blend, resulting in the highest naturally occurring Phyto-cannabinoids and Terpenes with THC (<0.3) to support your health.

5. cbdMD CBD Oil Tincture Natural 1500mg
cbdc overall score
CBDC Evaluation Table/Score
Overview

cbdMD’s CBD oil tinctures are made using only CBD sourced from medical hemp and MCT oil as a carrier oil. Tinctures are offered in orange, mint, natural, and berry flavors. Safe for daily use, the oil tinctures are packaged with a built-in rubber dropper to adjust CBD dosage easily. The packaging is made to be easy to transport and discreet to use.

6. CBDistillery THC Free CBD Oil Tinctures
cbdc overall score
CBDC Evaluation Table/Score
Overview

CBDistillery’s Isolate CBD Oil Tinctures harness the power of pure CBD. CBD Isolate Oil Tinctures include 0.0% THC. When you use CBDistillery CBD Isolate Oil Tinctures, you can be assured you’re using the highest quality CBD on the market.

7. NuLeaf Naturals 300mg Full Spectrum Hemp CBD Oil
cbdc overall score
CBDC Evaluation Table/Score
Overview

This is one of several concentrations from NuLeaf Naturals. As the lowest concentration, it is the company’s best option for those new to CBD oil. The product is lab-tested and fully organic. It is full-spectrum, so it contains THC in small quantities.

8. cbdMD CBD Oil Tincture Natural 750mg
cbdc overall score
CBDC Evaluation Table/Score
Overview

A 750mg bottle of cbdMD’s Broad Spectrum Oil Tincture does not contain THC. It also has a fairly wide flavor range which is perfect for those who prefer other taste. Vegan consumers are considered since cbdMD offers Vegan products. Aside from all of that, another reason why people love cbdMD is because it’s free from harmful chemicals.

9. Hemp Bombs 750mg CBD Oil
cbdc overall score
CBDC Evaluation Table/Score
Overview

Hemp Bombs offer CBD Oil Tinctures that come in a 30ml bottle containing 750mg of CBD. They provide a wide range of flavors perfect for those that have a knack for sweets. Consumers can safely intake this because it’s free of chemicals and pesticides. Hemp Bombs also offer a 20% off on products upon subscription.

10. Sunsoil CBD Oil Drops, Chocolate Mint Flavor
cbdc overall score
CBDC Evaluation Table/Score
Overview

The flavor profile is refreshingly sweet, and it balances well with the higher CBD concentration. Promotes the absorption of CBD into your blood circulation.

How We Rank
Our Ratings

How CBD Works to Help With Panic Attacks

CBD interacts with the endocannabinoid system (ECS). The ECS is a unique system that maintains our body’s homeostasis or biological balance in response to environmental changes (1) .

The ECS regulates physiological function, including mood, cognition, and chronic pain perception. Experts believe that the system can modulate these functions through its cannabinoid receptors (2) .

Studies suggest that cannabidiol (CBD) activates the 5-HT1A serotonin receptors in several brain regions (3) . This particular type of receptor contributes to the action mechanism of antidepressant and anti-anxiety drugs (4) .

In addition to serotonin chemical structures, CBD engages the CB1 and CB2 cannabinoid receptors of the ECS (5) . Both receptors are linked to the ECS’s involvement in neuropsychiatric disorders, particularly depression and anxiety (6) .

CB1 and CB2 are the primary types of receptors found in specific parts of the human body. These receptors have unique roles in the ECS.

The brain and the central nervous system contain most CB1 receptors . However, they are also located in the reproductive organs, liver, lungs, retina, and gastrointestinal and urinary tracts (7) .

CB1 receptors affect memory processing, appetite, motor regulation, pain sensation, sleep, and mood (8) .

The activation of CB1 receptors is linked to neuroprotective responses, suggesting that cannabinoids with a higher affinity for CB1 receptors may help with neurodegenerative conditions.

Neurodegenerative diseases are effects of miscommunications between brain cells, resulting in neuron death. Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis are among these neurodegenerative conditions.

Meanwhile, cells in the immune system and associated structures are the primary locations for CB2 receptors .

Triggering CB2 receptors stimulates a response that reduces pain, fights inflammation, and minimizes tissue damage.

These anti-inflammatory responses may help treat conditions linked to inflammation, including chronic inflammatory demyelinating polyneuropathy (CIDP), arthritis, Crohn’s disease, and inflammatory bowel syndrome (9) .

Researchers suggest that CBD’s purported anti-panic effects result from its interaction with various receptors in the body (10) .

How to Use CBD for Panic Attacks

You may take CBD for panic attacks in the form of edibles or capsules. These consumable forms may include CBD gummies , CBD brownies, and CBD tablets. This method of consuming CBD is more straightforward than other methods.

Another way to administer CBD is the sublingual method, suitable for a more controlled CBD intake. With this option, you would take the calibrated dropper included in CBD tincture products and apply a few drops of CBD oil under your tongue.

Leave the oil under your tongue for about 90 seconds before swallowing. This holding period allows your mucous membranes to absorb the tincture , so you feel CBD’s supposed anti-anxiety properties.

Some CBD companies sell CBD topical products, such as balms, salves, creams, and lotions. You may include CBD topicals in massage therapies for relaxation to improve therapeutic massage effectiveness for generalized anxiety disorder (GAD) (11) .

Meanwhile, you may prefer to inhale CBD through flavored or unflavored vaping products. This method i s an ideal option to avoid the natural, earthy flavor of pure CBD oil and choose peppermint or fruity flavors.

Vaping also gets CBD in your system quickly through your lungs. However, note that CBD vapes may worsen lung disorders (12) .

Thus, when using CBD for panic attacks for the first time , be sure to seek medical advice from a licensed physician. When buying CBD products, we recommend getting advice from a doctor with significant experience in CBD and cannabis product usage.

How Soon Does It Take to Feel CBD’s Effects for Panic Attacks ?

The time it takes for CBD to relieve panic attacks may depend on how the CBD product is used.

Taking CBD by Mouth

When you take CBD orally, you might ingest it in the form of food, drink, capsules, or gummies. These are straightforward ways to take CBD oil, especially if you are a beginner.

You can absorb CBD directly into your bloodstream by holding the liquid from a spray or tincture sublingually for 60 to 120 seconds.

You may find CBD oil’s natural flavor unpleasant through sublingual administration. However, you will be able to feel the effects of CBD within 15 to 45 minutes, which may last for 4 to 6 hours (13) .

If you prefer quick results and maximum dosage control, consider CBD oil tinctures or drops as your practical option.

Topical CBD Application

CBD topicals , such as CBD creams and CBD transdermal patches, work instantly after rubbing the product onto your skin.

You can also apply topical CBD oil alone or combine the product with cream or lotion (14) . If you combine CBD topicals with massage therapy, you can ideally feel relief in about 15 minutes (15) .

When you apply CBD topically, the CBD can avoid interacting with the ECS as a whole. Instead, it targets localized clusters of cannabinoid receptors .

However, determining whether the relieving properties of a CBD topical product comes from CBD or another ingredient is difficult. Topical products might include other common over-the-counter ingredients, such as camphor, menthol, or capsaicin.

Inhaling CBD

When using a vape pen to inhale CBD vape juices, you will feel its anti-anxiety effects within minutes, which will keep you steady between three to five hours after inhalation (16) .

However, the precise amount of CBD you get in each draw of CBD vapes is challenging to determine.

Still, inhaling CBD vapors may be the quickest way to get CBD into your body. CBD does not go through your digestive system since you allow CBD to enter your bloodstream through your lungs.

However, a 2018 study published in Molecules indicated the primary limitations of inhaling: the variability in your inhalation techniques and respiratory tract irritation upon inhalation (17) .

You must also consider the potential adverse effects of vaping, including chemical irritation or immune or allergic reactions to various chemicals or other foreign substances in the vapors you inhale (18) .

How to Choose CBD for Panic Attacks

CBD is not approved as a supplement for treating panic disorders , according to the United States Food and Drug Administration ( FDA ) (19) .

Still, you may choose from the three forms of CBD currently available on the market: full-spectrum CBD, broad-spectrum CBD , and CBD isolates .

Full-spectrum CBD oil contains all of the natural compounds present in Cannabis sativa plants, from terpenes and flavonoids to cannabinoids, including tetrahydrocannabinol (THC).

Quality full-spectrum hemp extract contains a high cannabidiol content and only low amounts of the other compounds.

CBD oil that contains all of cannabis’ naturally occurring chemical compounds produce the “ entourage effect .” This process involves combining all the components of cannabis plants to have synergistic effects in aiding anxiety disorders and mood disorders (20) .

To obtain full-spectrum CBD, manufacturers make industrial hemp plants undergo extraction methods , such as steam distillation, CO 2 extraction , or alcohol extraction. Manufacturers then mix the pure hemp oil with a carrier oil , such as hempseed oil or MCT oil .

Like full-spectrum CBD, the broad-spectrum CBD variant contains almost the same phytocannabinoids of full-spectrum products, except THC-free .

You may prefer broad-spectrum CBD over full-spectrum as the former does not contain the psychoactive THC compound.

Meanwhile, CBD isolate is the purest type of CBD on the market, which brands usually sell in crystalline or powdered form.

To obtain CBD isolate products, manufacturers remove all other hemp plants ’ compounds during the extraction process , leaving only pure CBD .

  • Look for the CBD product ’s certificate of analysis (COA) or third-party lab results . This document indicates that the item you selected has undergone thorough lab testing .
  • Ensure that the COA confirms the absence of pesticides , chemical additives , heavy metals, residual solvents , and other harmful contaminants .
  • Confirm whether the CBD product you plan to buy is derived from organic hemp . High-quality CBD products from organic hemp ensure that the amounts of THC are within the federal limit of less than 0.3%.
  • Look up the CBD legalities within your home state and the brand’s manufacturing location. Some of the reputable CBD brands source their high potency CBD hemp from farms in Colorado , Kentucky, Oregon, and North Carolina.
  • Consult your family health care professional before deciding to use CBD for alleviating panic disorder symptoms . We recommend consulting a medical practitioner with significant experience in medical cannabis and CBD usage.
  • Avoid purchasing CBD products from companies that claim to sell CBD derived from the seeds and stalks of hemp plants . Non-GMO industrial hemp stalks have very little CBD content, while its seeds have no cannabidiol .
  • Choose a CBD shop that offers a money-back guarantee for its products to ensure your satisfaction.

How Much CBD Should I Take for Panic Attacks ?

There is no official guide that details the proper CBD dosage for panic attacks because the FDA has not approved CBD for panic disorders .

However, you may consider the common factors in determining the correct dosage for an individual, including the results you desire from the product, amount or mg of CBD in the product, and your body weight.

A 2017 report published by the World Health Organization mentioned that researchers analyzed a study where human subjects received up to 600mg CBD . They noted that the participants did not experience any adverse reactions after taking CBD, despite the high dose (21) .

Another study reported that the chronic use of CBD oil, reaching as high as 1,500 mg a day , is safe for humans (22) . This study involved an even higher dose of CBD intake and has recorded no harmful side effects among its participants.

Meanwhile, in a 2016 study published in The Permanente Journal , researchers noted that CBD supplements given in 12 mg to 25 mg doses once a day appears to relieve anxiety and sleep problems with minor side effects (23) .

However, the researchers clarify that they do not have a foundation to suggest proper doses of CBD based on their existing data.

The subject of the 2016 study did not report any complaints or discomfort upon using CBD. Still, despite CBD’s purported safeness (24) , further large-scale prospective studies are necessary to develop a generalized CBD dosing for those with panic attacks .

Benefits of Using CBD for Panic Attacks

You may attribute CBD’s potential to help with panic attacks to its anxiolytic (anti-anxiety) properties (25) .

In 2015, the journal Neurotherapeutics published a study that presented CBD as a potential treatment for neuropsychiatric conditions, including panic disorder (26) .

Researchers noted that a systemic CBD administration conducted in animal model studies helped reduce rapid heart rate and blood pressure . The researchers also observed a decrease in the anxiety-inducing effects of stress among the subjects (27) .

Furthermore, the authors supported CBD’s potential as a treatment for anxiety disorders based on its anti-anxiety and panicolytic (anti-panic) actions.

The results in both human and animal studies support the concept that cannabidiol exhibits anti-panic properties. However, more longitudinal research needs to link CBD to panic disorders to validate health claims.

See also  what to look for with cbd oil vitamin shop

Risks of Using CBD for Panic Attacks

Despite the promising results from existing studies, there is minimal evidence that supports claims highlighting CBD as a viable treatment for panic attacks or any debilitating conditions.

Although the World Health Organization (WHO) says that CBD is “generally well-tolerated with a good safety profile (28) ,” the FDA still does not approve the marketing of CBD oil as dietary supplements or medicine for any condition (29) .

The FDA ensures the safety of human and animal drugs to protect public health (30) . The agency has approved Epidiolex as a CBD treatment for children with seizures associated with Dravet syndrome or Lennox-Gastaut syndrome, two rare forms of epilepsy.

With significant scientific evidence, Epidiolex is the first and only FDA-approved narcotic derived from marijuana plants (31) .

However, note that using CBD for panic attacks may induce side effects , including fatigue, diarrhea, nausea, drowsiness, and appetite changes (32) .

CBD also has the risk of interacting with certain medications or supplements that you may already be taking (33) .

Legality of CBD

There are currently only 47 out of the 50 states in the USA where you can use CBD legally on a federal level . Each state has varying degrees of regulation for using CBD (34) .

If you plan to travel with CBD, you may only do so between states that share similar CBD restrictions.

You would typically associate CBD’s legality in the US with the 2018 Farm Bill or the Agriculture Improvement Act of 2018 (35) . This law differentiated hemp plants from marijuana plants by redefining hemp as cannabis with less than 0.3% THC on a dry weight basis.

Marijuana plants are cannabis plants with more than the established limit. Cannabis sativa plants may come in hemp and marijuana varieties.

With hemp plants ’ declassification as marijuana plants, the 1970 Federal Controlled Substances Act no longer covers them in its Schedule I category (36) .

Before Congress passed the 2018 Farm Bill, both industrial hemp and marijuana plants were Schedule I drugs. Schedule I drugs consist of potentially abusive or addictive substances without any officially recognized health benefits .

Apart from hemp plants ’ redefinition based on their THC content, the 2018 Farm Bill granted FDA the authority to regulate CBD’s circulation on the market ( 37) . The agency penalizes CBD companies that use CBD’s unproven health benefits to sell CBD products .

Cannabis plants have many components, from terpenes , fatty acids, flavonoids, and cannabinoids . CBD and THC are present in both hemp and marijuana plants because they are the most abundant cannabinoids in cannabis plants .

The psychoactive properties of THC make people experience “getting high.” This euphoric effect is a critical factor in the legality of CBD products .

CBD oil with the federally legal limit of 0.3% THC by dry weight does not produce euphoria, yet you can still benefit from cannabis plants ’ purported benefits.

Although the 2018 Farm Bill relaxed the legal restrictions of producing, manufacturing, and owning hemp-derived CBD products , state laws are the primary authority in drug-related offenses, meaning local laws may supersede the federal law (38) .

Product Frequently
Asked Questions

Cannabidiol interacts with the endocannabinoid system , which maintains biological balance in the body (39) . Research suggests that CBD oil activates several receptors to bring about its potential to stop symptoms of anxiety and panic attacks (40) .

The time it takes for CBD to take effect varies on the method of administration. For example, inhaling CBD vapors may help you immediately feel CBD’s anti-anxiety properties (41) .

The journal Neurotherapeutics published a study in 2015, which supported CBD as a potential treatment for neuropsychiatric medical conditions , including panic disorder (42) .

Existing research linking CBD to anxiety and panic treatments shows no complaints from subjects who participated in a clinical trial assessing CBD oil’s effectiveness for pediatric anxiety and insomnia related to post-traumatic stress disorder (43) .

Still, drug interactions remain a possibility with CBD products and other medications (44) .

Cannabidiol may alter the way a drug works, leading to adverse reactions (45) . This possibility puts people who take panic attack or anxiety medications at risk of experiencing drug interactions when consuming CBD.

Professionals at the National Institute of Mental Health recommend either psychotherapy or prescription medications as a conventional treatment for patients with social anxiety disorders (46) . If you intend to include CBD with any of these treatments, be sure to consult with your medical practitioner first.

Cannabidiol does not show up on a drug test, unlike THC . If you take CBD for panic attacks , consider the best CBD oils for anxiety panic attacks from brands we have collected here.

H igh-quality products contain THC within the 0.3% limit. However, the volume of THC you consume may accumulate with frequent use.

Accumulated amounts may be detected on a drug test (47) . Thus, you should remain cautious when taking CBD products with THC , especially with a scheduled drug test.

There is no standard dosage for how much CBD you should take for panic attacks since the FDA has not approved CBD for panic disorders or different types of anxiety ( generalized anxiety disorder , public speaking anxiety).

However, a study reported that chronic use of CBD oil, reaching as high as 1,500 mg a day, is safe for humans (48) .

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.

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).

See also  cbd oil for macular pucker

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.

See also  cbd oil dosage for anxiety vape

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.

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.