Use of Cannabidiol for the Treatment of Anxiety: A Short Synthesis of Pre-Clinical and Clinical Evidence

View details for Cannabis and Cannabinoid Research cover image“Anxiety disorders have the highest lifetime prevalence of any mental illness worldwide, leading to high societal costs and economic burden. Current pharmacotherapies for anxiety disorders are associated with adverse effects and low efficacy.

Cannabidiol (CBD) is a constituent of the Cannabis plant, which has potential therapeutic properties for various indications. After the recent legalization of cannabis, CBD has drawn increased attention as a potential treatment, as the majority of existing data suggest it is safe, well tolerated, has few adverse effects, and demonstrates no potential for abuse or dependence in humans.

Pre-clinical research using animal models of innate fear and anxiety-like behaviors have found anxiolytic, antistress, anticompulsive, and panicolytic-like effects of CBD. Preliminary evidence from human trials using both healthy volunteers and individuals with social anxiety disorder, suggests that CBD may have anxiolytic effects.

Although these findings are promising, future research is warranted to determine the efficacy of CBD in other anxiety disorders, establish appropriate doses, and determine its long-term efficacy. The majority of pre-clinical and clinical research has been conducted using males only. Among individuals with anxiety disorders, the prevalence rates, symptomology, and treatment response differ between males and females. Thus, future research should focus on this area due to the lack of research in females and the knowledge gap on sex and gender differences in the effectiveness of CBD as a potential treatment for anxiety.”

https://pubmed.ncbi.nlm.nih.gov/32923656/

“Cannabidiol (CBD) is a constituent of the Cannabis plant, which has potential therapeutic properties across many neuropsychiatric disorders. Overall, existing pre-clinical and clinical evidence supports a possible role for CBD as a novel treatment for anxiety disorders.”

https://www.liebertpub.com/doi/10.1089/can.2019.0052

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The Pro-neurogenic Effects of Cannabidiol and Its Potential Therapeutic Implications in Psychiatric Disorders

Archive of "Frontiers in Behavioral Neuroscience". “During the last decades, researchers have investigated the functional relevance of adult hippocampal neurogenesis in normal brain function as well as in the pathogenesis of diverse psychiatric conditions.

Although the underlying mechanisms of newborn neuron differentiation and circuit integration have yet to be fully elucidated, considerable evidence suggests that the endocannabinoid system plays a pivotal role throughout the processes of adult neurogenesis. Thus, synthetic, and natural cannabinoid compounds targeting the endocannabinoid system have been utilized to modulate the proliferation and survival of neural progenitor cells and immature neurons.

Cannabidiol (CBD), a constituent of the Cannabis Sativa plant, interacts with the endocannabinoid system by inhibiting fatty acid amide hydrolase (FAAH) activity (the rate-limiting enzyme for anandamide hydrolysis), allosterically modulating CB1 and CB2 receptors, and activating components of the “extended endocannabinoid system.” Congruently, CBD has shown prominent pro-neurogenic effects, and, unlike Δ9-tetrahydrocannabinol, it has the advantage of being devoid of psychotomimetic effects.

Here, we first review pre-clinical studies supporting the facilitating effects of CBD on adult hippocampal neurogenesis and available data disclosing cannabinoid mechanisms by which CBD can induce neural proliferation and differentiation. We then review the respective implications for its neuroprotective, anxiolytic, anti-depressant, and anti-reward actions.

In conclusion, accumulating evidence reveals that, in rodents, adult neurogenesis is key to understand the behavioral manifestation of symptomatology related to different mental disorders. Hence, understanding how CBD promotes adult neurogenesis in rodents could shed light upon translational therapeutic strategies aimed to ameliorate psychiatric symptomatology dependent on hippocampal function in humans.”

https://pubmed.ncbi.nlm.nih.gov/32676014/

https://www.frontiersin.org/articles/10.3389/fnbeh.2020.00109/full

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Cannabidiol and Sports Performance: A Narrative Review of Relevant Evidence and Recommendations for Future Research

Sports Medicine - Open Cover Image “Cannabidiol (CBD) is a non-intoxicating cannabinoid derived from Cannabis sativa. CBD initially drew scientific interest due to its anticonvulsant properties but increasing evidence of other therapeutic effects has attracted the attention of additional clinical and non-clinical populations, including athletes.

Unlike the intoxicating cannabinoid, Δ9-tetrahydrocannabinol (Δ9-THC), CBD is no longer prohibited by the World Anti-Doping Agency and appears to be safe and well-tolerated in humans. It has also become readily available in many countries with the introduction of over-the-counter “nutraceutical” products.

The aim of this narrative review was to explore various physiological and psychological effects of CBD that may be relevant to the sport and/or exercise context and to identify key areas for future research. As direct studies of CBD and sports performance are is currently lacking, evidence for this narrative review was sourced from preclinical studies and a limited number of clinical trials in non-athlete populations.

Preclinical studies have observed robust anti-inflammatory, neuroprotective and analgesic effects of CBD in animal models. Preliminary preclinical evidence also suggests that CBD may protect against gastrointestinal damage associated with inflammation and promote healing of traumatic skeletal injuries. However, further research is required to confirm these observations.

Early stage clinical studies suggest that CBD may be anxiolytic in “stress-inducing” situations and in individuals with anxiety disorders. While some case reports indicate that CBD improves sleep, robust evidence is currently lacking. Cognitive function and thermoregulation appear to be unaffected by CBD while effects on food intake, metabolic function, cardiovascular function, and infection require further study.

CBD may exert a number of physiological, biochemical, and psychological effects with the potential to benefit athletes. However, well controlled, studies in athlete populations are required before definitive conclusions can be reached regarding the utility of CBD in supporting athletic performance.”

https://pubmed.ncbi.nlm.nih.gov/32632671/

“CBD has been reported to exert a number of physiological, biochemical, and psychological effects that have the potential to benefit athletes. For instance, there is preliminary supportive evidence for anti-inflammatory, neuroprotective, analgesic, and anxiolytic actions of CBD and the possibility it may protect against GI damage associated with inflammation and promote the healing of traumatic skeletal injuries.”

https://sportsmedicine-open.springeropen.com/articles/10.1186/s40798-020-00251-0

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Current Application of Cannabidiol (CBD) in the Management and Treatment of Neurological Disorders

SpringerLink“Cannabidiol (CBD), which is nonintoxicating pharmacologically relevant constituents of Cannabis, demonstrates several beneficial effects. It has been found to have antioxidative, anti-inflammatory, and neuroprotective effects. As the medicinal use of CBD is gaining popularity for treatment of various disorders, the recent flare-up of largely unproven and unregulated cannabis-based preparations on medical therapeutics may have its greatest impact in the field of neurology. Currently, as lot of clinical trials are underway, CBD demonstrates remarkable potential to become a supplemental therapy in various neurological conditions. It has shown promise in the treatment of neurological disorders such as anxiety, chronic pain, trigeminal neuralgia, epilepsy, and essential tremors as well as psychiatric disorders. While recent FDA-approved prescription drugs have demonstrated safety, efficacy, and consistency enough for regulatory approval in spasticity in multiple sclerosis (MS) and in Dravet and Lennox-Gastaut Syndromes (LGS), many therapeutic challenges still remain. In the current review, the authors have shed light on the application of CBD in the management and treatment of various neurological disorders.”

https://pubmed.ncbi.nlm.nih.gov/32556748/

https://link.springer.com/article/10.1007%2Fs10072-020-04514-2

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Cannabidiol Disrupts Conditioned Fear Expression and Cannabidiolic Acid Reduces Trauma-Induced Anxiety-Related Behaviour in Mice

Behavioural Pharmacology (journal) - Wikipedia“The major phytocannabinoid cannabidiol (CBD) has anxiolytic properties and lacks tetrahydrocannabinol-like psychoactivity. Cannabidiolic acid (CBDA) is the acidic precursor to CBD, and this compound appears more potent than CBD in animal models of emesis, pain and epilepsy. In this short report, we aimed to examine whether CBDA is more potent than CBD in disrupting expression of conditioned fear and generalised anxiety-related behaviour induced by Pavlovian fear conditioning. Mice underwent fear conditioning and 24 h later were administered CBD and CBDA before testing for fear expression and generalized anxiety-like behaviour. We found that CBD and CBDA had dissociable effects; while CBD but not CBDA disrupted cued fear memory expression, CBDA but not CBD normalized trauma-induced generalized anxiety-related behaviour. Neither phytocannabinoid affected contextual fear expression. Our findings form the basis for future experiments examining whether phytocannabinoids, alone and in combination, are effective in these mouse models of fear and anxiety.”

https://pubmed.ncbi.nlm.nih.gov/32483052/

https://journals.lww.com/behaviouralpharm/Abstract/9000/Cannabidiol_disrupts_conditioned_fear_expression.99176.aspx

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Effects of Chronic Cannabidiol Treatment in the Rat Chronic Unpredictable Mild Stress Model of Depression

biomolecules-logo“Several neuropharmacological actions of cannabidiol (CBD) due to the modulation of the endocannabinoid system as well as direct serotonergic and gamma-aminobutyric acidergic actions have recently been identified.

The current study aimed to reveal the effect of a long-term CBD treatment in the chronic unpredictable mild stress (CUMS) model of depression.

Adult male Wistar rats (n = 24) were exposed to various stressors on a daily basis in order to induce anhedonia and anxiety-like behaviors. CBD (10 mg/kg body weight) was administered by daily intraperitoneal injections for 28 days (n = 12). The effects of the treatment were assessed on body weight, sucrose preference, and exploratory and anxiety-related behavior in the open field (OF) and elevated plus maze (EPM) tests. Hair corticosterone was also assayed by liquid chromatography-mass spectrometry.

At the end of the experiment, CBD-treated rats showed a higher rate of body weight gain (5.94% vs. 0.67%) and sucrose preference compared to controls. A significant increase in vertical exploration and a trend of increase in distance traveled in the OF test were observed in the CBD-treated group compared to the vehicle-treated group. The EPM test did not reveal any differences between the groups. Hair corticosterone levels increased in the CBD-treated group, while they decreased in controls compared to baseline (+36.01% vs. -45.91%). In conclusion, CBD exerted a prohedonic effect in rats subjected to CUMS, demonstrated by the increased sucrose preference after three weeks of treatment.

The reversal of the effect of CUMS on hair corticosterone concentrations might also point toward an anxiolytic or antidepressant-like effect of CBD, but this needs further confirmation.”

https://pubmed.ncbi.nlm.nih.gov/32455953/

https://www.mdpi.com/2218-273X/10/5/801

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A Phase 1, Randomised, Placebo-Controlled, Dose Escalation Study to Investigate the Safety, Tolerability and Pharmacokinetics of Cannabidiol in Fed Healthy Volunteers.

SpringerLink“There is increasing interest in the use of purified cannabidiol (CBD) as a treatment for a wide range of conditions due to its reported anti-inflammatory, anxiolytic, antiemetic and anticonvulsant properties.

OBJECTIVE:

The objective of this study was to assess the safety, tolerability and pharmacokinetics of a single ascending dose of a new lipid-based oral formulation of CBD in healthy volunteers after a high-fat meal.

RESULTS:

CBD was well tolerated in the healthy volunteers (mean age: 24.0 years) treated with a single oral dose of CBD. There were no safety concerns with increasing the dose and the safety profiles of the CBD-treated and placebo-treated subjects were similar. The most frequently reported treatment emergent adverse events (TEAEs) were headache (17%) and diarrhoea (8%). There were no reported serious adverse events (SAEs) and no clinical laboratory findings, vital signs, ECGs or physical examination findings that were reported as TEAEs or were of clinical significance during the study. After a high-fat meal, CBD was detected in plasma samples at 15 min postdose; the median time to maximum plasma concentration (Tmax) was 4 h across all three CBD dose cohorts. The CBD plasma exposure [maximum observed plasma concentration (Cmax) and the area under the concentration-time curve (AUC)] increased in a dose-proportional manner and declined to levels approaching the lower level of quantification by day 8. The terminal elimination half-life was approximately 70 h, suggesting that 2-3 weeks are needed to fully eliminate CBD.

CONCLUSIONS:

This new CBD formulation demonstrated a favourable safety and tolerability profile in healthy volunteers that was consistent with the profiles reported for other purified CBD products. No severe or serious AEs were observed in this study and there were no safety concerns.”

https://www.ncbi.nlm.nih.gov/pubmed/32409982

“Cannabidiol (CBD) is a major nonpsychoactive cannabinoid derived from the Cannabis plant that has attracted significant interest due to its anti-inflammatory, anxiolytic, antiemetic and anticonvulsant properties. The findings of this study contribute to the evolving knowledge of cannabidiol pharmacokinetics and indicate that this new oral lipid-based formulation of cannabidiol is generally safe and well tolerated at all doses studied. No severe or serious AEs were observed and there were no safety concerns.”

https://link.springer.com/article/10.1007%2Fs13318-020-00624-6

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Two-weeks treatment with cannabidiol improves biophysical and behavioral deficits associated with experimental type-1 diabetes.

Neuroscience Letters“The prevalence rates of depression and anxiety are at least two times higher in diabetic patients, increasing morbidity and mortality.

Cannabidiol (CBD) has been identified as a therapeutic agent viable to treat diverse psychiatric disorders. Thus, this study aimed to investigate the effect of CBD treatment (once a day for 14 days starting two weeks after diabetes induction; at doses of 0, 3, 10 or 30 mg/kg, i.p.) on depression- and anxiety-like behaviors associated with experimental diabetes induced by streptozotocin (60 mg/kg; i.p.) in rats.

Levels of plasma insulin, blood glucose, and weight gain were evaluated in all experimental groups, including a positive control group treated with imipramine. The rats were tested in the modified forced swimming test (mFST) and elevated plus maze (EPM) test. Besides, the levels of serotonin (5-HT), noradrenaline (NA) and dopamine (DA) in two emotion-related brain regions, the prefrontal cortex (PFC) and hippocampus (HIP) were evaluated using high-pressure liquid chromatography.

Our results showed that CBD treatment (only at the higher dose of 30 mg/kg) reduced the exaggerated depressive- and anxiogenic-like behaviors of diabetic (DBT) rats, which may be associated with altered 5-HT, NA and/or DA levels observed in the PFC and HIP. Treatment with CBD (higher dose) also induced a significant increase in weight gain and the insulin levels (and consequently reduced glycemia) in DBT rats. The long-term CBD effects gave rise to novel therapeutic strategies to limit the physiological and neurobehavioral deficits in DBT rats.

This approach provided evidence that CBD can be useful for treating psychiatry comorbidities in diabetic patients.”

https://www.ncbi.nlm.nih.gov/pubmed/32360935

“Treatment of diabetic rats with cannabidiol induced antidepressant- and anxiolytic-like behaviors.”

https://www.sciencedirect.com/science/article/abs/pii/S0304394020302901?via%3Dihub

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Dosage, Efficacy and Safety of Cannabidiol Administration in Adults: A Systematic Review of Human Trials.

“Considering data from in vitro and in vivo studies, cannabidiol (CBD) seems to be a promising candidate for the treatment of both somatic and psychiatric disorders.

The aim of this review was to collect dose(s), dosage schemes, efficacy and safety reports of CBD use in adults from clinical studies.

From the controlled trials, we identified anxiolytic effects with acute CBD administration, and therapeutic effects for social anxiety disorder, psychotic disorder and substance use disorders.

There was evidence to support single dose positive effect on social anxiety disorder, short medium-term effects on symptomatic improvement in schizophrenia and lack of effect in the short medium-term on cognitive functioning in psychotic disorders.

Overall, the administration was well tolerated with mild side effects.”

https://www.ncbi.nlm.nih.gov/pubmed/32231748

https://www.jocmr.org/index.php/JOCMR/article/view/4090

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Cannabidiol in sport : ergogenic or else?

Pharmacological Research“In the sports domain, cannabis is prohibited by the World Anti-Doping Agency (WADA) across all sports in competition since 2004. The few studies on physical exercise and cannabis focused on the main compound i.e. Δ9-tetrahydrocannabinol. Cannabidiol (CBD) is another well-known phytocannabinoid present in dried or heated preparations of cannabis. Unlike Δ9-tetrahydrocannabinol, CBD is non-intoxicating but exhibits pharmacological properties that are interesting for medical use.

The worldwide regulatory status of CBD is complex and this compound is still a controlled substance in many countries. Interestingly, however, the World Anti-Doping Agency removed CBD from the list of prohibited substances – in or out of competition – since 2018. This recent decision by the WADA leaves the door open for CBD use by athletes.

In the present opinion article we wish to expose the different CBD properties discovered in preclinical studies that could be further tested in the sport domain to ascertain its utility. Preclinical studies suggest that CBD could be useful to athletes due to its anti-inflammatory, analgesic, anxiolytic, neuroprotective properties and its influence on the sleep-wake cycle. Unfortunately, almost no clinical data are available on CBD in the context of exercise, which makes its use in this context still premature.”

https://www.ncbi.nlm.nih.gov/pubmed/32205233

“Athletes could benefit from CBD to manage pain, inflammation and the swelling processes associated with injury. CBD could be useful to manage anxiety, fear memory process, sleep and sleepiness in athletes. CBD could be interesting for the management of mild traumatic brain injury and chronic traumatic encephalopathy.”

https://www.sciencedirect.com/science/article/abs/pii/S1043661819326143?via%3Dihub

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