Use of Cannabidiol for the Treatment of Anxiety : A Short Synthesis of Pre-Clinical and Clinical Evidence, Madison Wright et al., 2019

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

Madison Wright, Patricia Di Ciano, and Bruna Brands

Cannabis and Cannabinoid Research, 2019, Volume X, Number X, 1-6.

Doi : 10.1089/can.2019.0052



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.

Keywords : cannabinoids; cannabis; CBD; clinical trials; mental illness



Anxiety disorders are the most prevalent mental illnesses in the world, leading to high societal costs and
economic burden.1 Anxiety is characterized by excessive anticipation of future threats and accompanied by excessive fear, which is an emotional response to imminent threats.2 Persistent fear and anxiety lead to maladaptive behavioral disturbances and disability. Anxiety disorders are associated with panic attacks, avoidance behavior, and diminished sense of well-being, leading to troubled relationships, increased rates of unemployment, and elevated risk of suicide.3 Neuropsychiatric anxiety disorders include generalized anxiety disorder (GAD), social anxiety disorder (SAD; also known as social phobia), specific phobia, panic disorder, and agoraphobia. 2 Obsessive-compulsive disorder (OCD) and post-traumatic stress disorder (PTSD) are no longer classified as anxiety disorders in the Diagnostic and Statistical Manual of Mental Disorders-52; however, they both encompass excessive anxiety and share common symptomology with anxiety disorders.3 These disorders tend to be chronic and persistent, lasting 6 months or more, and have high comorbidity rates with other anxiety disorders and mental illnesses.2,4

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.5 These pharmacotherapies tend to have adverse effects and low efficacy (in only about 40–60% of patients),4 with the majority of patients failing to achieve complete remission.6 Anxiety disorders may additionally be treated using psychological approaches, including cognitive behavioral therapy, exposure therapy, and cognitive processing therapy,4 although these therapies tend to be costly and limited to some therapeutic contexts.7 Thus, there is a strong and urgent need to develop novel treatment approaches
for anxiety disorders.

Cannabidiol (CBD) is a constituent of the Cannabis plant, which has potential therapeutic properties across many neuropsychiatric disorders.8 Indeed, Epidiolex (99% CBD; 0.1% D-9-tetrahydrocannabinol [THC]) has been approved in some places for the treatment of epilepsy9 and clinical trials have established that CBD can be an effective treatment for pediatric epilepsy, 10,11 or epilepsy with a pediatric onset.12,13 Interest in the broader therapeutic potential of CBD is exemplified by the burgeoning number of systematic reviews and meta-analyses published within the past few years that champion its use in a number of potential therapeutic indications. CBD is well tolerated and effective in studies of social anxiety during public speaking tasks,1,14,15 demonstrates promising data from early trials in psychosis to treat schizophrenia16,17 and in the early studies of motor and nonmotor symptoms of Parkinson’s disease18; it has also shown some promise in colitis.19 Reviews of the pre-clinical literature have also shown some preliminary ability to ameliorate cancer tumors, alcohol use disorder,
20 pain,21 as well as acting as an anti-inflammatory, analgesic, antiarthritic, anti-Alzheimers, antidepressant, antidiabetic, as well as others.22

The primary psychoactive component of cannabis, THC, has its actions primarily at the cannabinoid type 1 (CB1) receptor.23 By comparison, the pharmacological profile of CBD is very different from THC and it is currently not fully understood.23 Nevertheless, it is known to have interactions with several receptors in both the central and peripheral nervous systems,24 which are known to regulate fear and anxiety. These receptors include the serotonin 5-HT1A receptor, the CB1 and CB2 receptors, and the transient receptor potential, vanilloid type 1 receptor (TRPV1).3,25 The acute anxiolytic effects of CBD at low and intermediate doses are thought to involve 5-HT1A activation.8,26 Whereas TRPV1 antagonism allows for the anxiolytic effects of higher CBD doses, the anxiogenic effects of higher CBD doses involves TRPV1 agonism.8,26 TRPV1 activity seems to be unique to CBD and a few other minor cannabinoids, as THC does not interact with this receptor channel.27

Another potential mechanism through which CBD produces anxiolytic effects is due to the action of the endogenous cannabinoid anandamide in the brain.28 CBD has been shown to increase cannabinoid receptor activation indirectly by elevating endocannabinoid levels through its action on endocannabinoid metabolism.29,30 CBD has the ability to inhibit fatty acid amide hydrolase (FAAH) enzyme, which metabolizes anandamide, consequently enhancing anandamide levels and indirectly increasing CB1 receptor activation.29 CB1 receptor activation has been thought tomediate the ability of CBD to regulate long-term learned fear processing.25 Endocannabinoid signaling is part of an endogenous anxiolytic neuromodulatory system, thus inhibition of FAAH activity is a potentially promising therapeutic approach for reducing anxiety-related symptoms.30

After the recent decriminalization and legalization of medical and recreational cannabis in certain countries and jurisdictions, cannabis use continues to increase. 31–33 CBD has drawn increased attention as a potential treatment, as the majority of existing data suggest that it is safe, well tolerated, and has few adverse effects.34 The World Health Organization stated that across a number of controlled open-label trials, CBD is generally well tolerated with a good safety profile. 35–37 Several studies propose that CBD is nontoxic, does not induce changes in food intake or catalepsy, does not affect physiological measures, and does not alter psychomotor or psychological functions.37 In addition, chronic use and high doses of up to 1500 mg/ day are reportedly well tolerated in humans.37