Evidences for the Anti-panic Actions of Cannabidiol
Vanessa P. Soares and Alline C. Campos
Current Neuropharmacology, 2017, 15, 291-299
DOI : 10.2174/1570159X14666160509123955
Background : Panic disorder (PD) is a disabling psychiatry condition that affects approximately 5% of the worldwide population. Currently, long-term selective serotonin reuptake inhibitors (SSRIs) are the first-line treatment for PD; however, the common side-effect profiles and drug interactions may provoke patients to abandon the treatment, leading to PD symptoms relapse. Cannabidiol (CBD) is the major non-psychotomimetic constituent of the Cannabis sativa plant with antianxiety properties that has been suggested as an alternative for treating anxiety disorders. The aim of the present review was to discuss the effects and mechanisms involved in the putative anti-panic effects of CBD.
Methods : electronic database was used as source of the studies selected selected based on the studies found by crossing the following keywords: cannabidiol and panic disorder; canabidiol and anxiety, cannabidiol and 5-HT1A receptor).
Results : In the present review, we included both experimental laboratory animal and human studies that have investigated the putative anti-panic properties of CBD. Taken together, the studies assessed clearly suggest an anxiolytic-like effect of CBD in both animal models and healthy volunteers.
Conclusions : CBD seems to be a promising drug for the treatment of PD. However, novel clinical trials involving patients with the PD diagnosis are clearly needed to clarify the specific mechanism of action of CBD and the safe and ideal therapeutic doses of this compound.
Keywords : Animal models, cannabidiol, human studies, 5-HT1A receptors, panic disorder, serotonin.
Panic disorder (PD) is a chronic and disabling psychiatric disorder that is characterised by unexpected and recurrent panic attacks and affects approximately 0.8-5% of all people worldwide and may vary according to socio-demographic factors . PD patients experience psychosocial impairment and a high risk of psychiatric co-morbidities and suicide . In the early 1960s, Donald Klein described the efficacy of the tricyclic antidepressant imipramine in blocking panic attacks . Currently, selective serotonin reuptake inhibitors (SSRIs) are the first-line compounds in the treatment of PD, although other drugs, such as tricyclic antidepressants and highly potent benzodiazepines, are also indicated. Less than half of the patients who suffer from PD show complete and sustained remission of the symptoms after long term treatments with the currently available treatments . This apparent discrepancy might be due to genetic variations in PD etiology that could affect the pharmacological responses and side effects . Thus, the development of more effective drugs with a better pharmacological profile than the current ones used to treat this psychiatric condition is needed.
Over the last two decades, the therapeutic potential of cannabinoids has been extensively studied. Although cannabis abuse is connected to marked anxiety, panic attacks, depersonalisation, and emotional liability (primarily due to the psychotropic effects of Δ9-THC) , a growing body of evidence suggests that non-psychotomimetic phytocannabinoids could be useful as therapeutic tools. The most promising of these compounds is cannabidiol (CBD), the major non-psychotomimetic constituent of Cannabis sativa. Different from the endogenous ligands anandamide and 2-arachidonylglycerol act as agonists of CB1/CB2 receptors [5, 6], CBD has a very low affinity for these receptors in vitro [7, 8] but it can facilitate endocannabinoid signalling by inhibiting the cellular uptake and enzymatic hydrolysis of endocannabinoids . Finally, CBD can also promote the blockade of adenosine uptake or act as an agonist of vanilloid (TRPV1) or 5-HT1A serotonergic receptors [9-12]. Pre-clinical studies have shown that systemically administered CBD induces anxiolytic-like effects in several animal models that have been associated with generalised anxiety (GAD), such as the elevated plus maze (EPM), the Vogel conflict test and aversive conditioning . Reinforcing these findings, human studies have suggested that the drug decreases generalised anxiety symptoms . The specific effects and the relevance of each of these mechanisms for the putative anti-panic effects of CBD are discussed in this review. MEDLINE/PubMed (www.pubmed.com) electronic database was used as source of the studies selected for this review (from 1990 to July 2015). Works were selected based on the studies found by crossing the following keywords: cannabidiol and panic disorder; Cannabidiol and anxiety, Cannabidiol and 5-HT1A receptor.
2. ANTI-PANIC EFFECTS OF CBD IN HUMANS
In humans, responses related to PD have been assessed in both healthy volunteers and panic patients submitted to controlled conditions of psychological or chemical-nature stimuli [15, 16]. For instance, in the simulated public speaking (SPS) test, the participant must prepare a speech and talk in front of a video camera . Indices of anxiety and other emotional states during the test are obtained by
applying scales, such as the Visual Analog Mood Scale (VAMS; ) and the Self-Statements during Public Speaking Scale .
Fear of public speaking is accepted to increase anxiety in healthy people, irrespective of their trait anxiety level . Classical benzodiazepines decrease the VAMS indices before and after the speech, without affecting speech preparation or performance (which is associated with “fear of speaking”). Conversely, speech preparation and performance are reduced by antidepressants . Based on
pharmacological studies, it has been proposed that the neural networks activated by SPS are involved in anxiety disorders  and, thus, that the fear of speaking provoked by the SPS test can be helpful in understanding the brain areas involved and potential new drugs targets for PD.
Regarding CBD, the work of Zuardi and coworkers  showed that a single dose of CBD (300 mg, p.o.) decreased anxiety after the SPS test in healthy volunteers. In another study, Bergamaschi et al.  showed that social anxiety disorder patients presented higher anxiety, cognitive impairment and discomfort, as well as increased alertness during their speech performance when compared with healthy controls. After CBD (600 mg, p.o.) treatment, however, a significant reduction in anxiety-related measures obtained during their speech performance was observed. These results have encouraged new approaches in the study of the putative effects of CBD on PD.