Multiple mechanisms involved in the large-spectrum therapeutic potential of cannabidiol in psychiatric disorders

Abstract

Cannabidiol (CBD) is a major phytocannabinoid present in the Cannabis sativa plant. It lacks the psychotomimetic and other psychotropic effects that the main plant compound D 9 -tetrahydrocannabinol (THC) being able, on the contrary, to antagonize these effects. This property, together with its safety profile, was an initial stimulus for the investigation of CBD pharmacological properties. It is now clear that CBD has therapeutic potential over a wide range of non-psychiatric and psychiatric disorders such as anxiety, depression and psychosis. Although the pharmacological effects of CBD in different biological systems have been extensively investigated by in vitro studies, the mechanisms responsible for its therapeutic potential are still not clear. Here, we review recent in vivo studies indicating that these mechanisms are not unitary but rather depend on the behavioural response being measured. Acute anxiolytic and antidepressant-like effects seem to rely mainly on facilitation of 5-HT1A-mediated neurotransmission in key brain areas related to defensive responses, including the dorsal periaqueductal grey, bed nucleus of the stria terminalis and medial prefrontal cortex. Other effects, such as anti-compulsive, increased extinction and impaired reconsolidation of aversive memories, and facilitation of adult hippocampal neurogenesis could depend on potentiation of anandamidemediated neurotransmission. Finally, activation of TRPV1 channels may help us to explain the antipsychotic effect and the bell-shaped dose-response curves commonly observed with CBD. Considering its safety profile and wide range of therapeutic potential, however, further studies are needed to investigate the involvement of other possible mechanisms (e.g. inhibition of adenosine uptake, inverse agonism at CB2 receptor, CB1 receptor antagonism, GPR55 antagonism, PPARg receptors agonism, intracellular (Ca 2þ ) increase, etc.), on CBD behavioural effects.

Cannabidiol as a Potential Treatment for Anxiety Disorders

“…The 2 major phyto-cannabinoid constituents with central nervous system activity are THC, responsible for the euphoric and mind-altering effects, and CBD, which lacks these psychoactive effects. Preclinical and clinical studies show CBD possesses a wide range of therapeutic properties, including antipsychotic, analgesic, neuroprotective, anticonvulsant, antiemetic, antioxidant, anti-inflammatory, antiarthritic, and antineoplastic properties (see [11,12,[16][17][18][19] for reviews). A review of potential side effects in humans found that CBD was well tolerated across a wide dose range, up to 1500 mg/day (orally), with no reported psychomotor slowing, negative mood effects, or vital sign abnormalities noted [20].…”

“…CBD has a broad pharmacological profile, including interactions with several receptors known to regulate fear and anxiety-related behaviors, specifically the cannabinoid type 1 receptor (CB 1 R), the serotonin 5-HT 1A receptor, and the transient receptor potential (TRP) vanilloid type 1 (TRPV1) receptor [11,12,19,21]. In addition, CBD may also regulate, directly or indirectly, the peroxisome proliferator-activated receptor-γ, the orphan G-protein-coupled receptor 55, the equilibrative nucleoside transporter, the adenosine transporter, additional TRP channels, and glycine receptors [11,12,19,21].…”

“…In addition, CBD may also regulate, directly or indirectly, the peroxisome proliferator-activated receptor-γ, the orphan G-protein-coupled receptor 55, the equilibrative nucleoside transporter, the adenosine transporter, additional TRP channels, and glycine receptors [11,12,19,21]. In the current review of primary studies, the following receptor-specific actions were found to have been investigated as potential mediators of CBD's anxiolytic action: CB 1 R, TRPV1 receptors, and 5-HT 1A receptors.…”

“…CBD has broad therapeutic properties across a range of neuropsychiatric disorders, stemming from diverse central nervous system actions [11,12]. In recent years, CBD has attracted increasing interest as a potential anxiolytic treatment [13][14][15].…”

Endocannabinoids in nervous system health and disease: the big picture in a nutshell

“…Given the widespread and strong expression of ECS molecules, it is not surprising that exposure of the developing and maturing nervous system to marijuana-derived cannabinoid impacts behavioural aspects in the control of emotions and cognitive responses. Given the implications of cannabinoid exposure in human neuropsychiatric disorders (see Puighermanal et al [11]; Melis & Pistis [12]; Campos et al [13]), investigations on the mechanism of action and neurobiological substrate underlying the developmental action of cannabinoids have gained traction. Endocannabinoids, acting via the CB1 receptor comprise, in effect, neurodevelopmental signalling cues which exert a regulatory role on the molecular and cellular mechanisms involved in brain development.…”