Multiple mechanisms involved in the large-spectrum therapeutic potential of cannabidiol in psychiatric disorders
Alline Cristina Campos, Fabricio Araujo Moreira, Felipe Villela Gomes, Elaine Aparecida Del Bel and Francisco Silveira Guimaraes
Philosophical Transactions of The Royal Society Bulletin, 2012, 367, 3364–3378
Cannabidiol (CBD) is amajor phytocannabinoid present in the Cannabis sativa plant. It lacks the psychotomimetic and other psychotropic effects that the main plant compound D9 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 thatCBDhas 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-HT1Amediated 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 (Ca2þ) increase, etc.), on CBD behavioural effects.
Keywords : cannabidiol; anxiety; depression; psychosis; serotonin; anandamide
Cannabidiol (CBD) is the main non-psychotropic phytocannabinoid present in the Cannabis sativa
plant, constituting up to 40 per cent of its extract. The chemical characterization of the main cannabinoids present in this plant by Mechoulam’s group in the 1960s  originated the first wave of scientific interest in this compound. With the discovery of the endocannabinoid (eCB) system in the early 1990s and the rise, in the words of Bill Devane , of the new dawn of cannabinoid pharmacology, there was a renewed interest in CBD, with the number of related published studies growing exponentially since then.
Recent comprehensive reviews suggest that this compound is one of the most promising candidates for a therapeutic tool in a wide range of disorders [3,4]. In the present paper, we will review the evidence that supports its use in psychiatric disorders and the proposal mechanisms that try to explain it.
2. CANNABIDIOL AND ANXIETY
Early reports describing the effects of CBD in animal models of anxiety were inconsistent. Silveira Filho & Tufik  did not find any effect of CBD (100 mg kg21) in rats tested in the classical Geller- Seifter conflict model of anxiety, whereas Zuardi & Karniol  described that a much lower CBD dose (10 mg kg21) attenuated conditioned emotional responses. These apparent contradictory results were subsequently explained by Guimara˜es et al. . Using an ethologically based model of anxiety, the elevated plus maze, they showed that CBD promotes anxiolytic-like effects with an inverted U-shaped dose-response curve, higher doses (more than 20 mg kg21 in rats) being ineffective (table 1).
The anti-anxiety properties of CBD in rats were later confirmed in different species (mice) and animal models, including the Vogel conflict test and contextual fear conditioning [8–10]. More recently, CBD was shown to decrease defensive behaviours evoked by predator exposure, a proposed model of panic attacks and posttraumatic stress disorder (PTSD) [11,13]. CBD also reduces marble burying behaviour in mice, suggesting that this compound could be effective in obsessive-compulsive disorder (OCD) . Moreover, CBD can interfere in learning and/or memory of aversive events, processes that have been associated with PTSD pathophysiology . Intracerebroventricular administration of CBD facilitates extinction in a contextual aversive conditioning model . In this same paradigm, it can also impair reconsolidation, resulting in the attenuation of the aversive memory trace. In this study, the impairment
of contextual fear memory did not show reinstatement and was long-lasting (22 days) . Contrasting with these results, Elbatsh et al.  have recently reported that repeated (14 days) administration of CBD increases freezing in a contextual fear conditioning test. The reasons for this difference is unknown, but may involve the distinct conditioning protocols and drug administration regime (chronic versus acute) used compared with other studies that investigated the effects of CBD in this model [15,21,23]. Moreover, in this study, it is also possible that CBD could have interfered in learning/memory mechanisms, because the animals were conditioned under the drug effect .