Cannabis sativa contains over 100 compounds called phytocannabinoids. Two of them demonstrate considerable therapeutic potential: Δ9-tetrahydrocannabinol (Δ⁹-THC), considered the main component responsible for the psychoactive effects of the plant, and CBD, the main non-psychotomimetic constituent of Cannabis (Adams et al., 1940; Mechoulam and Shvo, 1963; Gaoni and Mechoulam, 1964). CBD constitutes about 40% of the active substances of the plant (Crippa et al., 2009). However, its pharmacological effects are different from, and often even opposite to, those of Δ9-THC, and are not related to the development of tolerance and withdrawal syndrome (Mechoulam et al., 2007; Bergamaschi et al., 2011).

In this context, it is also important to highlight the eCB system, discovered in the 20th century and responsible for a revolution in the understanding of numerous neuropsychological functions related to the modulation of emotional responses (Lutz, 2009). The eCB system comprises two different cannabinoid receptors, their endogenous ligands, and enzymes involved in the synthesis and degradation thereof (Di Marzo, 2009). eCB signaling is distributed throughout the CNS and peripheral tissues, regulating presynaptic release of both excitatory and inhibitory neurotransmitters. Cannabinoid type 1 (CB1) receptors are expressed by peripheral and central neurons, particularly in the central regions known to play important roles in anxiety and aversive learning, such as the amygdala, hippocampus, and cerebral cortex (Childers and Breivogel, 1998). In contrast, CB2 receptors are expressed mostly in immune cells, while also being present in the brain (Van Sickle et al., 2005).

The two major endogenous ligands for CB1 and CB2 receptors are AEA and 2-AG. These eCBs are synthesized on demand, mainly postsynaptically, and act as retrograde messengers regulating the presynaptic release of various neurotransmitters, as mentioned above. AEA acts as a partial agonist of both CB1 and CB2 receptors, with a higher affinity for the former. In the CNS, 2-AG is the most abundant eCB, and non-selectively activates CB1 and CB2 receptors. AEA, 2-AG, and Δ⁹-THC, have been shown to exert their effects mainly through activation of CB1 receptors (Di Marzo, 2009; Castillo et al., 2012). In the case of eCBs, the effects are rapidly terminated through carrier-mediated uptake followed by intracellular enzymatic degradation. AEA and 2-AG are metabolized by monoacylglycerol lipase and FAAH, respectively. The eCBs regulate neuronal activity and plasticity by depolarization-induced suppression of inhibition or excitation (Wilson and Nicoll, 2002). Both phenomena are forms of short-term synaptic plasticity that contribute to the regulation of a number of physiological functions, including memory and emotion. Additionally, eCBs appear to modulate the memory process by changing synaptic plasticity and mediating more persistent forms of synaptic plasticity (e.g., LTP and depression) in several brain areas (Maldonado et al., 2006; Di Marzo, 2009; Sidhpura and Parsons, 2011).

These findings have established the importance of the eCB system in a number of neurophysiological functions and led to an emerging interest in the eCB-mediated modulation of emotionality. The first study to address the role of the eCB system in fear memory, specifically in its extinction, was published at the beginning of the last decade by Marsicano et al. (2002). In this study, the authors showed that genetic deletion of the CB1 receptor or its pharmacological blockade strongly impaired extinction of auditory-conditioned fear and that eCBs were released in the BLA during extinction. This discovery revealed that the eCB system has a central function in the extinction of aversive memories and may therefore be a promising target for the treatment of disorders related to inappropriate retention of such memories (for details see Marsicano et al., 2002). Precisely what processes underlie this function of the eCB system is presently unclear, raising the question whether CBD exerts its effects through a different pathway(s). Previous reports on eCB system involvement in CBD-induced effects have been equivocal. Because the endogenous ligands (e.g., AEA) and Δ⁹-THC act directly on the CB1 receptor, it is possible that some of the effects of CBD are also mediated by this receptor, albeit indirectly. Indeed, CBD may exert its therapeutic effect on PTSD through inhibition of the uptake or enzymatic degradation of eCBs (Bisogno et al., 2001), as suggested by some recent studies (Bitencourt et al., 2008; Do Monte et al., 2013; Elmes et al., 2015; Stern et al., 2015). However, if this is the case, what is the advantage of using CBD over agents that act directly on the CB1 receptor? The answer is simple: fewer complications (specifically, anxiogenic side effects). Agents that target the eCB system directly, such as THC, CB1 agonists, and FAAH inhibitors, have a biphasic effect, in which low doses are anxiolytic, but higher doses can be anxiogenic, in both preclinical models and humans. In contrast, CBD, when administered in acute systemic doses in models of general anxiety, does not cause anxiety even at high doses. However, few studies have examined chronic dosing effects of CBD in models of generalized anxiety, and such studies are needed for the safe long-term use of CBD (Blessing et al., 2015).

Trauma-related disorders may involve dysregulation of the learning process of aversive memories. This process is fundamental for the individual to survive, because through it we avoid potentially dangerous situations without having to respond in a way that damages mental health (Quirk and Mueller, 2008). Consistent with this concept, neural circuits that support fear conditioning are related to circuits that are affected in clinical conditions such as PTSD (Davis and Whalen, 2001). That the available drugs (such as antidepressants and anxiolytics) do not specifically target the memory process may be one of the reasons that pharmacological treatment of PTSD is so difficult (Singewald et al., 2015). Currently approved treatments for PTSD include SSRIs and serotonin/noradrenaline reuptake inhibitors, both with low efficacy (Bernardy and Friedman, 2015). The response rate for SSRIs rarely exceeds 60%, of which less than 30% represents complete remission (Berger et al., 2009). Moreover, the available treatments have considerable side effects, which may limit tolerance or even decrease adherence to the treatment (Shin et al., 2014). In this regard, interventions that act on the eCB system have shown promise since they can affect both the emotional (e.g., relieve PTSD symptoms) and cognitive (e.g., increase the efficiency of psychological approaches) aspects of the disorder (Izzo et al., 2009; Steckler and Risbrough, 2012; Trezza and Campolongo, 2013).

Two important observations led to the consideration of cannabinoids for the treatment of PTSD: (i) patients with PTSD appear to be more likely to smoke Cannabis; and (ii) patients with PTSD have increased levels of cannabinoid receptors and reduced peripheral levels of AEA, suggesting that the CB1 receptor upregulation may be a result of low receptor occupancy caused in turn by the deficiency of AEA (Hauer et al., 2013; Hill et al., 2013a; Neumeister, 2013; Neumeister et al., 2013; Loflin et al., 2017). Consistent with these observations, studies have made use of treatment with cannabinoids in animal models of traumatic event exposure to reduce the appearance of PTSD-like behavioral responses. These studies have demonstrated great potential of cannabinoids in the mitigation of maladaptive responses to trauma (for a more detailed review, see Zer-aviv et al., 2016).

When administered after a traumatic situation, cannabinoids may interfere with the acquisition and consolidation of memories of the event, thus mitigating the risk of subsequent symptoms. However, intervention at this stage may be inadvisable because not all people exposed to a traumatic situation will later manifest PTSD. Alternatively, cannabinoids may reduce traumatic memory by affecting its retrieval or reconsolidation, or by stimulating the process of aversive memory extinction. The latter mechanism may hold the most therapeutic promise, especially when taking into account exposure-based psychotherapies, which extinction mechanisms are thought to be engaged (reviewed in Berardi et al., 2016).

Additionally, studies have shown CBD, in its isolated form, to be a constituent of Cannabis with enormous therapeutic potential not only for trauma-related disorders, but also for various other psychiatric and neurological disorders (Campos et al., 2012b). Among the advantages of CBD are its high efficacy, lack of psychotomimetic properties or anxiogenic effects caused by eCB transmission activation, inability to induce tolerance and dependence, and safety at high doses both in humans and in animals (Bergamaschi et al., 2011). However, an alternative view must also be considered, according to which the therapeutic effects of Cannabis result from the interaction of all the compounds present in the plant (particularly THC and CBD) rather than the isolated action of a single compound. Such interaction, called in the pharmacology the “entourage effect” (Ben-Shabat et al., 1998), still needs to be better studied (for further discussion of the use of the term “entourage effect” on plants effect, see Rosenberg et al., 2015). In this review, we will focus on CBD effects in isolation.