We attempted to assess, for the first time, the influence of acute CBD injections on memory impairment provoked by MK-801 in mice. We found that an acute injection of CBD at non-effective doses (1 and/or 5 mg/kg) attenuated the consolidation and restoration of long-term fear memory impairment, while an acute administration of CBD had no influence on MK-801 memory impairment during the acquisition phase in the PA test in mice.

It should be emphasized that the earlier measurement of CBD’s effects on locomotor activity, as well as the use of ineffective CBD doses in the PA tests, prevent us from concluding that the reversal of MK-801-induced memory disorders in mice (in the PA test) by CBD (1 and 5 mg/kg) was either a false positive or a false negative result.

The examinations of the preclinical efficacy of CBD in treating/controlling cognitive disturbances in neuropsychiatric disorders—e.g., during schizophrenia—are rather limited [22]. Consequently, there are few available data describing the influence of CBD on the cognitive-related symptoms of schizophrenia. One such relevant study is an experiment in which the researchers used rats prenatally infected with the poly I:C virus as a model of schizophrenia. The administration of poly I:C during mid-to-late pregnancy induced less sociability and other (negative and cognitive) symptoms of schizophrenia in the offspring. The administration of CBD in the offspring improved social interactions in the group [32].

Other studies described the role of CBD in modulating other types of memory, such as novel object and social recognition, in cognitively impaired animals [28,33]. Fagherazzi et al. [33] used an animal model of cognitive impairment induced by iron overload. Both an acute injection of CBD at the highest dose and a chronic administration of CBD improved recognition memory in iron-treated rats in the NOR task. Neither acute nor chronic CBD doses affected memory in control rats [33].

Our results are consistent with other available preclinical studies describing the positive influence of CBD on various disturbances provoked by the preclinical schizophrenia model of NMDA receptor hypofunction. A systemic administration of CBD was able to attenuate MK-801-induced hyperactivity, deficits in pre-pulse inhibition (PPI), and social withdrawal [34]. In addition, an injection of CBD attenuated MK-801-induced prolonged PPI in a murine sensory gating model, similarly to clozapine—a drug used in the treatment of schizophrenia [35]. In another study with MK-801 (1 mg/kg), mice were administered CBD for 22 days and then examined in the NOR test. The discrimination index, measured in the NOR test, was significantly higher in the MK-801-treated mice administered with the highest dose of CBD (60 mg/kg), compared to the control group [36]. Contrary to the results cited above, Deiana et al. [37] found that an acute injection of CBD prior to MK-801 (0.08 mg/kg) did not prevent the MK-801-provoked deficits in social recognition memory, while administration of CBD to control rats had had no significant effect on social recognition [37]. The results from the cited studies indicate that high doses of CBD may alleviate the dysfunction of object recognition memory, but not social recognition memory, as observed in the MK-801-related rodent model of schizophrenia.

As we have mentioned before, CBD, along with Δ9-THC, is the most abundant bioactive compound of Cannabis sativa. Δ9-THC demonstrates strong psychotic properties, while, in contrast to Δ9-THC, CBD is devoid of any psychotropic effects [38].

The psychotropic effects of Δ9-THC are due to the activation of the CB1 receptor, which is one of the receptors most highly expressed in the central nervous system, where it mediates the signaling of the endocannabinoids in the brain: N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG). Moreover, the activation of the CB1 receptor acts as negative regulation of the NMDA receptor, causing its hypofunction [39,40]. The dysfunction of the NMDA receptor is associated with the dopaminergic dysregulation observed in schizophrenic patients, giving rise to the hypothesis that glutamatergic/NMDA dysfunction underlies schizophrenic symptoms, including psychosis and memory impairment.

CBD’s effects on memory and learning are dose-dependent, and are connected with the ECS system. CBD shows a low affinity for the CB1 and CB2 receptors, and is capable of altering the functions of CB receptors by antagonizing CB1 and CB2 receptor agonists, such as AEA and 2-AG [21,41]. CBD acts as a negative allosteric modulator on the CB1 receptor [41], which could explain—at least in part—its balancing effects on the psychotic effects of Δ9-THC. Moreover, CBD is able to interfere with the effects of Δ9-THC, suggesting that the Δ9-THC/CBD ratio in cannabis might moderate the adverse effects after its consumption. Additionally, Leweke et al. [42] and Bisogno et al. [43] found that CBD increased the levels of AEA, reducing cellular uptake and inhibiting hydrolytic degradation of AEA [42,43]; thus, they presented a hypothesis describing the role of AEA in counteracting the overactivity of dopamine D2 receptors. For this reason, we may assume that CBD could have antipsychotic properties, enhancing the synaptic AEA level to rebalance the D2 receptor overactivation. In addition, CBD suppresses the expression and activity of fatty acid amide hydrolase (FAAH)—an enzyme required for the degradation of both AEA and 2-AG [14,15,44].

However, the underlying mechanism of the involvement of CBD in the MK-801-induced memory impairment presented in our experiments remains unclear. It is possible that a non-CB1-related mechanism is involved in these effects of CBD. Thus, it is worth mentioning the additional beneficial pharmacological effects of CBD, including its anti-inflammatory, antioxidant, and neuroprotective properties. These properties of CBD seem to be important not only in the context of the positive role of CBD in memory, but also in the context of cognitive disorders connected with the NMDA receptor blockade.

Such non-CB-receptor-mediated actions would explain the finding that CBD modulates a number of neurotransmitter systems, e.g., glutamatergic activity. CBD reduced glutamate-mediated neurotoxicity observed in the hippocampus and prefrontal cortex [45], as the modulation of glutamate release by cannabinoids is maintained in CB1-receptor-mutant mice [46]. Moreover, this protection of neurons from glutamate-induced death, observed after CBD administration, was unaffected by the CB receptor antagonist, indicating it to be CB-receptor-independent. Consistent with those data are our findings that a low dose of CBD (1 and 5 mg/kg) induced a tendency towards the reversal of MK-801-induced memory deficit via a possible interaction between CBD and the glutamatergic system. Thus, we may suggest that CBD may also reverse memory deficits via the glutamatergic mechanism.

Moreover, previous studies have shown that glutamate toxicity may be prevented by CBD’s antioxidant properties. As we have already mentioned, CBD was demonstrated to be an antioxidant by cyclic voltammetry, while CBD’s neuroprotective properties, mentioned below, could also be caused by an antioxidant effect. CBD, like other antioxidants, interrupts free radical chain reactions, capturing free radicals or transforming them into less active forms. An analysis of CBD’s antioxidant activity showed that it could regulate the state of redox, either directly, by affecting the components of the redox system, or indirectly, by interacting with other molecular targets associated with the redox system components. The direct antioxidant effects of CB are associated with its influence on the pro-oxidant enzyme activity, chelation of transition metal ions, interruptions of free radical chain reactions, antioxidant enzyme activity, non-enzymatic antioxidant levels, oxidative modifications of lipid protein, DNA, etc. For example, CBD reduces oxidative conditions by preventing the formation of superoxide radicals, which are mainly generated by xanthine oxidase (XO) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX1 and NOX4, respectively) [47,48]. CBD also reduces the production of reactive oxygen species (ROS) by chelating transition metal ions, involved in the Fenton reaction, to form extremely reactive hydroxyl radicals [49]. In turn, the indirect antioxidant effects of CBD are associated with its influence on AEA concentrations and, thus, on the activation/inhibition of CB receptors [50,51,52]. Interestingly, CBD was found to be more protective against glutamate toxicity than either of the dietary antioxidants—i.e., α-tocopherol or ascorbate [45]—indicating it to be a potent antioxidant. In addition, CBD strengthens the adenosine A2A receptor, which suppresses the activity of immune cells, thus protecting tissues against inflammation [53,54].

CBD has also been found to exert some agonist activity on the serotonin (5-HT) receptor type 5-HT1, in addition to inhibiting 5-HT reuptake and reducing the overall 5-HT neurotransmission [55]. However, it is not clear whether 5-HT1A’s participation in the effects of CBD is a consequence of increased serotonin availability, or of direct receptor activation/facilitation by CBD itself. Russo et al. [56] demonstrated that CBD, while showing a low-affinity agonism towards the 5-HT1A receptor, could enhance 5-HT1A-mediated neurotransmission [56].

CBD induces various pharmacological effects, possibly by enhancing 5-HT neurotransmission, followed by a subsequent activation of the postsynaptic 5-HT1A receptors. In addition to this mechanism, however, there is also some evidence that CBD can facilitate serotonin action on 5-HT1A receptors—probably through an allosteric mechanism [57]. CBD can also stimulate the 5-HT1A receptor indirectly by increasing AEA levels [58]. However, the activated 5-HT1A receptor can act as a membrane antioxidant by capturing ROS [59].

As such, the affinity of CBD for the 5-HT receptors seems to be responsible for its neuroprotective effects, but not exclusively. As we have mentioned before, CBD demonstrates anxiolytic, antidepressant, and analgesic effects, and it is known that the anxiolytic and antioxidant effects of CBD depend, at least in part, on the activation of 5-HT1A [58,60].

Our findings and the literature data cited above indicate that CBD has a supporting effect on the memory process. These beneficial effects of CBD on memory are likely dose-dependent, but the mechanism of their action is not yet entirely clear. First, it should be noted that CBD exerts a significant influence on memory and learning processes by modulating the ECS functions, where the receptors of the ECS are located, e.g., in the hippocampus, the key structure that is responsible for creating memory routes. Moreover, CBD, by acting not only on the ECS but also on the other above-mentioned receptors, can encompass more complex mechanisms of action and different targets, resulting in various behavioral effects. The influence of CBD on the dopaminergic, glutamatergic, and serotoninergic receptors, or on the inhibition of inflammatory processes in the brain and the progressive degeneration of nerve cells, may also underlie the memory improvement mechanisms.

Taking into account the broad beneficial pharmacological properties of CBD, it appears to be a potentially useful therapeutic agent for the prevention and treatment of many diseases, the etiology of which may be associated with redox imbalance, inflammation, or neurodegeneration, e.g., diabetes, diabetes-related cardiomyopathy, cardiovascular diseases (including stroke, arrhythmia, atherosclerosis, and hypertension), cancer, arthritis, anxiety, psychosis (schizophrenia), epilepsy, and neurodegenerative diseases (i.e., Alzheimer’s) [60].