Experimental studies suggest that high-dose CBD may decrease anxiety and increase mental sedation in healthy individuals. Clinical trials suggest the high-dose CBD may be useful for the treatment of social anxiety disorder, and possibly, insomnia and epilepsy. The anxiolytic effect associated with CBD may be the result of its 5-HT_1A agonism, which has been evidenced in a number of behavioral studies [78,79,80,81]. Paradoxically, some animal studies have found that the dose-response of CBD follows an inverted U shape, leading to an anxiogenic effect through its agonism of TRPV_1–2 receptors (which are believed to be responsible for detection and regulation of body temperature, and thermal nociception) [82]. Alternatively, it is possible that the anxiolytic properties of CBD are mediated by its action at CB₁ receptors, because CB₁ antagonists were found to attenuate amphetamine and/or nicotine-induced anxiety in mice [83]. Indeed, there is evidence that both CBD and AM404 (an anandamide transporter/FAAH inhibitor and TRPV₁ agonist) facilitated extinction of contextual fear memory in rats and this was reversed by the CB₁-receptor antagonist SR141716A, but not by the TRPV₁-selective antagonist, capsazepine [84]. It is equally possible that the anxiolytic effect of CBD is explained by inhibition of FAAH. Animal studies have demonstrated that FAAH inhibitors possess anxiolytic properties in a number of paradigms including marble burying, light/dark box, elevated zero maze, and isolation-induced ultrasonic emission test [85,86,87]. However, CBD has been shown to both inhibit and stimulate activity FAAH [35,36,37]. Consequently, it is yet unclear whether there is a role for inhibition of endocannabinoid catabolic enzymes in the anxiolytic effects of CBD.

A possible analgesic effect of CBD-alone, and CBD added to ∆9-THC was observed in two studies among mixed neurogenic (MS and neuropathic pain) and cancer pain patients [73,75]. However, both studies administered low doses of CBD (2.5 mg CBD and ∆9-THC per spray), used more than one scale to measure pain outcomes and their results were not consistent across scales. Also confounding interpretation is the fact that some of the clinical trials allowed the use of “rescue medication”, which may have led overestimation of the effects of CBD-alone [75,76]. In support, other studies did not find an analgesic effect of CBD-alone, or in combination with ∆9-THC [70,74,77]. In animals, there is evidence that ∆9-THC and cannabinol (a weak partial CB₁ agonist) suppressed the abdominal constriction response to formic acid in mice, whereas CBD was inactive at doses of up to 200 mg/kg [88]. In that study, the analgesic effects of ∆9-THC and cannabinol were additive and CBD antagonised these effects in a dose-dependent manner. Likewise, ∆9-THC, cannabinol and cannabis extract produced an analgesic effect in the hot-plate test in mice; however, CBD was without effect at doses of up to 30 mg/kg [89]. By contrast, CBD (5 mg/kg IP or 25 mg/kg PO) was shown to block disease progression in murine collagen-induced arthritis—an animal model of rheumatoid arthritis—and this was accompanied by reductions in type-II collagen-specific proliferation, interferon—gamma production, and release of tumour necrosis factor-alpha by synovial cells [90]. The same group later demonstrated that the synthetic CBD derivative—HU-320—exerted more potent effects in the same direction [91]. More recently, there is evidence that cannabidiol derivative, O-1602, reduced movement-evoked firing of nociceptive C fibres in a rat model of acute inflammatory joint pain [92]. Interestingly, this effect was blocked by the GPR55-receptor antagonist, O-1918, but not by the CB₁ and CB₂ antagonists, AM281 and AM630, respectively. As a whole, these data indicate that CBD and its analogues may be beneficial for pain resulting from inflammation, however, human studies on this topic are lacking.

The strength of the antiepileptic effects of CBD may be difficult to judge clinically because of its potent antagonism of multiple CYP isoenzymes, potentially reducing plasma levels of concomitant anticonvulsants. Preclinical data has indicated that CBD displays antiepileptiform and antiseizure properties in vitro and in vivo CBD may possess antiepileptic properties via different mechanisms. For instance, there is evidence that CBD can block low-voltage-activated (T-type) Ca² channels, and increase the activity of inhibitory glycine receptors [33,34]. More recently, Jones et al. [5] used extracellular multi-electrode array recordings to show that CBD decreased epileptiform activity in the Mg²-free and 4-aminopyridine in vitro models of hippocampal epilepsy in the mammalian hippocampus—a key epileptogenic brain region. Additionally, the authors examined the effects of CBD (1, 10, and 100 mg/kg) in vivo using the pentylenetetrazole model of generalized seizures. Their results revealed that the incidence of severe seizures and mortality was significantly attenuated in rats treated with the high dose of CBD (100 mg/kg), relative to vehicle-treated rats. The antiepileptic effects associated with CBD were suggested to be due a potentially CB₁ independent mechanism because CBD acted with only low affinity at CB₁ receptor and displayed no agonist activity in [³⁵S]guanosine 5'-O-(3-thio)-triphosphate assays in cortical membranes. In support of this interpretation, there is evidence that the anticonvulsant properties of CBD in the maximal electroshock model were not affected by the CB₁-recepetor antagonist, SR141716A, whereas those of ∆9-THC and the CB₁-receptor agonist, WIN55,212-2, were blocked [93].

Despite its putative benefits for social anxiety disorder, insomnia and epilepsy studies suggest that high-dose CBD (400–700 mg) may increase mental sedation in normal individuals and aggravate cognitive deficits in schizophrenia—without altering physical sedation [42,62,67]. While the mechanism that is responsible for these effects is not clear, the fact that they exist is not surprising because most anxiolytics/sedatives/anticonvulsants produce their therapeutic action by decreasing CNS activation, and consequently, alertness. Some research does suggest, however, that CBD may improve cognition when used in combination with ∆9-THC. For instance, there is evidence that mixed neurogenic patients given oromucosal CBD/∆9-THC performed as well as patients given placebo on the Short Orientation-Memory-Concentration test, whereas patients given ∆9-THC-alone performed significantly worse than placebo-treated patients [75]. Similarly, there is evidence that healthy subjects given oromucosal CBD/∆9-THC (15 and 15 mg) performed equally well as placebo-treated individuals on tests of delayed and immediate word recall, whereas subjects treated with ∆9-THC-alone performed significantly worse than placebo-treated subjects on those tasks and they exhibited less wakefulness [55]. However, the treatments were not significantly different from placebo on digit symbol substitution, choice reaction, sustained attention, six-letter memory recall, digit memory recall. Moreover, Karniol et al. [49] showedthat oral CBD (15, 30, and 60 mg) inhibited the time production impairment associated with ∆9-THC (30 mg) [49]. On the other hand, Dalton et al. [56] found that a high dose of smoked CBD (150 µg/kg) failed to block perturbations of stability of stance, motor performance, mental performance induced by a much lower dose of smoked Δ9-THC (25 µg/kg).

Current evidence is equivocal regarding a potential antipsychotic effect of CBD. For example, Zuardi et al. [65,66] did not find CBD monotherapy (up to 1,280 mg) to be effective relative to placebo in a case-series of bipolar mania and treatment-resistant schizophrenia patients. Likewise, the CB₁ antagonist, SR141716, was ineffective for the treatment of positive or negative symptoms in schizophrenia [94]. In another study, oral CBD (600 mg) enhanced the psychomotor activating effects of intravenous ketamine, without significantly altering ketamine-induced psychiatric symptoms [47]. On the other hand, preliminary data from a four-week, randomized-controlled trial of CBD (600 mg) versus amisulpride (600 mg) for schizophrenia did not reveal any significant differences between the groups—suggesting that the former exerted an antipsychotic effect [64].

Intriguingly, some studies show that CBD can potentiate and some that that it can attenuate the psychotomimetic effects associated with Δ9-THC, depending on the measure, route of administration, and dose-ratio between the cannabinoids. For example, Karniol et al. [49] found that a low dose of CBD potentiated Δ9-THC-induced increases in pulse rate, whereas an equal or higher dose of CBD attenuated these increases. A dose-dependent interaction was also evidenced in the study by Ilan et al. [57] wherein high doses of CBD potentiated anxiety induced by low doses of Δ9-THC, but they reduced anxiety induced by high doses of Δ9-THC. In addition, Hollister and Gallespie [50] found that oral CBD (40 mg) caused a slight delay and prolongation/intensification of the psychotomimetic effects of Δ9-THC (20 mg). By contrast, Dalton et al. [56] showed that a high dose of smoked CBD (150 µg/kg) minimally (p < 0.05) inhibited the psychotomimetic effects associated with smoked Δ9-THC (25 µg/kg). However, there is also evidence that large doses of intravenous CBD (5 mg) completely blocked elevations in PANSS positive symptoms induced by intravenous Δ9-THC (1.25 mg) [58]. Another group found significantly greater MMN amplitude values at central electrodes following treatment with combined CBD (5.4 mg) and Δ9-THC (10 mg; but not Δ9-THC-alone), indicating that the former may have exerted an antipsychotic effect [52]. Finally, a study using nabilone (1 mg) showed that the molecule significantly impaired binocular depth inversion (an illusion of visual perception that provides a model of impaired perception during psychotic states) and this effect was partially reversed by CBD (200 mg) [48].

Overall, the human data regarding CBD’s potential to reverse the cognitive perturbations and psychotomimetic symptoms induced by Δ9-THC are difficult to interpret due to the possibility of a pharmacokinetic interaction between CBD and Δ9-THC (or other molecules) following oral/oromucosal administration. A review of 1970s studies found that the ratio of CBD/Δ9-THC was 8.1 when the CBD displayed antagonistic effects and 1.8 when it enhanced the effects of Δ9-THC [95,96]. Moreover, there is evidence that combination of CBD (1–10 mg/kg IP over 21 days) with equivalent doses of ∆9-THC increased blood and brain levels of the latter, decreased levels of 11-OH-THC and THC-COOH, and augmented the anxiogenic and locomotor suppressant effects and social interaction deficits seen with ∆9-THC [97]. Interestingly, CBD did not change the THC-induced decrease in CB₁ receptor binding and none of the treatments altered 5-HT_1A binding, suggesting that pharmacokinetic factors may have played a role.

The presence of a pharmacokinetic interaction between CBD and Δ9-THC is supported by results of two early phase studies of nabiximols—an oromucosal spray that contains an equivalent dose of the cannabinoids [98,99]. For instance, the addition of CBD (20 mg) to ∆9-THC (20 mg) significantly increased the area under-the-curve (AUC) of 11-hydroxy-THC [98]. The same group also demonstrated that concomitant CBD (10 mg) and ∆9-THC (10 mg) lead to a significantly later T_max for ∆9-THC, relative to treatment with ∆9-THC-alone [99]. These pharmacokinetic data roughly correspond to mean intoxication ratings across time, indicating that CBD slightly delayed and prolonged the subjective effects associated with ∆9-THC. By contrast, Nadulski et al. [18,19] found that oral CBD (5.4 mg), combined with ∆9-THC (10 mg) (non-significantly) increased the AUC and maximum concentration of ∆9-THC by approximately 20%, suggesting that CBD inhibited the conversion of ∆9-THC into 11-hydroxy-THC. Nevertheless, the pharmacokinetic impact of CBD was small compared to other factors such as gender and body mass index.

On the other hand, it remains true that a few human studies showed that oral/oromucosal CBD attenuated the psychoactive and therapeutic effects associated with ∆9-THC at low doses and dose-ratios between the cannabinoids [49,55,74,75]. Indeed, Karniol et al. [49] found that oral CBD (15 mg) was sufficient to reverse ∆9-THC-induced (30 mg) impairment on a time estimation task. In a similar fashion, there is evidence that oromucosal CBD (15 mg) attenuated verbal memory deficits induced by ∆9-THC (15 mg) [55]. Clinical studies using equal ratios of CBD to ∆9-THC show that the former may alter both the benefits and side-effects associated with the latter. For instance, CBD attenuated the antiemetic effects of ∆9-THC in cancer patients [73]. Moreover, CBD attenuated the antispastic, memory-impairing, and intoxicating effects associated with ∆9-THC and increased the prevalence of adverse events among MS patients (e.g., dizziness, ataxia, gastrointestinal) [68,71,73,74,75]. Nonetheless, clinical trials did not consistently show significant benefit/drawbacks of combining CBD with ∆9-THC. Some of the variability in results may be attributed to the fact that studies contained small sample sizes and measured multiple variables, leading to the possibility of a Type-I error(s). Likewise, some variability may explained by the fact that a number of clinical trials treated patients with CBD/Δ9-THC during a “run-in” period, which may have biased results towards CBD/Δ9-THC because individuals who did not respond or could not tolerate the medication would have withdrawn early [74,75,76]. Alternatively, CBD may exhibit a flat dose-response curve, whereby all doses are able to partially reverse the effects of Δ9-THC because of its non-competitive antagonist action at CB₁ receptors [9]. A final explanation for the disparate results is that oral CBD has the ability to attenuate/potentiate some and (but not other) effects associated with Δ9-THC due to activity at receptors other than CB₁, even at low doses and small ratios of CBD/Δ9-THC. Such an effect may be one reason why some studies found contradictory results using similar dose-ratios between the cannabinoids [51,55].