The endocannabinoid system is important to cognitive processes, including learning and memory (Marsicano and Lafenetre, 2009), and prolonged use of cannabis (Meier et al, 2012) has been associated with cognitive impairment. Meier et al (2012) reviewed records of 1037 individuals born between 1972 and 1973 in New Zealand. Neuropsychiatric testing was conducted before age 13 years and again at age 38 years. At several yearly intervals, participants were followed and questioned about their cannabis use. These who reported persistently using cannabis at ⩾3 interval times had a full-scale intelligence quotient that was about 10 points lower at age 38 years than those that reported never using cannabis or never regularly using cannabis.

Acute exposure to THC as well (D'Souza et al, 2004; Ranganathan and D'Souza, 2006) produces acute, transient, and dose-related cognitive impairments in executive function, abstract ability, and decision making. The most robust effects are on verbal learning, short-term memory, working memory, and attention (Hart et al, 2001; Heishman et al, 1990; Hooker and Jones, 1987; Leweke et al, 1998; Marks and MacAvoy, 1989; Miller et al, 1977; Ranganathan and D'Souza, 2006), consistent with effects in rodents and nonhuman primates (Lichtman et al, 2002; Wilson and Nicoll, 2002). CBD by itself does not appear to produce cognitive deficits. On the other hand, some studies suggest that CBD may decrease the cognitive impairing effects of THC, although the results are mixed.

Morgan et al (2010b) have conducted a series of cross-sectional studies examining the subchronic and acute effects of cannabis in recreational and heavy cannabis users. Cannabis-using individuals completed the same verbal memory at baseline and then returned 7 days later with their own supply of cannabis and completed the verbal memory task while intoxicated (Morgan et al, 2010b). Cognition was examined at baseline when subjects were not acutely intoxicated as well as after acute cannabis ingestion. Samples of cannabis smoked were assayed for the levels of THC and CBD. In this study, specimens with higher levels of CBD were associated with better prose recall (Morgan et al, 2010b). In a follow-up study, recreational and heavy users were examined while not intoxicated (subchronic THC exposure). Hair samples were obtained to assay for the THC/CBD levels. Daily cannabis users with high hair THC concentrations performed worse on verbal recall. Although CBD was not associated with a difference in prose recall in this sample, the presence of CBD was associated with better recognition recall (Morgan et al, 2012). Taken together, these data suggested that the presence of CBD in recreational cannabis may protect against the memory-impairing effects of THC. However, it must be noted that these cross-sectional studies are limited by self-report with regard to dose, frequency, and potency of cannabis used, possible relationship of type of cannabis with individual factors (eg, it cannot be determined whether individuals who sought more perceptual-altering effects used cannabis with greater THC content or vice versa), and recall bias regarding the types of symptoms experienced. Furthermore, the studies relied on individuals who continued to use cannabis and therefore possibly excluded those who may have had worse experiences.

Experimental laboratory-based studies can address some of these limitations of epidemiological studies and have also examined the effects of THC and CBD on cognition in humans. In a series of experiments, the effects of oral CBD (600 mg) and oral THC (10 mg) in a healthy cohort have been examined on verbal memory, executive function, and attention (Bhattacharyya et al, 2010; Borgwardt et al, 2008). Interestingly, in these studies, neither CBD nor THC significantly affected performance on cognitive tasks in these studies, although there were differences in brain-activation patterns as described below. It is possible that the lack of effects on performance reflects load/timing of the task or the dose/oral route of THC and CBD. Of note, these studies compared the effects of THC and CBD but did not examine the interactive effects. In contrast, Englund et al (2013) pretreated healthy subjects with CBD (600 mg PO)/placebo prior to receiving i.v. THC and demonstrated a protective effect on CBD on THC-induced verbal learning deficits.

Wade et al (2003) evaluated the effects of both THC and CBD in a clinical population of 24 individuals with a range of neurological symptoms, including multiple sclerosis, spinal cord injuries, brachial plexus damage, and neurofibromatosis. Individuals were given a 2.5 mg sublingual dose of CBD and then evaluated on the Short Orientation-Memory Concentration (SOMC) test (Wade and Vergis, 1999). CBD did not affect memory and concentration when administered alone but reversed the deficits on the SOMC seen with sublingual THC (2.5 mg).

The effects of cannabinoids on social cognition have also been evaluated. A large randomized double-blind placebo controlled crossover study of 48 cannabis users (n=24 light users, n=24 heavy users) examined the effects of oral CBD (16 mg), oral THC (8 mg), placebo, or the combination of THC+CBD on an emotional facial recognition task (Hindocha et al, 2015). The task consisted of showing a range of emotions of varying intensities from 20 to 100%. The results found that CBD improved facial recognition at the 60% emotional intensity, while THC impaired facial recognition of ambiguous faces at 40% intensity. The combination of THC+CBD resulted in no difference in emotion recognition from placebo, suggesting that CBD attenuated the THC-induced impairments.

Data from Neuroimaging Studies

Brain imaging studies employing functional magnetic resonance imaging (fMRI) and electrophysiology outcome measures provide an opportunity to assess the effects of THC/CBD in the brain during various perceptual/cognitive tasks. One of the earliest reported fMRI studies on the interactions of THC and CBD examined the effects of oral THC 10 mg, oral CBD 600 mg, and placebo on a go/no go task on three separate test days in 15 healthy volunteers in a double-blind randomized study (Borgwardt et al, 2008). In general, performance was similar on the task during all 3 test days. However, CBD decreased the BOLD response in the left insula and left superior/transverse gyri relative to placebo and THC decreased the BOLD response in the right inferior frontal gyrus, anterior cingulate gyrus, and bilaterally in the precuneus. THC also increased the BOLD response in the right hippocampus/para hippocampal gyrus, temporal gyrus, caudate and fusiform gyrus, and in the left posterior cingulate gyrus, suggesting that THC may specifically target areas involved in response inhibition, unlike CBD.

The same research group has published several other fMRI studies with oral THC 10 mg, oral CBD 600 mg, and placebo in healthy volunteers (Bhattacharyya et al, 2015; Bhattacharyya et al, 2010; Fusar-Poli et al, 2010; Fusar-Poli et al, 2009). Fusar-Poli et al (2009) evaluated the BOLD response related to THC and CBD during a fearful face task. Relative to placebo, CBD decreased activation in the left medial temporal region (including the amygdala and anterior para hippocampal gyrus), the anterior and posterior cingulate gyrus, the left middle occipital gyrus, and the right lobe of the cerebellum. THC increased BOLD response in the left precuneus and bilaterally in the primary sensory cortex, but decreased BOLD response bilaterally in the middle frontal gyrus and in the posterior cingulate gyrus. A connectivity analysis showed that CBD but not THC decreased forward connectivity with the amygdala and the anterior cingulate cortex (Fusar-Poli et al, 2010), suggesting that CBD may target a neural mechanism underlying anxiety disorders or posttraumatic stress disorder.

Bhattacharyya et al (2010) demonstrated that THC and CBD had diametrically opposite effects on BOLD response relative to placebo in the striatum during verbal recall, in the hippocampus while conducting an inhibition task, in the amygdala during a fearful face task, in the superior temporal cortex during a verbal listening task, and in the occipital cortex during a visual processing task. During an oddball salience processing task, THC and CBD also had opposite effects on functional connectivity between the dorsal striatum, prefrontal cortex, and hippocampus. These studies show opposing actions on regional activation by THC and CBD but need replication given their relatively small sample size. Significantly larger fMRI studies with behavioral outcomes will be required to continue to determine the neurobiological interactions of THC and CBD with acute administration.

To summarize, limited epidemiological and experimental data suggest that CBD may have a protective effect against THC-induced learning deficits. Further studies with larger sample sizes are needed to examine dose-related acute as well as chronic effects and to examine the interactive effects of CBD on THC rather than comparative effects on patterns of brain activation.