Does Cannabis Composition Matter? Differential Effects of Delta-9-tetrahydrocannabinol and Cannabidiol on Human Cognition
Marco Colizzi & Sagnik Bhattacharyya
Current Addiction Reports, 2017, 4, 62–74
Purpose of Review : The lack of clarity about the effect of cannabis use on cognition may be attributable to the considerable heterogeneity among studies in terms of cannabis composition. This article selectively reviews studies examining the distinctive effects of cannabinoids on human cognition, particularly those of delta-9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD).
Recent Findings : Research indicates that Δ9-THC administration acutely impairs cognition, particularly memory and emotional processing. Limited evidence suggests that CBD administration might improve cognition in cannabis users but not in individuals with neuropsychiatric disorders. Moreover, studies indicate that some acute Δ9-THC induced cognitive impairments may be prevented if Δ9-THC is administered in combination or following CBD treatment. Δ9- THC and CBD have also shown opposite effects on cognition related brain activation, possibly reflecting their antagonistic behavioral effects.
Summary : Research suggests greater cognitive impairments in individuals when exposed to high Δ9-THC or low CBD cannabis. It is unclear whether at specific concentrations CBD might outweigh any harmful effects ofΔ9-THC on cognition.
Keywords : Cannabis . Delta-9-tetrahydrocannabinol . Cannabidiol . Cognitive processing . Brain function
Interest in the effects of cannabis on human cognition stems from evidence regarding its role as the most widely used illicit drug  as well as an important risk factor for the development of psychosis [2, 3] and its relapse [4–8], the latter being a l s o cons i s t e n t w i t h e v i de n c e t h a t de l t a – 9 – tetrahydro-cannabinol (Δ9-THC), the main psychoactive ingredient of the Cannabis sativa plant, can induce transient psychotic symptoms upon acute administration in healthy volunteers [9–11]. This body of research is also consistent with independent evidence of endocannabinoid system abnormalities in psychosis , a disorder characterized by abnormalities in different cognitive processes .
However, evidence regarding the association between cannabis use and impairments in cognitive processing is less clear. While one may intuitively expect cannabis to have a deleterious effect on cognitive performance, studies in healthy volunteers have reported some discrepancies. For example, some studies suggest that healthy cannabis users show poorer cognitive performance [14–17]. Others report no difference in cognitive processing as a function of cannabis use . Even more conflicting results are present in studies in patients with schizophrenia. While some studies suggest poorer cognitive functions in patients with a history of cannabis exposure , others indicate better performance [15, 20] or no change [17, 21] in cannabis-using patients.
Variation in the results of studies investigating the effect of cannabis use on cognitive functioning, as outlined above, might have several explanations. These discrepancies may be because of genetic variation having an impact on cognitive phenotypes [22–29]. Moreover, it may reflect selective effect on certain aspects of cognition as suggested by available evidence, with a robust but modest deleterious impact on global memory function, a more pronounced detrimental effect on specific memory sub-domains such as prospective and retrospective verbal and visual memory, and limited effect on other cognitive domains [17, 30]. It may also reflect variation between different studies in the duration of cannabis exposure and/or of abstinence at the time of cognitive testing of study participants, as available evidence points towards a dosedependent effect with cognitive impairment being more marked following persistent cannabis use and incomplete restoration of function following cessation of use . Evidence from imaging studies also suggests that both chronic [32, 33] and acute cannabis exposure  might disrupt activity in brain networks involved in cognitive processing without necessarily affecting behavioral performance, suggesting either a deployment of greater neural effort or a change in strategy to maintain adequate task performance , thereby accounting for different effects in different individuals.
Independent of these potential explanations, the lack of a clear association between cannabis use and impairments in cognition may also to a large extent be attributable to the considerable heterogeneity in recreational cannabis that participants in these studies may have been exposed to, as well as the differing effects on cognition of the various chemicals found in the extract of the cannabis plant. The extract of Cannabis sativa has over 60 different cannabinoids , with Δ9-THC and cannabidiol (CBD) being the most prominent among them. However, while Δ9-THC is thought to be responsible for most of its psychotropic effects , CBD is under investigation for its potential antipsychotic effects, in opposition to the propsychotic effects of Δ9-THC. Research also suggests that CBD can counteract the negative effects of Δ9-THC, as investigated in both humans and animal models at a behavioral and neurochemical level [38–41]. This is of crucial importance considering that case-control studies suggest that the risk of development and relapse of psychosis in cannabis users depends on both frequency of use and cannabis potency [5, 42], with the risk being the highest in individuals exposed on a daily basis to cannabis with a high Δ9-THC concentration, and unchanged among users of cannabis with a lower Δ9-THC concentration and a more balanced Δ9-THC:CBD ratio. In line with evidence from human studies, research investigating the effect of different cannabinoids in animal models has consistently reported behavioral abnormalities following Δ9-THC exposure. Δ9-THC exposure during adolescence has been associated with long-term behavioral alterations in adult rats, such as recognition memory deficits, social withdrawal, and altered emotional reactivity . Other evidence suggests enduring cognitive impairment in the offspring of rats exposed to Δ9-THC during the perinatal period . Interestingly, altered behavior and cognition in animal models may be directly related to the Δ9-THC induced dysfunction of the glutamatergic and noradrenergic systems via cannabinoid receptor 1 activation, and this altered neurotransmission can be prevented or reversed if CBD is administered before or after Δ9- THC exposure, respectively [40, 43, 44].
Together, these findings underscore how the effects of different cannabinoids, which are often present in varying concentration in the cannabis available for use in the street, may confound the results of human studies investigating cognitive alterations associated with recreational cannabis use. In this article, we carry out a narrative review of studies examining the acute effects of cannabis on human cognition and related brain function, with emphasis on the distinctive effects of the different cannabinoids that have been examined to date, particularly Δ9-THC and CBD, in order to disentangle their contribution to specific cognitive processes.