cbd and memoryDecember 15, 2021
Previous episodic memory studies indicate that cannabinoids such as CBD may counteract the effects of THC. Chronic benefits of CBD were suggested in a study showing better recognition memory for words in regular cannabis users with CBD present in their hair (Morgan et al. 2012). A prior naturalistic study assessed acute effects in users who already prefer high-CBD strains (Morgan et al. 2010b). Prose recall was significantly higher after use of cannabis that was high in CBD compared to the low CBD group. Other previous studies have suggested that CBD acutely reduces THC-related learning and memory impairments in well-controlled human (Englund et al. 2013) and animal studies (Vann et al. 2008; Wright Jr. et al. 2013). In one clinical study, subjects were given an oral dose of CBD (600 mg) or a placebo 210 min ahead of an intravenous injection of THC (1.5 mg). Those in the CBD group showed better episodic memory (delayed free recall) compared to the placebo group (Englund et al. 2013). On the other hand, another prose recall study compared placebo, THC 8 mg, CBD 16 mg and THC 8 mg + CBD 16 mg in a randomized, double-blind crossover design with vaporizer inhalation (Morgan et al. 2018). Both the THC and THC + CBD conditions impaired memory, but CBD had no effects, even though the same subjects showed some protective effects of CBD in identification of facial emotions (Hindocha et al. 2015). These studies highlight that the effects of THC and CBD on memory may vary by dose, timing, and form of administration. Furthermore, they point to the need for measuring blood cannabinoid levels after cannabis administration to determine THC and CBD exposure.
Because University research staff are not permitted to handle legal market cannabis, we asked participants to weigh their product with a study-provided scale [American Weigh Scale, Gemini Series Precision Digital Milligram Scale (GEMINI-20)] at the experimental appointment both before and after ab libitum use. Although blood THC, CBD, and metabolite measures remain our primary measure of individual cannabinoid exposure, the weight that each participant provided (mg) was used to further estimate the amount of each cannabinoid consumed based on the percentages of THC and CBD contained in their specific study strain. While these mg estimates are not considered a primary measurement of cannabinoid dose, we include these data in order to facilitate integration and interpretation of our findings with prior controlled laboratory studies.
In addition to being a small feasibility study that needs to be replicated, there are three primary limitations of the present study. First, like Morgan et al. (2010a, 2010b), assignment of subjects to strains was not completely random, so pre-existing differences between participants could have influenced the results. For example, regular users of high potency THC concentrates may be more or less susceptible to its acute effects than other subjects. Bidwell et al. (2018) and Englund et al. (2013) used random assignment, but only Bidwell et al. (2018) used naturalistic administration. Second, the 50 min that elapsed after consumption prior to the memory assessment (which occurred.
Consistent with our approach for d’ , each of the other performance measures was separately analyzed in a mixed-design analysis of variance (ANOVA) with session (pretest, posttest) as a within-subject factor, and strain (THC, THC + CBD) as a between-subject factor. Results are presented without a covariate. When adding log (THC) as a covariate, no significant effects were observed for the 4 measures. Analysis of false alarm (FA) rate indicated a significant main effect of session, F (1, 29) = 18.45, p < .001, \( _p^2 \) = 0.39, showing a higher rate of FA at posttest compared to pretest. Session also interacted with strain for FA, F (1, 29) = 4.86, p < .05, \( _p^2 \) = 0.14, such that only the posttest FA rate was higher for the THC group than for the THC + CBD group (Table 3). Analysis of response bias ( c ) indicated a significant effect of session, F (1, 29) = 5.79, p < .05, \( _p^2 \) = 0.17, such that subjects were somewhat conservative pretest (tended to respond “no” more than “yes”) but somewhat liberal posttest (tended to respond “yes” more than “no”). Analysis of hit rate and reaction time revealed no significant effects. The presence of significant posttest hit rate effects in the t tests (Table 3), but not in the ANOVA, suggests that ANOVA did not have sufficient power to detect the session × strain interaction for this outcome.
First, we ran a regression model (Eq. 1) to examine how cannabinoid levels (THC + metabolites and CBD) were associated with accuracy (d’). The model revealed that the level of THC + metabolites was significantly negatively correlated to accuracy ( p < .05, \( _p^2 \) = 0.28) (Fig. 2a), but neither the effect of CBD (Fig. 2b) nor the THC × CBD interaction was significant. This result was observed across the two strain groups, and neither THC nor CBD blood levels were significantly correlated with d ′ within each strain group.
This study demonstrates the feasibility of a brief and mobile verbal recognition memory task for naturalistic and experimental studies of the acute effects of cannabis. Participants completed a recognition memory task before (pretest) and shortly after (posttest) ad libitum acute administration of cannabis products with varying THC:CBD ratios. Participants using products containing primarily THC showed significantly worse memory accuracy ( d’ ) after use than before use, whereas subjects using strains containing both THC and CBD showed no differences between pre- and posttest memory performance. When blood cannabinoid levels were considered, d’ was negatively correlated with THC levels, whereas performance showed no association with CBD levels. Thus, acute THC use was associated with impaired memory in a dose dependent manner, whereas the combination of THC and CBD was not associated with impaired memory.
One of the 32 participants was excluded from analyses because their pretest blood levels exceeded mean + 3 standard deviation over all participants, when considering the combination of THC + metabolites level (sum of THC, THC-COOH and 11-OH-THC) and CBD level. Footnote 3 This reduced the THC + CBD strain group from 17 to 16 participants (see Table 1).
The ratio of ∆9-tetrahydrocannabinol (THC) to cannabidiol (CBD) varies widely across cannabis strains. CBD has opposite effects to THC on a variety of cognitive functions, including acute THC-induced memory impairments. However, additional data are needed, especially under naturalistic conditions with higher potency forms of cannabis, commonly available in legal markets. The goal of this study was to collect preliminary data on the acute effects of different THC:CBD ratios on memory testing in a brief verbal recognition task under naturalistic conditions, using legal-market Colorado dispensary products. Thirty-two regular cannabis users consumed cannabis of differing THC and CBD levels purchased from a dispensary and were assessed via blood draw and a verbal recognition memory test both before (pretest) and after (posttest) ad libitum home administration in a mobile laboratory. Memory accuracy decreased as post-use THC blood levels increased ( n = 29), whereas performance showed no relationship to CBD blood levels. When controlling for post-use THC blood levels as a covariate, participants using primarily THC-based strains showed significantly worse memory accuracy post-use, whereas subjects using strains containing both THC and CBD showed no differences between pre- and post-use memory performance. Using a brief and sensitive verbal recognition task, our study demonstrated that naturalistic, acute THC use impairs memory in a dose dependent manner, whereas the combination of CBD and THC was not associated with impairment.
We do not have the specific time point for the memory assessment for each participant, so the time given here is an estimate based on the general flow of the protocol. The timing of the protocol should not differ between participants.
Past-month use of cannabis.
17% THC, < 1% CBD; n = 11) or a + THC/+CBD strain (8% THC, 16% CBD; n = 12) that was acquired from a local dispensary. Participants used the assigned cannabis strain in accordance with their normal usage habits for 3 days, including a final use on the third day. Immediately after this final use, participants were transported to the lab by the research team for a detailed assessment of its effects on neuro- and bio- behavioral functions, including memory. Blood draws were collected before the three-day use period (i.e., baseline), immediately upon arrival at the lab (within 15 min of last cannabis use), and at the end of the two-hour assessment in order to verify effective strain assignment and cannabinoid exposure. Testing included the International Shopping List Task (ISLT) as a measure of verbal recall (Thompson et al. 2011). The ISLT consists of a 12-item shopping list that was read out loud to the participant three times in the same order. After 30 min, a delayed free recall test was given. Results suggested that recall performance was negatively correlated with THC blood levels for the THC-only strain (+THC/−CBD), but recall performance was not significantly correlated with THC blood levels for the CBD-containing strain (+THC/+CBD). These preliminary findings suggest that the strain type differentially affected recall and prompt further research into the impacts of naturalistic administration of legal market THC and CBD on memory function.
Our primary measure of recognition memory performance was d’, but Table 3 shows other performance measures for completeness , including the hit and false alarm rates used to calculate d’ . Table 3 shows a measure of response bias ( c = − 1/2 * [ z H − z FA ]), where negative values indicate a liberal bias to respond “old” and positive values indicate a conservative bias to respond “new”. Table 3 also shows response time (RT). Each of these performance measures were separately analyzed in a mixed-design analysis of variance (ANOVA) with session (pretest, posttest) as a within-subject factor, strain group (THC and THC + CBD) as a between-subject factor, and THC + metabolite levels as a covariate.
After participants obtained the study product, they were asked to use it exclusively, and ad libitum , for the 5 days leading up to the experimental appointment, which took place in a mobile laboratory outside of the participants’ place of residence. Participants were asked to abstain from using cannabis on the day of the appointment, prior to the experiment. At the first assessment of the day (pre-use), participants completed a blood draw and the primary outcome measures, followed by the first administration of the recognition task. Footnote 1 Then they returned home to use their study cannabis ad libitum with their normally preferred method of administration. The THC group used 6 different administration methods: oil rig ( n = 6), bong ( n = 4), vaporizer ( n = 1), glass straw ( n = 2), joint ( n = 1) and bubbler ( n = 1). The THC + CBD group used 4 different administration methods: pipe ( n = 7), bong ( n = 5), vaporizer ( n = 2) and joint ( n = 2). Shortly thereafter, they returned to the mobile lab to complete the blood draw to estimate peak cannabinoid exposure, the primary outcome measures, and the recognition memory task again, while acutely intoxicated (acute post-use). The post-use recognition memory task took place 35 min after participants returned to the van. Footnote 2.
Compared to other recent studies examining the acute effects of THC on episodic memory, the present study included more naturalistic methods of cannabis use and higher dosage. Recognition accuracy was better before than after THC consumption and decreased as THC blood levels increased. Our participants self-administered their assigned products ad libitum using their normally preferred methods at home. The mean estimated THC dosage across both the THC and THC + CBD strain groups was 58.61 mg (range = 1.92–235.8 mg). In a broad review of studies of cannabis use on human cognition from 2004 to 2015, Broyd et al. (2016) identified 11 studies investigating acute effects on verbal episodic memory. Of those demonstrating acute memory deficits, five administered intravenous (IV) THC (D’Souza et al. 2004; D’Souza et al. 2008; Englund et al. 2013; Morrison et al. 2009; Ranganathan et al. 2012), two administered vaporized cannabis (Liem-Moolenaar et al. 2010; Theunissen et al. 2015), and one administered oral THC (nabilone) (Wesnes et al. 2009). Dosage in these studies ranged from 2 to 12 mg of THC. More recent studies have documented episodic memory impairments after acute use of 8 mg of THC with a vaporizer (Morgan et al. 2018) and 10.73 mg of THC with experimenter-regimented joint smoking (Hindocha et al. 2015). Thus, we have replicated prior work under more naturalistic conditions and higher doses, as well as replicating our previous free recall results in a separate sample of participants with a recognition memory task (Bidwell et al. 2018).
Multiple comparisons were assessed with Bonferroni post-hoc tests (with corresponding p -values reported as p bf ) for all analyses.
As is typical in recognition memory research (Macmillan and Creelman 2005; Malmberg 2008; Neath and Surprenant 2003; Wixted 2007) and consistent with previous studies on the effects of THC and CBD on recognition memory (Morgan et al. 2012; Morgan et al. 2010b), d’ (accuracy in discriminating old vs. new words) was used as the primary measure of memory performance. The hit rate ( H , proportion of correct “old” responses to studied words) and false alarm rate ( FA , proportion of incorrect “old” responses to non-studied words) are used to calculate d’ ( d′ = z H − z FA , where z is the standard normal distribution). Given the distribution of the metabolites, we performed a log transformation of the metabolite data.
Analysis of cannabinoid plasma biomarker levels revealed a main effect of session, F (1,29) = 11.44, p < .001, \( _p^2 \) = 0.28, and a significant main effect of cannabinoid type, F (1,29) = 16.12, p < .001, \( _p^2 \) = 0.36. Cannabinoid type interacted with strain group, F (1,29) = 5.25, p < .05, \( _p^2 \) = 0.15, showing that sum THC + metabolite levels were higher for the THC group compared to the THC + CBD group ( p bf < .05). Cannabinoid type interacted with session, F (1,29) = 7.69, p < .01, \( _p^2 \) = 0.21, showing that the level of sum THC + metabolites was higher at posttest (i.e., after cannabis use) compared to pretest ( p bf < .001). There was a significant 3-way interaction between cannabinoid type, strain group, and session, F (1,29) = 5.42, p < .05, \( _p^2 \) = 0.16. When this interaction was decomposed with Bonferroni-corrected post hoc tests, they indicated that the strain groups did not differ on any pretest levels, but posttest sum THC + metabolites levels were higher for the THC group than the THC + CBD group ( p bf < .001). When testing each measure separately (Table 2), we only observed a significant difference for THC levels at pretest. Posttest CBD levels were higher for the THC + CBD group than the THC group, whereas posttest THC levels and sum THC + metabolites were higher for the THC group than the THC + CBD group.
Because the recognition task was added onto another ongoing protocol, it was always run after the primary outcome measures for the main study which included assessments of other memory tasks, attention, inhibitory control, balance, and subjective drug effects. These tasks are unlikely to interfere with recognition memory results. The only other verbal memory test included was the International Shopping List Task (ISLT), which used different words than the recognition task. Our larger study found that THC administration was negatively associated with ISLT performance, but CBD results await ongoing data collection and analysis (Bidwell et al. 2020).
In an observational study, cannabis flower and concentrate users were assigned to purchase and use a legal market THC only or THC + CBD product. Participants completed a verbal recognition memory task at baseline and during an experimental mobile laboratory assessment approximately 50 min after ad libitum administration of their product. Thus, product strain was manipulated between participants and pre/post-use memory assessment was manipulated within participants.
Copyright © 2021 Batalla, Bos, Postma and Bossong.
Keywords: Cannabis (marijuana); cannabidiol; delta9-tetrahydrocannabinol; functional MRI; neuroimaging.
Background: Accumulating evidence suggests that the non-intoxicating cannabinoid compound cannabidiol (CBD) may have antipsychotic and anxiolytic properties, and thus may be a promising new agent in the treatment of psychotic and anxiety disorders. However, the neurobiological substrates underlying the potential therapeutic effects of CBD are still unclear. The aim of this systematic review is to provide a detailed and up-to-date systematic literature overview of neuroimaging studies that investigated the acute impact of CBD on human brain function. Methods: Papers published until May 2020 were included from PubMed following a comprehensive search strategy and pre-determined set of criteria for article selection. We included studies that examined the effects of CBD on brain function of healthy volunteers and individuals diagnosed with a psychiatric disorder, comprising both the effects of CBD alone as well as in direct comparison to those induced by ∆9-tetrahydrocannabinol (THC), the main psychoactive component of Cannabis . Results: One-ninety four studies were identified, of which 17 met inclusion criteria. All studies investigated the acute effects of CBD on brain function during resting state or in the context of cognitive tasks. In healthy volunteers, acute CBD enhanced fronto-striatal resting state connectivity, both compared to placebo and THC. Furthermore, CBD modulated brain activity and had opposite effects when compared to THC following task-specific patterns during various cognitive paradigms, such as emotional processing (fronto-temporal), verbal memory (fronto-striatal), response inhibition (fronto-limbic-striatal), and auditory/visual processing (temporo-occipital). In individuals at clinical high risk for psychosis and patients with established psychosis, acute CBD showed intermediate brain activity compared to placebo and healthy controls during cognitive task performance. CBD modulated resting limbic activity in subjects with anxiety and metabolite levels in patients with autism spectrum disorders. Conclusion: Neuroimaging studies have shown that acute CBD induces significant alterations in brain activity and connectivity patterns during resting state and performance of cognitive tasks in both healthy volunteers and patients with a psychiatric disorder. This included modulation of functional networks relevant for psychiatric disorders, possibly reflecting CBD’s therapeutic effects. Future studies should consider replication of findings and enlarge the inclusion of psychiatric patients, combining longer-term CBD treatment with neuroimaging assessments.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.