The negative health effects of THC(Tetrahydrocannabinol) on memory function of human brain

Epilepsy & Behavior 70 (2017) 349–354

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Epilepsy & Behavior

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Review

Neuroimaging studies towards understanding the central effects of pharmacological cannabis products on patients with epilepsy

Jane B. Allendorfer ⁎, Jerzy P. Szaflarski Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, USA

Abbreviations: fMRI, functionalmagnetic resonance ima CBD, cannabidiol; THCV, tetrahydrocannabivarin; PWE, pers ⁎ Corresponding author at: Department of Neurolo

Birmingham (UAB) Epilepsy Center, 312 Civitan Internati Avenue South, Birmingham, AL 35294, USA.

E-mail address: [email protected] (J.B. Allendor

http://dx.doi.org/10.1016/j.yebeh.2016.11.020 1525-5050/© 2016 Elsevier Inc. All rights reserved.

a b s t r a c t

a r t i c l e i n f o

Article history: Received 31 October 2016 Revised 11 November 2016 Accepted 14 November 2016 Available online 18 January 2017

Recent interest for the use of cannabis-derived products as therapeutic agents in the treatment of epilepsies has necessitated a reevaluation of their effects on brain and behavior. Overall, prolonged cannabis use is thought to result in functional and structural brain alterations. These effects may be dependent on a number of factors: e.g., which phytocannabinoid is used (e.g., cannabidiol (CBD) vs. tetrahyrocannabinol (THC)), the frequency of use (occasional vs. heavy), and at what age (prenatal, childhood, adulthood) the use began. However, due to the fact that there are over seven hundred constituents that make up the Cannabis sativa plant, it is difficult to de- termine which compound or combination of compounds is responsible for specific effects when studying recre- ational users. Therefore, this review focuses only on the functional MRI studies investigating the effects of specific pharmacological preparations of cannabis compounds, specifically THC, tetrahydrocannabivarin (THCV), and CBD, on brain function in healthy individuals and persons with epilepsy with references to non- epilepsy studies only to underline the gaps in research that need to be filled before cannabis-derived products are considered for a wide use in the treatment of epilepsy.

This article is part of a Special Issue entitled "Cannabinoids and Epilepsy" © 2016 Elsevier Inc. All rights reserved.

Keywords: Epilepsy Cannabis Tetrahydrocannabinol (THC) Tetrahydrocannabivarin (THCV) Cannabidiol (CBD) Functional MRI (fMRI)

1. Introduction

The use of products derived from Cannabis sativa for the treatment of various medical conditions has long been of popular, research, andmed- ical interest; its use has beenwidely debated (e.g., the CNN “Weed” series by Dr. Sanjay Gupta). This public resurgence in interest for the indication of cannabis products as therapeutic agents in the treatment of epilepsies has necessitated a reevaluation of the known effects on brain and behav- ior [1,2]. These popular trends and assertions were recently fueled by positive results from three cannabidiol (CBD) studies for the treatment of the Dravet and Lennox–Gastaut syndromes [3–5] and by human data supporting the importance of the endocannabinoid system to the onset and generation of seizures [6–8]. In particular, one study docu- mented lower levels of anandamide in the cerebrospinal fluid of patients with new-onset temporal lobe epilepsy when compared to healthy con- trols [6], another study indicated a downregulation of cannabinoid 1 (CB1) receptor mRNA when compared to non-epilepsy controls that re- sulted in lower production of diacylglycerol lipase-alpha, an enzyme

ging; THC, tetrahydrocannabinol; ons with epilepsy. gy, University of Alabama at onal Research Center, 1719 6th

fer).

responsible for “on demand” production of 2-arachidonoylglycerol (2- AG) [7] and, finally, a PET study showed increased availability of CB1 re- ceptors in the temporal lobes of patients with epilepsy when compared to healthy controls [8]. These and other studies support further develop- ment of cannabinoids for the treatment of epilepsy [9,10]. But, the poten- tial benefits of phytocannabinoids need to be viewed through the prism of their known and unknown effects on brain development and function. The overall consensus is that prolonged cannabis use may result in functional and structural brain alterations that persist beyond the intox- ication period, and that onset of use during the neurodevelopmental period may be associated with greater cognitive deficits [11–13]. For example, evidence from early development studies indicates that recre- ational cannabis use in expectant mothers has short- and long-term ef- fects on the developing and mature brain and that these effects are different from the effects of tobacco use [11]. Another recent cannabis and neuroimaging study of structural changes in the developing brain documented negative effects onbrain diffusion parameters thatwere de- pendent on the age of cannabis use initiation [14]. Thus, early exposure to cannabis productsmay result in the alteration of the endocannabinoid system functionwhichmay be important for cognitive development [15] and relevant to the use of such products in children and adolescents.

Functional neuroimaging, in particular, functional magnetic reso- nance imaging (fMRI), allows for the non-invasive examination of how cannabis acts on the human brain to affect, behavior. A recent

350 J.B. Allendorfer, J.P. Szaflarski / Epilepsy & Behavior 70 (2017) 349–354

review in chronic cannabis users described varying patterns of resting brain activity in adolescents and adults, as well as altered brain activa- tion while performing cognitive tasks (e.g., tasks assessing attention, memory, motor function, inhibition, affect, and decision-making) when compared to healthy control subjects; the authors suggest that these differences are compensatory as a result of chronic cannabis use [11]. Functional magnetic resonance imaging (fMRI) has also been help- ful in investigating the acute effects of cannabis and specific cannabis compounds on brain functions, with a review of drug challenge studies that utilized either cannabis or tetrahydrocannabinol (THC) showing that task difficulty affects the impact of drug administration and that participants can achieve normal performance after drug administration on less demanding tasks but with alterations in neural recruitment or increased neural effort [16].

An important consideration in cannabis studies is that there are over seven hundred constituents that make up the Cannabis sativa plant, more than 100 ofwhich are classified as cannabinoids [17]. Due to the nu- merous available preparations of cannabis and the variability in concen- trations of different compounds in such preparations [18], not to mention the potential for and high likelihood of contaminants, it is diffi- cult to ascertain which compound or combination(s) of compounds are responsible for specific effects, cognitive or otherwise,when studying rec- reational users. Pharmacological studies using purified cannabis com- pounds provide insight into specific effects on human brain and behavior, and are more informative when considering the use of such compounds for therapeutic indications. Tetrahydrocannabinol (THC) is the most studied cannabis compound, although there have not been as many human studies investigating its neural effects as there have been on its subjective, cognitive, and behavioral effects. In addition to studies of the effects of THC, few recent neuroimaging studies have focused on the central effects of other phytocannabinoids — tetrahydrocannabivarin (THCV) and cannabidiol (CBD). In this review, we will summarize fMRI studies focusing on the effects of pharmacological preparations of THC, THCV, and CBD on brain function in healthy individuals and persons with epilepsy (PWE).

2. Functional MRI studies of cannabis compounds in healthy individuals

2.1. Tetrahydrocannabinol (THC)

Tetrahydrocannabinol, the main psychoactive component of canna- bis, acts centrally as a partial agonist to CB1 receptors in the brain tome- diate release of various neurotransmitters including acetylcholine, glutamate, and dopamine to name a few [19,20]. In humans, CB1 recep- tors have a high density in the medial temporal, prefrontal, and anterior cingulate cortex [21], brain regions that are critical to a number of cogni- tive and emotion processes which are frequently affected by epilepsy. In healthy individuals, THChas been shown to impair learning andmemory performance [22], as well as performance on motor control, executive function, motor impulsivity, and risk-taking tasks [23]. The earliest reported human fMRI study of pharmacological THC administration was a double-blind, placebo-controlled investigation of amygdala reac- tivity to explore the anxiolytic properties of THC and the potential to target the endocannabinoid system in the treatment of anxiety/social fear disorders [24]. This was followed by a series of fMRI studies investi- gating the acute effects of THC on sensory,motor, emotion, and cognitive processing in healthy male volunteers using a double-blind, placebo- controlled cross-over design [25–33]. The Pharmacological Imaging of the Cannabinoid System study also utilized a randomized, placebo- controlled cross-over design to assess acute effects of THC on memory, reward, attention, emotion, motor, and resting state processes in males [34–41]. Further, THC has been shown to alter resting state brain activity with increased amplitude of fluctuations compared to placebo in a num- ber of brain regions including the insula, substantia nigra, and cerebel- lum [36]. The studies described in greater detail below further illustrate

how THC acutely alters patterns of activation during a number of cogni- tive processes.

2.1.1. Sensory and motor processes The first fMRI study investigating the effects of THC on neural circuit-

ry showed no effect on primary visual andmotor activation during a pas- sive visual/motor task in which subjects viewed a flashing checkerboard while pressing their right index finger [24]. However, another study uti- lizing a passive sensory stimulation task showed that THC elicited both decreased and increased activation in regions of the visual cortex and cerebellum bilaterally during visual processing of a radial checkerboard with different flicker rates [29]. These two studies suggest that THC may not alter brain activity in response to simple visual andmotor stim- uli but does so with respect to more complex visual stimuli. Winton- Brown et al. also showed that during auditory processing, THC decreased activation compared to placebo bilaterally in temporal regions, insulae, and supramarginal gyri, and in the right inferior frontal gyrus and cere- bellum [29]. Compared to placebo, THC also elicited reduced activation during motor response inhibition in the right inferior frontal gyrus, and in the bilateral anterior cingulate and precuneus, but increased activation in right temporal and subcortical brain regions as well as the left poste- rior cingulate and precuneus [25]. There was no difference between task performance following administration of placebo or THC in the study by Borgwardt et al. [25] but a later study showed that those who experienced THC-induced psychotic effects had decreased task perfor- mance and decreased activation in the left parahippocampal/fusiform gyrus, left middle temporal gyrus, and right cerebellum extending into the fusiform gyrus, as well as increased activation in the right middle temporal gyrus in those who did not experience psychotic effects [32].

2.1.2. Learning and memory For verbal learning and memory, THC disturbed the normal pattern

observed with placebo of decreasing activation with repeated presenta- tion of encoding blocks (e.g., in parahippocampal gyrus and cerebellum) and recall blocks (e.g., in dorsoanterior cingulate/medial prefrontal cor- tex) during a paired associates learning task; this decrement in neural re- cruitment with learning was associated with an improvement in recall score in the placebo condition; this effect was abolished with THC ad- ministration [28]. A follow-up study revealed that a particular genetic profile for the dopamine transporter (DAT1) and the protein kinase B (AKT1), both involved in dopamine neurotransmission, increased sensi- tivity to the effects of THC and altered activity in the striatum during encoding aswell as in themidbrain during recall [33]. For pictorial learn- ing and memory, THC decreased activation in the right inferior frontal gyrus, right insula, and left middle occipital gyrus during encoding, and increased precuneus activation bilaterally during recall [39]. While there was no difference in task performance between placebo and THC conditions, the negative correlation between task accuracy and brain ac- tivity during recall (in the left fusiform/parahippocampal gyrus and bilat- eral middle occipital gyrus) that was observed for the placebo condition did not exist under the THC condition [39], similar to the pattern of dis- ruption observed by Bhattacharyya et al. [28] with the paired associates task. Finally, THCwas shown to impairworkingmemory performanceon the Sternberg item-recognition task compared to placebo, and instead of the linear increase in brain activity with increasing working memory load that was observed with placebo, THC enhanced brain activity even in the low working memory load conditions [40].

2.1.3. Emotion processing Using an emotion perception task inwhich subjects had tomatch up

faces displaying the same emotion (i.e., angry, fearful or happy), THC was shown to attenuate activation in the right amygdala compared to placebo when processing threatening (i.e., angry and fearful) faces but did not affect task accuracy or response times [24]. Utilizing a similar emotion perception task, Bossong et al. [41] showed that THC relative to the placebo condition did not affect overall response times or

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accuracy for matching happy faces, but reduced accuracy for matching fearful faces. Furthermore, region-of-interest analysis showed reduced activity while processing fearful faces in a network of brain regions in- cluding amygdala, hippocampus, orbital frontal gyrus, prefrontal cortex, parietal gyrus, and occipital cortex [41]. Fusar-Poli et al. [27] utilized a different emotion perception task in which subjects viewed faces with intensely fearful, mildly fearful or neutral expressions and were asked to distinguish male versus female faces. In this paradigm, there were no differences in task performance, but THC relative to placebo de- creased activation during the processing of fearful faces in the right in- ferior frontal gyrus, superior temporal gyrus, and left medial frontal gyrus, while increasing activation in the left precuneus [27]. However, THC did not modulate the anterior cingulate–amygdala effective con- nectivity that was identified in the placebo condition when processing fearful faces [26]. Taken together, THC may have potential utility in the treatment of anxiety/social fear disorders as suggested by Phan et al. [24].

2.1.4. Attention The effect of THC on various attention-related processes has been in-

vestigated. Utilizing a visual oddball detection task, THC compared to placebo increased response time and attenuated activation during sa- lience processing (i.e., when presented with rare or deviant stimuli) in the right caudate/putamen, insula, and thalamus but enhanced re- sponse in the right prefrontal cortex [31]. Follow-up analysis revealed that THC reduced the fronto-striatal functional connectivity between thedorsal striatumandprefrontal cortex, but enhanced connectivity be- tween the hippocampus and prefrontal cortex [30]. Bossong et al. [34] examined executive function using a continuous performance task in which subjects had to respond quicklywhen they are presented consec- utive numbers that are identical. Relative to placebo, THC impaired task performance (i.e., increasing false alarms and reducing target accuracy) and induced less deactivation in regions associated with the default mode network including the posterior cingulate and angular gyrus; less deactivation was associated with poorer performance [34].

2.1.5. Reward processing Modified versions of a monetary incentive delay task (i.e., subjects

were cued as towhether or not the trial was rewarded or neutral before being given a target in which they had to press a button, followed by performance feedback)were used to investigate the effect of THC on re- ward processing [35,38]. THC relative to placebo did not alter the pat- tern of faster response times during reward trials compared to neutral trials, did not affect activation during the anticipation period, but did at- tenuate activation to feedback in reward trials in feedback-related brain regions including bilateral inferior parietal and temporal gyrus, posteri- or and anterior cingulate, and middle orbitofrontal gyrus, as well as the right superior frontal gyrus [38]. Anatomical region-of-interest analysis was later performed to investigate specific THC effects on caudate, puta- men, and nucleus accumbens which are implicated in reward process- ing, and showed that THC elicited a significant reduction in nucleus accumbens activation during anticipation to reward in healthy individ- uals addicted to nicotine but not in those who were not addicted [35].

2.1.6. Summary The overall impression of acute THC effects on human brain function

is that it does not significantly impair performance on some cognitive tasks, specifically, on tasks of motor response inhibition, verbal and pic- torial learning andmemory, emotion processing, and reward processing as described above, but that the typical patterns of task-related activa- tionwere disrupted. The ability of THC to attenuate brain activation dur- ing the processing of threatening (i.e. angry or fearful) faces may prove beneficial in the treatment of anxiety/social fear disorders. However, performance on tasks assessing working memory (i.e. Sternberg task) and attentional processes (i.e. visual oddball and continuous

performance tasks) seems to be particularly sensitive to THC-induced impairments and changes in neural recruitment.

2.2. Tetrahydrocannabivarin (THCV)

Like THC, the central effects of THCV are also mediated through CB1 receptors, but have some differing effects [20]. Namely, THCV can also act as a neutral antagonist of CB1 receptors, meaning that it does not af- fect the constitutive or basal activity level of CB1 receptors but can block the activity of other CB1 receptor compounds [20,42]. The neural effects of THCV in humans have been investigated using a model of reward and aversion processing during fMRI as it has been considered a possible treatment for obesity [43]. Compared to placebo, THCV increased BOLD responses to rewarding stimuli (i.e., chocolate) in the anterior cingulate cortex, caudate, putamen, and midbrain, and to aversive stimuli (image ofmoldy strawberries and less pleasant strawberry taste) in the caudate, putamen, amygdala, insula, and orbitofrontal cortex [43]. A follow-up resting state fMRI study showed that a single dose of THCV reduced func- tional connectivity between amygdala and regions in the default mode network including the posterior cingulate cortex (PCC), while also in- creasing connectivity between regions involved in executive control such as between the dorsal medial prefrontal cortex and the inferior frontal gyrus [44].

2.3. Cannabidiol (CBD)

Cannabidiol is a non-psychoactive component of cannabis, although it has been shown to have antipsychotic effects (see [45] for review) as well as anxiolytic properties [46,47]. Themechanism of action for CBD's central effects remains unclear, and while it is thought to be mainly in- dependent of CB1 receptor mechanisms due to its low receptor affinity, there is some evidence that CBD can act as an inverse agonist for the CB1 receptor such that it induces effects opposite to that of an agonist like THC, which may underlie some of the observed neurophysiological and behavioral effects that are opposite to those of THC [20,48]. The same studies that had investigated acute THC effects on various brain functions in healthy males during fMRI also assessed acute effects of CBD compared to placebo [25–31,49]. The results for CBD relative to placebo in these studies will be discussed here, as findings with THC were included in the section above.

Compared to placebo, CBD elicited decreased activity during motor response inhibition in the left insula, superior temporal gyrus, and trans- verse temporal gyrus and did not affect task performance [25]. CBDmod- ulated sensory processing compared to placebo by increasing activation in the temporal and insular cortex and by reducing activation in other parts of the posterior left temporal cortex, insula, and supramarginal gyrus during auditory processing, and during visual processing, CBD also increased activation in the right occipital lobe [29]. For verbal learn- ing andmemory, however, CBDdid not differ fromplacebo in its ability to modulate activation (i.e., to decrease engagement of particular brain re- gions) over repeated word pair encoding and word retrieval blocks [28], consistent with previous work showing that CBD does not affect learning andmemory [22,50]. CBDdoes appear to affect emotionprocess- ing, as it attenuated the fMRI response to fearful faces compared to place- bo in the left anterior cingulate and amygdala and the right posterior cingulate and cerebellum, aswell as reducing autonomic arousal [27]. Ad- vanced analysis using dynamic causal modeling showed that during the neural response to fearful faces, the left anterior cingulate cortex and the left amygdala were functionally coupled, with the driving inputs en- tering through the anterior cingulate that has forward connectivity to the amygdala, and this intrinsic connection is disrupted by CBD [26]. Com- pared to placebo, CBD also attenuated the neural response to processing stimulus salience in the left medial prefrontal cortex, but enhanced re- sponse in the right caudate, parahippocampal gyrus, insula, precentral gyrus, and thalamus [31]. Connectivity analysis for salience processing re- vealed that CBD reduced functional connectivity between the prefrontal

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cortex and hippocampus, but enhanced connectivity between the dorsal striatum and prefrontal cortex [30].

3. Functional MRI studies of cannabinoids in persons with epilepsy

To date, there are no publications of fMRI utilization to study brain function in patients with epilepsy taking pharmacologic cannabis prod- ucts. However, these studies are currently underway. An abstract presented at the 2016 Meeting of the Organization for Human Brain Mapping evaluated the effects of CBD treatment on fMRI activity during an attentional Flanker task in which PWE were presented with congru- ent or incongruent visual stimuli, e.g., a row of five fish all pointing in the samedirection (congruent condition) orwith the centerfishpointing in the direction opposite the other surrounding fish (incongruent condi- tion). This study is part of the UAB Cannabidiol Program, an ongoing open-label study of adjunct pharmaceutical grade CBD (Epidiolex) for the treatment of treatment-resistant epilepsy (NCT02695537, NCT02700412). Initial reports on small numbers of subjects documented a trend of improvement (not statistically significant) in behavioral per- formance that paralleled changes in attention-related brain activity, as well as overall improvement in seizure control in patients after achieving a stable dose of CBD (20 mg/kg or 25 mg/kg) when compared to the same subjects prior to the initiation of therapy with CBD. Results of follow-up analyses in 11 PWE (6 females), that were presented at the 2016 Annual Meeting of the American Epilepsy Society (AES), showed similar trends in improving performance on an attentional Flanker task and changes in brain activity during response inhibition, particularly in the left inferior frontal gyrus (Fig. 1). Additional preliminary results for a modified Sternberg working memory task showed an overall increase in the recruitment of brain regions during load-sensitive encoding (Fig. 2A) and decreased recruitment during retrieval (Fig. 2B) after CBD treatment compared to pre-CBD; these changes in neural recruitment were coupled with a non-significant trend in improving task accuracy. The caveats to research in such a diverse patient population of treatment-resistant epilepsies include the inter-subject variability in neurophysiological and treatment response, potential interactions with other medications or comorbid conditions, and overall differences in cognitive performance of the participants, all of which could influence activation during fMRI. However, the authors concluded that the prelim- inary findings are promising in that they illustrate the potential for CBD treatment to improve cognition, in addition to seizure control, in PWE.

Fig. 1. Preliminary results of regression analysis in patients receiving CBD treatment for epilepsy who performed an attentional Flanker task during fMRI. Results show a greater response difference between congruent and incongruent conditions at visit 2 compared to pre-CBD fMRI in the left inferior frontal gyrus — an area involved in many cognitive processes including executive control and working memory. Left in the image is left in the brain.

4. Discussion

There is little doubt of the therapeutic potential of products derived from the Cannabis sativa plant. However, we still have much to learn about the safety and efficacy of such compounds for the treatment of var- ious conditions including epilepsy and of their effects on brain and be- havior. While THC is the most studied phytocannabinoid to date, the majority of pharmacological neuroimaging studies included only male subjects, calling into question the generalizability of the results. Further- more, increased research into the effects of other phytocannabinoids is necessary as they may be of greater (or different) utility for particular medical conditions including epilepsy. For instance, if further research determines that THCV or CBD are as effective for the treatment of epilep- sy, the anti-obesity effects of THCV may guide the therapy in patients with co-existing weight problems or the antipsychotic and anxiolytic ef- fects of CBD may also be more desirable for patients with epilepsy and co-existingmood issues. Investigation into dose response and interaction effects of different cannabis compounds and their various combinations are warranted. Finally, because of the possibility of an entourage effect, while the efficacy of combinations of phytocannabinoids is being exam- ined, the effects of such combinations on brain and behavior in patients with epilepsy need to be investigated in parallel.While the preclinical re- search of phytocannabinoids is necessary and informs us of the mecha- nisms of action, studies in humans are important for providing us with information on brain and behavior effects that cannot be mimicked in animalmodels. A recent example is the assessment of THCV as a possible treatment for obesity when compared to the drug Rimonabant, which waswithdrawn from clinical use due to the increased rates of depression in those using it [51], an effect that was not observed in the animal screening of the drug [52].

An issue that must be considered with fMRI studies in general is the replicability of results. Many factors contribute to this including the task utilized during fMRI, the cohort of individuals being studied, sample size, data processing stream, and statistical inference applied in the in- terpretation of results, just to name a few. The use of standard sets of tasks (akin to the NIH Common Data Elements) and neuroimaging pa- rameters (e.g. those developed by the Human Connectome Project) and clear dissemination of methods used in data acquisition and analy- sis help to alleviate this issue. However, itmust also be kept inmind that human cognition is complex, and with the rapid pace of technological advancement we are continually developing potentially better ways of testing various cognitive processes and data analysis techniques. Therefore, we should not impede these advancements for the sake of standardization, but rather stress the importance of complete and trans- parent reporting of methods used to acquire and analyze data to allow for independent laboratories to replicate results. Since there have been relatively few pharmacological fMRI studies investigating the brain and behavior effects of cannabis-derived compounds, results of these initial studies have yet to be replicated. However, findings from pharmacological fMRI studies performed by three independent labora- tories investigating acute THC effects on emotion processing of threatening (i.e. angry and/or fearful) faces have been consistent and suggest potential utility of THC in treating anxiety/social fear disorders [24,27,41]. Future studies should consider utilizing the cognitive tasks and data acquisition parameters used in these earlier reports.

There are, of course, a number of important considerations when conducting human studies of cannabis compounds. Factors that may be of significance include a person's cannabis use history (e.g., drug- naïve versus occasional versus heavy use), which has previously been shown to affect THC-induced impairments [53]. Individual differences in a person's behavioral, neural, and cognitive responses to phytocannabinoids need to be considered [32], as well as specific genetic variations that may influence a person's sensitivity to drug effects [33]. Finally,we knowvery little of the long-termeffects of phytocannabinoids. A 2012 Cochrane Review that included four studies that used CBD as treatment in a total of 48 PWE found that a 200–300 mg/day dose of

A High Load Encoding

Low Load Encoding

B Retrieval after High Load / Long Delay

Retrieval after Low Load / Short Delay

Fig. 2. Preliminary results in patients receiving CBD treatment for epilepsy who performed a modified Sternberg task during fMRI. (A) Regression analysis revealed changes in neural recruitment of brain regions from pre-CBD to visit 2 fMRI during working memory encoding of 6 letters (high load condition; top row) and 2 letters (low load condition; bottom row), with regions in orange representing increased activation and regions in blue representing decreased activation at visit 2 compared to pre-CBD fMRI. (B) Compared to pre-CBD fMRI, neural recruitment of brain regions was decreased at visit 2 fMRI during working memory retrieval following high load/long delay (6 letters/12 s; top row) and low load/short delay (2 letters/4 s; bottom row) conditions, as represented by regions in blue. Left in the image is left in the brain.

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CBDwas safely tolerated in the small sample of patients for a short period of time, but the authors could not form any conclusions regarding the efficacy of phytocannabinoids as a treatment for epilepsy or effects of prolonged treatment [54]. In addition to the three randomized, placebo- controlled trials of CBD (Epidiolex) showing drug efficacy and patient tolerability [3–5], a 12-week open label trial of CBD recently showed that itmight reduce seizure frequency andmay have an acceptable safety profile in children and young adults with treatment-resistant epilepsy [55]. Thus, the ongoing open-label CBD neuroimaging study described in Section 3 and other ongoing studies are very important for the assess- ment of the central effects of cannabinoids and show promising prelimi- nary results of not only reducing seizure frequency, but also potentially improving cognitive processes and performance. However, further ran- domized, double-blind, placebo-controlled trials and longitudinal studies are necessary to better characterize and assess the central effects of CBD and other cannabis compounds.

Disclosures

Drs. Allendorfer and Szaflarski receive salary support and research funding from the State of Alabama Department of Commerce for their work in the UAB Cannabidiol Program, an open-label study of CBD in the treatment of seizures. Dr. Allendorfer has received research funding from the University of Alabama at Birmingham (UAB) and serves as an associate editor of the journal Restorative Neurology and Neuroscience. Dr. Szaflarski serves as a consultant regarding cannabis education and has received funding from GW Pharmaceuticals. He has also received

research funding from the National Institutes of Health, Shor Foundation for Epilepsy Research, Epilepsy Foundation of America, Food and Drug Administration, Compumedics Neuroscan, Inc., Department of Defense, National Science Foundation, Eisai Pharmaceuticals Inc. and UAB. He serves as an associate editor of journals Restorative Neurology and Neuro- science and Journal of Epileptology, as contributing editor to Epilepsy Cur- rents and on editorial boards of the journals Conference Papers in Medicine, Epilepsy & Behavior, Folia Medica Copernicana and Journal of Medical Science.

References

[1] Maa E, Figi P. The case for medical marijuana in epilepsy. Epilepsia 2014;55(6): 783–6.

[2] Mathern GW, Beninsig L, Nehlig A. Fewer specialists support using medical marijua- na and CBD in treating epilepsy patients compared with other medical professionals and patients: result of Epilepsia's survey. Epilepsia 2015;56(1):1–6.

[3] GW Pharmaceuticals announces positive phase 3 pivotal trial results for Epidiolex (cannabidiol) in the treatment of Lennox–Gastaut syndrome. June 2016; Available from: http://www.gwpharm.com/GW Pharmaceuticals Announces Positive Phase 3 Pivotal Trial Results for Epidiolex cannabidiol in the Treatment of Lennox–Gastaut Syndrome.aspx.

[4] GW Pharmaceuticals announces second positive phase 3 pivotal trial for Epidiolex (cannabidiol) in the treatment of Lennox–Gastaut syndrome. Available from: http://www.gwpharm.com/PR260916.aspx; September 2016.

[5] GW Pharmaceuticals announces positive phase 3 pivotal study results for Epidiolex (cannabidiol) March 2016; Available from: http://www.gwpharm.com/GW Phar- maceuticals Announces Positive Phase 3 Pivotal Study Results for Epidiolex cannabidiol.aspx.

[6] Romigi A, Bari M, Placidi F, Marciani MG, Malaponti M, Torelli F, et al. Cerebrospinal fluid levels of the endocannabinoid anandamide are reduced in patients with un- treated newly diagnosed temporal lobe epilepsy. Epilepsia 2010;51(5):768–72.

354 J.B. Allendorfer, J.P. Szaflarski / Epilepsy & Behavior 70 (2017) 349–354

[7] Ludanyi A, Eross L, Czirjak S, Vajda J, Halasz P,WatanabeM, et al. Downregulation of the CB1 cannabinoid receptor and relatedmolecular elements of the endocannabinoid sys- tem in epileptic human hippocampus. J Neurosci 2008;28(12):2976–90.

[8] Goffin K, Van PaesschenW, Van Laere K. In vivo activation of endocannabinoid system in temporal lobe epilepsy with hippocampal sclerosis. Brain 2011;134(Pt 4):1033–40.

[9] Szaflarski JP, Bebin EM. Cannabis, cannabidiol, and epilepsy—from receptors to clin- ical response. Epilepsy Behav 2014;41:277–82.

[10] Friedman D, Devinsky O. Cannabinoids in the treatment of epilepsy. N Engl J Med 2015;373(11):1048–58.

[11] Batalla A, Bhattacharyya S, Yucel M, Fusar-Poli P, Crippa JA, Nogue S, et al. Structural and functional imaging studies in chronic cannabis users: a systematic review of ad- olescent and adult findings. PLoS One 2013;8(2), e55821.

[12] Lorenzetti V, Lubman DI, Whittle S, Solowij N, Yucel M, Structural MRI. Findings in long-term cannabis users: what do we know? Subst Use Misuse 2010;45(11): 1787–808.

[13] Lisdahl KM, Wright NE, Kirchner-Medina C, Maple KE, Shollenbarger S. Considering cannabis: the effects of regular cannabis use on neurocognition in adolescents and young adults. Curr Addict Rep 2014;1(2):144–56.

[14] Zalesky A, Solowij N, Yucel M, Lubman DI, Takagi M, Harding IH, et al. Effect of long- term cannabis use on axonal fibre connectivity. Brain 2012;135(Pt 7):2245–55.

[15] Harkany T, GuzmanM, Galve-Roperh I, Berghuis P, Devi LA, Mackie K. The emerging functions of endocannabinoid signaling during CNS development. Trends Pharmacol Sci 2007;28(2):83–92.

[16] Bossong MG, Jansma JM, Bhattacharyya S, Ramsey NF. Role of the endocannabinoid system in brain functions relevant for schizophrenia: an overview of human chal- lenge studies with cannabis or 9-tetrahydrocannabinol (THC). Prog Neuro- Psychopharmacol Biol Psychiatry 2014;52:53–69.

[17] Radwan MM, ElSohly MA, El-Alfy AT, Ahmed SA, Slade D, Husni AS, et al. Isolation and pharmacological evaluation of minor cannabinoids from high-potency Cannabis sativa. J Nat Prod 2015;78(6):1271–6.

[18] Vandrey R, Raber JC, RaberME, Douglass B,Miller C, Bonn-MillerMO. Cannabinoid dose and label accuracy in edible medical cannabis products. JAMA 2015;313(24):2491–3.

[19] Grotenhermen F. Cannabinoids. Curr Drug Targets CNS Neurol Disord 2005;4(5): 507–30.

[20] Pertwee RG. The diverse CB1 and CB2 receptor pharmacology of three plant cannabi- noids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Br J Pharmacol 2008;153(2):199–215.

[21] Eggan SM, Lewis DA. Immunocytochemical distribution of the cannabinoid CB1 re- ceptor in the primate neocortex: a regional and laminar analysis. Cereb Cortex 2007;17(1):175–91.

[22] Ilan AB, Gevins A, ColemanM, ElSohly MA, deWit H. Neurophysiological and subjec- tive profile of marijuana with varying concentrations of cannabinoids. Behav Pharmacol 2005;16(5–6):487–96.

[23] Ramaekers JG, Kauert G, van Ruitenbeek P, Theunissen EL, Schneider E, Moeller MR. High-potency marijuana impairs executive function and inhibitory motor control. Neuropsychopharmacology 2006;31(10):2296–303.

[24] Phan KL, Angstadt M, Golden J, Onyewuenyi I, Popovska A, de Wit H. Cannabinoid modulation of amygdala reactivity to social signals of threat in humans. J Neurosci 2008;28(10):2313–9.

[25] Borgwardt SJ, Allen P, Bhattacharyya S, Fusar-Poli P, Crippa JA, Seal ML, et al. Neural basis of delta-9-tetrahydrocannabinol and cannabidiol: effects during response inhi- bition. Biol Psychiatry 2008;64(11):966–73.

[26] Fusar-Poli P, Allen P, Bhattacharyya S, Crippa JA, Mechelli A, Borgwardt S, et al. Mod- ulation of effective connectivity during emotional processing by delta 9- tetrahydrocannabinol and cannabidiol. Int J Neuropsychopharmacol 2010;13(4): 421–32.

[27] Fusar-Poli P, Crippa JA, Bhattacharyya S, Borgwardt SJ, Allen P, Martin-Santos R, et al. Distinct effects of {delta}9-tetrahydrocannabinol and cannabidiol on neural activa- tion during emotional processing. Arch Gen Psychiatry 2009;66(1):95–10.

[28] Bhattacharyya S, Fusar-Poli P, Borgwardt S, Martin-Santos R, Nosarti C, O'Carroll C, et al. Modulation of mediotemporal and ventrostriatal function in humans by delta9-tetrahydrocannabinol: a neural basis for the effects of Cannabis sativa on learning and psychosis. Arch Gen Psychiatry 2009;66(4):442–51.

[29] Winton-Brown TT, Allen P, Bhattacharyya S, Borgwardt SJ, Fusar-Poli P, Crippa JA, et al. Modulation of auditory and visual processing by delta-9-tetrahydrocannabinol and cannabidiol: an FMRI study. Neuropsychopharmacology 2011;36(7):1340–8.

[30] Bhattacharyya S, Falkenberg I, Martin-Santos R, Atakan Z, Crippa JA, Giampietro V, et al. Cannabinoid modulation of functional connectivity within regions processing attentional salience. Neuropsychopharmacology 2015;40(6):1343–52.

[31] Bhattacharyya S, Crippa JA, Allen P, Martin-Santos R, Borgwardt S, Fusar-Poli P, et al. Induction of psychosis by delta9-tetrahydrocannabinol reflects modulation of pre- frontal and striatal function during attentional salience processing. Arch Gen Psychi- atry 2012;69(1):27–36.

[32] Atakan Z, Bhattacharyya S, Allen P, Martin-Santos R, Crippa JA, Borgwardt SJ, et al. Cannabis affects people differently: inter-subject variation in the psychotogenic

effects of delta9-tetrahydrocannabinol: a functional magnetic resonance imaging study with healthy volunteers. Psychol Med 2013;43(6):1255–67.

[33] Bhattacharyya S, Atakan Z, Martin-Santos R, Crippa JA, Kambeitz J, Prata D, et al. Pre- liminary report of biological basis of sensitivity to the effects of cannabis on psychosis: AKT1 and DAT1 genotype modulates the effects of delta-9-tetrahydrocannabinol on midbrain and striatal function. Mol Psychiatry 2012;17(12):1152–5.

[34] Bossong MG, Jansma JM, van Hell HH, Jager G, Kahn RS, Ramsey NF. Default mode network in the effects of delta9-tetrahydrocannabinol (THC) on human executive function. PLoS One 2013;8(7), e70074.

[35] Jansma JM, van Hell HH, Vanderschuren LJ, Bossong MG, Jager G, Kahn RS, et al. THC reduces the anticipatory nucleus accumbens response to reward in subjects with a nicotine addiction. Transl Psychiatry 2013;3, e234.

[36] van Hell HH, Bossong MG, Jager G, Kristo G, van OschMJ, Zelaya F, et al. Evidence for involvement of the insula in the psychotropic effects of THC in humans: a double- blind, randomized pharmacological MRI study. Int J Neuropsychopharmacol 2011; 14(10):1377–88.

[37] van Hell HH, Bossong MG, Jager G, Kahn RS, Ramsey NF. Methods of the pharmaco- logical imaging of the cannabinoid system (PhICS) study: towards understanding the role of the brain endocannabinoid system in human cognition. Int J Methods Psychiatr Res 2011;20(1):10–27.

[38] van Hell HH, Jager G, Bossong MG, Brouwer A, Jansma JM, Zuurman L, et al. Involve- ment of the endocannabinoid system in reward processing in the human brain. Psychopharmacology 2012;219(4):981–90.

[39] Bossong MG, Jager G, van Hell HH, Zuurman L, Jansma JM, Mehta MA, et al. Effects of delta9-tetrahydrocannabinol administration on human encoding and recall memory function: a pharmacological FMRI study. J Cogn Neurosci 2012;24(3):588–99.

[40] Bossong MG, Jansma JM, van Hell HH, Jager G, Oudman E, Saliasi E, et al. Effects of delta9-tetrahydrocannabinol on human working memory function. Biol Psychiatry 2012;71(8):693–9.

[41] Bossong MG, van Hell HH, Jager G, Kahn RS, Ramsey NF, Jansma JM. The endocannabinoid system and emotional processing: a pharmacological fMRI study with 9-tetrahydrocannabinol. Eur Neuropsychopharmacol 2013;23(12):1687–97.

[42] Kenakin T. Principles: receptor theory in pharmacology. Trends Pharmacol Sci 2004; 25(4):186–92.

[43] Tudge L, Williams C, Cowen PJ, McCabe C. Neural effects of cannabinoid CB1 neutral antagonist tetrahydrocannabivarin on food reward and aversion in healthy volun- teers. Int J Neuropsychopharmacol 2015;18(6).

[44] Rzepa E, Tudge L, McCabe C. The CB1 neutral antagonist tetrahydrocannabivarin re- duces default mode network and increases executive control network resting state functional connectivity in healthy volunteers. Int J Neuropsychopharmacol 2016; 19(2).

[45] Zuardi AW, Crippa JA, Hallak JE, Bhattacharyya S, Atakan Z, Martin-Santos R, et al. A critical review of the antipsychotic effects of cannabidiol: 30 years of a translational investigation. Curr Pharm Des 2012;18(32):5131–40.

[46] Crippa JA, Zuardi AW, Garrido GE, Wichert-Ana L, Guarnieri R, Ferrari L, et al. Effects of cannabidiol (CBD) on regional cerebral blood flow. Neuropsychopharmacology 2004;29(2):417–26.

[47] Crippa JA, Derenusson GN, Ferrari TB, Wichert-Ana L, Duran FL, Martin-Santos R, et al. Neural basis of anxiolytic effects of cannabidiol (CBD) in generalized social anxiety disorder: a preliminary report. J Psychopharmacol 2011;25(1):121–30.

[48] Thomas A, Baillie GL, Phillips AM, Razdan RK, Ross RA, Pertwee RG. Cannabidiol dis- plays unexpectedly high potency as an antagonist of CB1 and CB2 receptor agonists in vitro. Br J Pharmacol 2007;150(5):613–23.

[49] Bhattacharyya S, Morrison PD, Fusar-Poli P, Martin-Santos R, Borgwardt S, Winton- Brown T, et al. Opposite effects of delta-9-tetrahydrocannabinol and cannabidiol on human brain function and psychopathology. Neuropsychopharmacology 2010; 35(3):764–74.

[50] Fadda P, Robinson L, Fratta W, Pertwee RG, Riedel G. Differential effects of THC- or CBD-rich cannabis extracts on working memory in rats. Neuropharmacology 2004; 47(8):1170–9.

[51] Christensen R, Kristensen PK, Bartels EM, Bliddal H, Astrup A. Efficacy and safety of the weight-loss drug rimonabant: a meta-analysis of randomised trials. Lancet 2007;370(9600):1706–13.

[52] Griebel G, Stemmelin J, Scatton B. Effects of the cannabinoid CB1 receptor antagonist rimonabant in models of emotional reactivity in rodents. Biol Psychiatry 2005; 57(3):261–7.

[53] Ramaekers JG, Kauert G, Theunissen EL, Toennes SW, Moeller MR. Neurocognitive performance during acute THC intoxication in heavy and occasional cannabis users. J Psychopharmacol 2009;23(3):266–77.

[54] Gloss D, Vickrey B. Cannabinoids for epilepsy. Cochrane Database Syst Rev 2012;6, CD009270.

[55] Devinsky O,Marsh E, Friedman D, Thiele E, Laux L, Sullivan J, et al. Cannabidiol in pa- tients with treatment-resistant epilepsy: an open-label interventional trial. Lancet Neurol 2016;15(3):270–8.