Article

Dorsolateral Prefrontal Cortex N-Acetylaspartate/Total Creatine (NAA/tCr) Loss in Male Recreational Cannabis Users

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  • Central Institute of Mental Health (CIMH) University of Heidelberg
Article

Dorsolateral Prefrontal Cortex N-Acetylaspartate/Total Creatine (NAA/tCr) Loss in Male Recreational Cannabis Users

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Abstract

Cannabinoids present neurotoxic and neuroprotective properties in in vitro studies, inconsistent alterations in human neuroimaging studies, neuropsychological deficits, and an increased risk for psychotic episodes. Proton magnetic resonance spectroscopy ((1)H-MRS), neuropsychological testing, and hair analysis for cannabinoids was performed in 13 male nontreatment-seeking recreational cannabis users and 13 male control subjects. A significantly diminished N-acetylaspartate/total creatine (NAA/tCr) ratio in the dorsolateral prefrontal cortex (DLPFC) was observed in cannabis users (p = .0003). The NAA/tCr in the putamen/globus pallidum region correlated significantly with cannabidiol (R(2) = .66, p = .004). Results of the Wisconsin Card Sorting test, Trail making Test, and D2 test for attention were influenced by cannabinoids. Chronic recreational cannabis use is associated with an indication of diminished neuronal and axonal integrity in the DLPFC in this study. As chronic cannabis use is a risk factor for psychosis, these results are interesting because diminished NAA/tCr ratios in the DLPFC and neuropsychological deficits were also reported in schizophrenia. The strong positive correlation of NAA/tCr and cannabidiol in the putamen/globus pallidum is in line with neuroprotective properties of cannabidiol, which were also observed in in vitro model studies of Parkinson's disease.

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... College student marijuana use has been found to be associated with anxiety, depression, hostility, interpersonal sensitivity, paranoia, and psychoticism (Buckner et al., 2010). Marijuana use is associated with the impairment of many cognitive functions that affect academic performance, including attention, concentration, memory, verbal fluency, processing speed, planning, and decision making (Caldeira et al., 2008;Churchwell et al., 2010;Hermann et al., 2007;McHale et al., 2008;Ramaekers et al., 2006;Shillington and Clapp, 2001;Vadhan et al., 2007;Wadsworth et al., 2006). Marijuana use reduces brain volume, affects brain metabolism, alters brain circuitry, and restricts blood flow to the brain, thereby reducing cognitive performance (Battistella et al., 2014;Block et al., 2002;Churchwell et al., 2010;Hermann et al., 2007;Verdejo-García et al., 2006;Yücel et al., 2008). ...
... Marijuana use is associated with the impairment of many cognitive functions that affect academic performance, including attention, concentration, memory, verbal fluency, processing speed, planning, and decision making (Caldeira et al., 2008;Churchwell et al., 2010;Hermann et al., 2007;McHale et al., 2008;Ramaekers et al., 2006;Shillington and Clapp, 2001;Vadhan et al., 2007;Wadsworth et al., 2006). Marijuana use reduces brain volume, affects brain metabolism, alters brain circuitry, and restricts blood flow to the brain, thereby reducing cognitive performance (Battistella et al., 2014;Block et al., 2002;Churchwell et al., 2010;Hermann et al., 2007;Verdejo-García et al., 2006;Yücel et al., 2008). Chronic marijuana use poses even more risks. ...
... This association may be explained by the fact that marijuana users tend to skip more classes and in turn, earn lower GPAs (Arria et al., 2013a(Arria et al., , 2015. The relationship between marijuana use and impaired mental functioning (Caldeira et al., 2008;Churchwell et al., 2010;Hermann et al., 2007;McHale et al., 2008;Ramaekers et al., 2006;Shillington and Clapp, 2001;Vadhan et al., 2007;Wadsworth et al., 2006) could also explain poorer performance among marijuana users. ...
Article
Background: Marijuana is the most commonly used illicit drug by college students. Prior studies have established an association between marijuana use and poor academic performance in college, but research on the frequency of marijuana use over the entire college career is limited. The study objective was to examine the association of marijuana use trajectories on academic outcomes, including senior year enrollment, plans to graduate on time, and GPA. Methods: Data were collected from a cohort of 3146 students from 11 colleges in North Carolina and Virginia at six time points across the college career. Group-based trajectory models were used to characterize longitudinal marijuana use patterns during college. Associations between marijuana trajectory groups and academic outcomes were modeled using random-effects linear and logistic regressions. Results: Five marijuana trajectory groups were identified: non-users (69.0%), infrequent users (16.6%), decreasing users (4.7%), increasing users (5.8%), and frequent users (3.9%). Decreasing users and frequent users were more likely to drop out of college and plan to delay graduation when compared to non-users. All marijuana user groups reported lower GPAs, on average, than non-users. Conclusion: These results identify marijuana use patterns that put students at risk for poor academic performance in college. Students who use marijuana frequently at the beginning of the college career are especially at risk for lower academic achievement than non-users, suggesting that early intervention is critical.
... For the vast majority of these studies, additional (comorbid) drug use was either excluded from study, treated as a nuisance variable and/or simply acknowledged as a study limitation. In brief, this research has demonstrated that monoabuse of or dependence on alcohol, cocaine, methamphetamine, or cannabis is associated with cognitive dysfunction (Hester & Garavan, 2004;Kalechstein, Newton, & Green, 2003;Kubler, Murphy, & Garavan, 2005;Lundqvist, 2005;McKetin & Mattick, 1997;Oscar-Berman, 1997Salo et al., 2002;Simon, Dacey, Glynn, Rawson, & Ling, 2004;Solowij et al., 2002;Verdejo-Garcia et al., 2012, primarily in learning/memory (Barber, Panikkar, & McKeith, 2001;Lundqvist, 2005;Oscar-Berman, 2000;Pope, Gruber, Hudson, Huestis, & Yurgelun-Todd, 2001;Pope & Yurgelun-Todd, 1996;Simon et al., 2000;Solowij et al., 2002;Volkow, Chang, Wang, Fowler, Leonido-Yee, et al., 2001), working memory (Lundqvist, 2005;Oscar-Berman, 2000), and executive skills (Barber et al., 2001;Hermann et al., 2007;Hester & Garavan, 2004;Kim et al., 2005;Moeller et al., 2005;Oscar-Berman, 2000;Pope et al., 2001;Pope & Yurgelun-Todd, 1996;Salo et al., 2002;Simon et al., 2000;Solowij et al., 2002). Recent reviews of AUD patients describe deficits related to working memory, visuospatial functions, inhibition, and executive-based functions such as mental flexibility, problem solving, divided attention (Bernardin, Maheut-Bosser, & Paille, 2014), and cognitive control (Wilcox, Dekonenko, Mayer, Bogenschutz, & Turner, 2014). ...
... They include low cerebral blood flow (Chang et al., 2002;Ernst, Chang, Leonido-Yee, & Speck, 2000;Ernst, Chang, Oropilla, Gustavson, & Speck, 2000;Gansler et al., 2000;Heinz, Beck, Grusser, Grace, & Wrase, 2009;Hwang et al., 2006;Nicolas et al., 1993;Oishi, Mochizuki, & Shikata, 1999;Rogers, Meyer, Shaw, & Mortel, 1983;Tunving, Thulin, Risberg, & Warkentin, 1986;Volkow, Mullani, Gould, Adler, & Krajewski, 1988) and altered regional brain glucose metabolism (Eldreth, Matochik, Cadet, & Bolla, 2004;Kim et al., 2005;Volkow, Chang, Wang, Fowler, Leonido-Yee, et al., 2001;Volkow et al., 1993;Volkow, Hitzemann, Wang, Fowler, Burr, et al., 1992;Volkow et al., 1988Volkow et al., , 1994. Furthermore, proton MR spectroscopy (MRS) revealed metabolic abnormalities in chronic substance users that are consistent with abnormal markers of neuronal integrity (via lower concentrations of regional N-acetylaspartate, NAA), cell membrane turnover/synthesis (via altered levels of choline-containing metabolites, Cho), and gliosis (via altered levels of myo-inositol, mI) (Durazzo, Gazdzinski, Banys, & Meyerhoff, 2004;Durazzo, Gazdzinski, Yeh, & Meyerhoff, 2008;Durazzo, Pathak, Gazdzinski, Mon, & Meyerhoff, 2010;Ernst, Chang, Leonido-Yee, et al., 2000;Ernst, Chang, Oropilla, et al., 2000;Fein, Meyerhoff, & Weiner, 1995;Hermann et al., 2007;Ke et al., 2004;Meyerhoff et al., 2004;Meyerhoff, MacKay, Weiner, & Fein, 1994;Nordahl et al., 2005;Parks et al., 2002;Sailasuta, Abulseoud, Hernandez, Haghani, & Ross, 2010) [reviewed by (Meyerhoff, Durazzo, & Ende, 2013)]. These studies have indicated that different substances similarly alter neuronal integrity, energy metabolism, membrane turnover, neurotransmission (glutamate, GABA), and inflammatory processes (Licata & Renshaw, 2010;Yang et al., 2009), albeit via different neural pathways. ...
... These studies have indicated that different substances similarly alter neuronal integrity, energy metabolism, membrane turnover, neurotransmission (glutamate, GABA), and inflammatory processes (Licata & Renshaw, 2010;Yang et al., 2009), albeit via different neural pathways. Nevertheless, neuroimaging of abusers of different individual substances describes alterations in largely similar brain regions, primarily in the prefrontal cortex (PFC), the underlying white matter, basal ganglia, and thalami Dom, Sabbe, Hulstijn, & van den Brink, 2005;Eldreth et al., 2004;Ernst, Chang, Leonido-Yee, et al., 2000;Ernst, Chang, Oropilla, et al., 2000;Franklin et al., 2002;Hermann et al., 2007;Holman et al., 1991;Matochik et al., 2005Matochik et al., , 2003Nordahl et al., 2005;Sorg et al., 2012;Sullivan, 2000;Sullivan, Rosenbloom, & Pfefferbaum, 2000;Thompson et al., 2004;Volkow, Hitzemann, Wang, Fowler, Burr, et al., 1992;Wang et al., 2015;Weber et al., 1993), all regions critically involved in cognitive control, drug-seeking behavior, and reward. ...
Chapter
Polysubstance use (PSU) refers to the simultaneous or concurrent use of more than one addictive substance. Polysubstance users comprise the largest subgroup of both substance users and treatment seekers in the developed world today. However, little is known about the neuroadaptations and cognitive deficits associated with chronic misuse of multiple substances, brain changes with abstinence, and the relationship of these deficits to treatment outcome. As most previous research has been conducted on individuals ostensibly using a single substance, its results may not generalize well to the majority of substance users today. The dearth of knowledge on neuropathological mechanisms and potential interactions of simultaneously abused substances possibly contributes to the low treatment success in individuals with PSU. After brief overviews of the neuropsychological and brain imaging research on the abuse of single drugs, we review the corresponding literature on PSU. Distinct differences in neuropsychological and brain measures between mono- and polysubstance users have functional significance and may demand different treatment approaches. This chapter also discusses the challenges and promises of including polysubstance users in clinical research.
... Given the known role of PFC cannabinoid signaling in the mediation of cognitive flexibility processing [27,28], we first examined how intra-PFC THC or CBD may modulate set-shifting (see Methods). Histological analyses (Fig. 1a, b) confirmed that injections were within the anatomical boundaries of PFC [25]. ...
... The set-shifting procedure used here is an analog of the Wisconsin Card Sorting Task (WCST) used in human research for testing frontal executive function [36]. Interestingly, marijuana users showing high CBD hair concentrations, although displaying improved attention and concentration, showed impaired performance in the WCST [27]. Accordingly, we show that intra-PFC CBD, did not affect memory recall but selectively impaired set-shifting (Fig. 3), suggesting that CBD might interfere with PFC circuitry responsible for inhibitory control over behavioral responding [37]. ...
Article
The use of cannabis for therapeutic and recreational purposes is growing exponentially. Nevertheless, substantial questions remain concerning the potential cognitive and affective side-effects associated with cannabis exposure. In particular, the effects of specific marijuana-derived phytocannabinoids on neural regions such as the prefrontal cortex (PFC) are of concern, given the role of the PFC in both executive cognitive function and affective processing. The main biologically active phytocannabinoids, ∆-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), interact with multiple neurotransmitter systems important for these processes directly within the PFC. Considerable evidence has demonstrated that acute or chronic THC exposure may induce psychotomimetic effects, whereas CBD has been shown to produce potentially therapeutic effects for both psychosis and/or anxiety-related symptoms. Using an integrative combination of cognitive and affective behavioral pharmacological assays in rats, we report that acute intra-PFC infusions of THC produce anxiogenic effects while producing no impairments in executive function. In contrast, acute infusions of intra-PFC CBD impaired attentional set-shifting and spatial working memory, without interfering with anxiety or sociability behaviors. In contrast, intra-PFC CBD reversed the cognitive impairments induced by acute glutamatergic antagonism within the PFC, and blocked the anxiogenic properties of THC, suggesting that the therapeutic properties of CBD within the PFC may be present only during pathologically aberrant states within the PFC. Interestingly, the effects of PFC THC vs. CBD were found to be mediated through dissociable CB1 vs. 5-HT1A-dependent receptor signaling mechanisms, directly in the PFC.
... They include functionally relevant low cerebral blood flow (Rogers et al., 1983;Tunving et al., 1986;Volkow et al., 1988;Nicolas et al., 1993;Oishi et al., 1999;Ernst et al., 2000a,b;Gansler et al., Chang et al., 2002;Hwang et al., 2006;Heinz et al., 2009;Murray et al., 2018), altered brain glucose metabolism (Volkow et al., 1993;Volkow et al., 1994;Volkow et al., 2001;Eldreth et al., 2004;Kim et al., 2005), and altered brain metabolite levels measured by proton magnetic resonance spectroscopy (MRS). MRS studies revealed regional metabolic abnormalities in those with alcohol and SUDs that are consistent with abnormal markers of neuronal integrity (as measured by lower concentrations of N-acetylaspartate [NAA] or glutamate [Glu]), cellular bioenergetics (as indicated by lower concentrations of creatine-containing metabolites, Cr), glial or cell membrane turnover/synthesis (as indicated by altered levels of choline-containing metabolites, Cho), and glial content/gliosis or osmoregulation (as reflected in altered levels of myo-inositol [mI]) (Meyerhoff et al., 1994;Fein et al., 1995;Meyerhoff et al., 1999;Ernst et al., 2000a,b;O'Neill et al., 2001;Parks et al., 2002;Durazzo et al., 2004;Ke et al., 2004;Meyerhoff et al., 2004;Nordahl et al., 2005;Chang et al., 2007;Hermann et al., 2007;Durazzo et al., 2008a,b;Durazzo et al., 2010b;Sailasuta et al., 2010;Prescot et al., 2011;Prescot et al., 2013;Murray et al., 2016) (also reviewed by Meyerhoff et al., 2013). These studies indicate that alcohol and illicit substances alter regional neuronal integrity, energy metabolism, membrane synthesis/turnover, the metabolic pools of Glu and gamma-aminobutyric acid (GABA) that are in equilibrium with their neurotransmitter pools, and gliotic/ inflammatory processes (Yang et al., 2009;Licata and Renshaw, 2010). ...
... Furthermore, chronic cigarette smoking compounds and regional brain metabolite abnormalities (and neurocognitive dysfunction, see above) are observed in AUD (Meyerhoff, 2007;Wang et al., 2009;. The chronic abuse of different substances is associated with tissue alterations in largely similar brain regions, primarily in the prefrontal cortex (PFC), the underlying white matter, the thalami, and the basal ganglia including striatal structures (Holman et al., 1991;Volkow et al., 1992;Weber et al., 1993;Ernst et al., 2000a,b;Sullivan, 2000;Sullivan et al., 2000;Franklin et al., 2002;Matochik et al., 2003;Eldreth et al., 2004;Thompson et al., 2004;Dom et al., 2005;Matochik et al., 2005;Nordahl et al., 2005;Bae et al., 2006;Hermann et al., 2007;Sorg et al., 2012;Wang et al., 2015;Murray et al., 2016). Specifically, the dorsolateral PFC is implicated in executive functions involving planning and organization, response inhibition, working memory, reasoning, problem solving, set shifting, and goal-directed behavior (e.g., Goldstein and Volkow, 2011). ...
... After prolonged periods of abstention (28 days), adolescents showed a deficit of "historical" (semantic) memory [Medina et al., 2007], though visuospatial memory remained unimpaired [Medina et al., 2007;Schweinsburg et al., 2010]. Defi cit of this type of memory was seen in adult cannabis consumers abstaining for some period of time [Hermann et al., 2007;McHale and Hunt, 2008], though other studies found associative memory and semantic memory to be intact [Chang et al., 2006;Wadsworth et al., 2006;Fisk and Montgomery, 2008]. ...
... In contrast, other authors found that selective and divided attention remained intact in adolescents after 45 days of abstinence [Jacobson et al., 2004]. Adult marijuana consumers abstaining for periods from several hours to a week demonstrated impaired attention and concentration [Wadsworth et al., 2006;Hermann et al., 2007]; however, other studies reported the absence of any such impairments [Chang et al., 2006;Grant et al., 2011]. ...
Article
Full-text available
Cannabinoids are natural compounds found in the hemp (Cannabis sativa). Scientific interest in cannabinoids arose after the discovery of the major psychoactive component in hemp, Δ9-tetrahydrocannabinol. Subsequent studies detected receptors in the brain subject to the actions of this compound, along with ligands for these receptors, i.e., endogenous cannabinoids (EC), which make up, along with the enzymes synthesizing, transporting, and degrading them, the endocannabinoid system (ECS). Interest in EC has consistently increased in recent years, especially after their important role in cognitive functions was discovered. They are regulators of synaptic transmission in the brain, mediate numerous forms of plasticity, and control neuron energy metabolism. EC exert influences using a series of mechanisms and interactions with neuromediators, neurotrophic factors, and neuropeptides. The main functions of EC in the brain are retrograde synaptic signaling and neuromodulation, which maintain cellular homeostasis. Information on the influences of cannabinoid drugs on cognitive functions is very contradictory. The cause of this may be that there are still inadequate strictly scientific data from clinical and sociological studies, while in animal experiments different authors use different methods and approaches for actions on the ECS. Thus, effects can differ depending on the substances used, their doses, and routes of administration, and the tasks and experimental conditions selected for testing. There is an extensive literature on the protective effect of ECS activation in neurodegenerative diseases in humans and models of cognitive deficit in animals. This review addresses data providing evidence of the influences of cannabinoid drugs and activation of the EC system on cognitive functions in the normal brain and in neurodegenerative diseases, Alzheimer’s disease, and temporal epilepsy. The possible causes of contradictions in existing data are also discussed.
... ACC Glu and NAA were not related to opiate use, consistent with previous reports [11]. However, greater cocaine and marijuana misuse in our OD group was associated with significantly lower metabolite concentrations, commensurate with findings in other substance using/dependent populations [62][63][64]. Metabolite concentrations in the DLPFC and ACC of OD related to executive function, visuospatial skills, global cognition and working memory, but not to self-regulation measures. Previous 1H MRS studies in opiate dependence did not report on such relationships, but studies in marijuana-dependent and recreational ecstasy users reported relationships between altered frontal metabolite levels and impaired cognition or higher impulsivity [56,65,66]. ...
... The greater DLPFC metabolite abnormalities in OD may relate to the greater relapse rate in opiate than alcohol dependence [73], which may require differently tailored approaches for treatment of OD and ALC. Metabolite deficits in the DLPFC of OD are more reminiscent of 1H MRS results in polysubstance users [49,64], recreational cannabis users [62], and methamphetamine dependent individuals [63]. The DLPFC is critically involved in executive functions, such as working memory, cognitive flexibility, planning, inhibition, and abstract reasoning. ...
Article
Full-text available
Objective Proton magnetic resonance spectroscopy (1H MRS) in opiate dependence showed abnormalities in neuronal viability and glutamate concentration in the anterior cingulate cortex (ACC). Metabolite levels in dorsolateral prefrontal cortex (DLPFC) or orbitofrontal cortex (OFC) and their neuropsychological correlates have not been investigated in opiate dependence. Methods Single-volume proton MRS at 4 Tesla and neuropsychological testing were conducted in 21 opiate-dependent individuals (OD) on buprenorphine maintenance therapy. Results were compared to 28 controls (CON) and 35 alcohol-dependent individuals (ALC), commonly investigated treatment-seekers providing context for OD evaluation. Metabolite concentrations were measured from ACC, DLPFC, OFC and parieto-occipital cortical (POC) regions. Results Compared to CON, OD had lower concentrations of N-acetylaspartate (NAA), glutamate (Glu), creatine +phosphocreatine (Cr) and myo-Inositol (mI) in the DLPFC and lower NAA, Cr, and mI in the ACC. OD, ALC, and CON were equivalent on metabolite levels in the POC and γ-aminobutyric acid (GABA) concentration did not differ between groups in any region. In OD, prefrontal metabolite deficits in ACC Glu as well as DLPFC NAA and choline containing metabolites (Cho) correlated with poorer working memory, executive and visuospatial functioning; metabolite deficits in DLPFC Glu and ACC GABA and Cr correlated with substance use measures. In the OFC of OD, Glu and choline-containing metabolites were elevated and lower Cr concentration related to higher nonplanning impulsivity. Compared to 3 week abstinent ALC, OD had significant DLPFC metabolite deficits. Conclusion The anterior frontal metabolite profile of OD differed significantly from that of CON and ALC. The frontal lobe metabolite abnormalities in OD and their neuropsychological correlates may play a role in treatment outcome and could be explored as specific targets for improved OD treatment.
... Some studies have focused only on males, given higher use rates in males versus females. 123,124 In most cases, last marijuana use was reported at 20 or more days per month. Lower levels of Glu, N-acetyl-aspartate (NAA), and myo-inositol (mIns) were observed in marijuana users compared to controls in regions known to be associated with substance use, including the basal ganglia (lower Glu, NAA and choline, 125 lower glutamine [Glx] and higher mIns in females), 126 thalamus (higher total creatine [tCr]), 125 cingulate cortex (lower Glu, NAA, tCr, and mIns), 127 dorsolateral prefrontal cortex (lower NAA), 124 and the striatum as well as posterior cortical regions (lower mIns). ...
... 123,124 In most cases, last marijuana use was reported at 20 or more days per month. Lower levels of Glu, N-acetyl-aspartate (NAA), and myo-inositol (mIns) were observed in marijuana users compared to controls in regions known to be associated with substance use, including the basal ganglia (lower Glu, NAA and choline, 125 lower glutamine [Glx] and higher mIns in females), 126 thalamus (higher total creatine [tCr]), 125 cingulate cortex (lower Glu, NAA, tCr, and mIns), 127 dorsolateral prefrontal cortex (lower NAA), 124 and the striatum as well as posterior cortical regions (lower mIns). 123 Because of the limitations of the single voxel approach, it is unclear whether these findings would generalize to ventral striatal regions. ...
Article
Adolescence is characterized by heightened risk-taking, including substance misuse. These behavioral patterns are influenced by ontogenic changes in neurotransmitter systems, particularly the dopamine system, which is fundamentally involved in the neural coding of reward and motivated approach behavior. During adolescence, this system evidences a peak in activity. At the same time, the dopamine (DA) system is neuroplastically altered by substance abuse, impacting subsequent function. Here, we describe properties of the dopamine system that change with typical adolescent development and that are altered with substance abuse. Much of this work has been gleaned from animal models due to limitations in measuring dopamine in pediatric samples. Structural and functional neuroimaging techniques have been used to examine structures that are heavily DA-innervated; they measure morphological and functional changes with age and with drug exposure. Presenting marijuana abuse as an exemplar, we consider recent findings that support an adolescent peak in DA-driven reward-seeking behavior and related deviations in motivational systems that are associated with marijuana abuse/dependence. Clinicians are advised that (1) chronic adolescent marijuana use may lead to deficiencies in incentive motivation, (2) that this state is due to marijuana's interactions with the developing DA system, and (3) that treatment strategies should be directed to remediating resultant deficiencies in goal-directed activity.
... Some studies of chronic cannabis use have found significant impairments in memory function of young (Fried et al. 2005) and older adults (Wadsworth et al. 2006;Lovell et al. 2018), as well as learning in young (Becker et al. 2014;Gonzalez et al. 2012) and older adults (Lovell et al. 2018). Furthermore, cognitive impairments have also been found in the domains of attention/ concentration in adults ages 18-55 (Solowij et al. 2002;Hermann et al. 2007;Cousijn et al. 2013;Field 2005;Bolla et al. 2002). Conversely, other studies have reported no significant differences between users and nonusers in young adults (Grant et al. 2012;Ramaekers et al. 2009), middleaged adults (Pope Jr et al. 2001Harding et al. 2012), and older adults (Lovell et al. 2018) on a broad range of cognitive functions. ...
... One cognitive process that has garnered major interest in this literature is attention processing. Several studies have suggested that attention function may be impaired in regular adult cannabis users (Hart et al. 2011;Wadsworth et al. 2006;Solowij et al. 2002;Hermann et al. 2007;Chang et al. 2006). Specifically, studies have shown that adult chronic regular users exhibit impairments on measures of divided attention (Bosker et al. 2013), sustained attention (Hunault et al. 2009), visual information processing (Wadsworth et al. 2006), and selective attention (Solowij et al. 1995). ...
Article
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Rationale and objectives Cognitive processing impairments have been associated with acute cannabis use, but there is mixed evidence regarding the cognitive effects of chronic cannabis use. Several neuroimaging studies have noted selective-attention processing differences in those who chronically use cannabis, but the neural dynamics governing the altered processing is unclear. Methods Twenty-four adults reporting at least weekly cannabis use in the past 6 months on the Cannabis Use Disorder Identification Test – Revised were compared to 24 demographically matched controls who reported no prior cannabis use. All participants completed a visual selective attention processing task while undergoing magnetoencephalography. Time-frequency windows of interest were identified using a data-driven method, and spectrally specific neural activity was imaged using a beamforming approach. Results All participants performed within normal range on the cognitive task. Regular cannabis users displayed an aberrant cognitive interference effect in the theta (4–8 Hz) frequency range shortly after stimulus onset (i.e., 0–250 ms) in the right occipital cortex. Cannabis users also exhibited altered functional connectivity between the right prefrontal cortex and right occipital cortices in comparison to controls. Conclusions Individuals with a history of regular cannabis use exhibited abnormal theta interference activity in the occipital cortices, as well as altered prefrontal-occipital functional connectivity in the theta range during a visual selective attention task. Such differences may reflect compensatory processing, as these participants performed within normal range on the task. Understanding the neural dynamics in chronic, regular cannabis users may provide insight on how long-term and/or frequent use may affect neural networks underlying cognitive processes.
... A positive correlation was found between ethanol intake and GSK3β expression. Ethanol consumption leads to GSK3β overexpression, which makes the brain more sensitive to the anxiety effects of ethanol abstinence, resulting in increased ethanol self-administration [194]. It is known that during repeated cycles of excessive alcohol administration and withdrawal, the activity of Akt and PI3K signaling in the NAcc is increased [181], and phosphorylation at Ser9 residue of GSK3β is increased [195]. ...
... By inducing the translation of synaptic proteins, mTOR enables neuroadaptations resulting from excessive alcohol intake. Induction of mTOR activity is enabled by inhibition of GSK3β, confirming its important role in ethanol dependence [194]. ...
Article
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Glycogen synthase kinase-3β (GSK3β), primarily described as a regulator of glycogen metabolism, is a molecular hub linking numerous signaling pathways and regulates many cellular processes like cytoskeletal rearrangement, cell migration, apoptosis, and proliferation. In neurons, the kinase is engaged in molecular events related to the strengthening and weakening of synapses, which is a subcellular manifestation of neuroplasticity. Dysregulation of GSK3β activity has been reported in many neuropsychiatric conditions, like schizophrenia, major depressive disorder, bipolar disorder, and Alzheimer’s disease. In this review, we describe the kinase action in reward circuit-related structures in health and disease. The effect of pharmaceuticals used in the treatment of addiction in the context of GSK3β activity is also discussed.
... Recent neuroimaging research indicates that marijuana use in recreational users was associated with structural abnormalities in neural regions that process reward (left nucleus accumbens) and affect (right amygdala) (Gilman et al., 2014), and chronic recreational marijuana has been suggested to impact executive function via its effects on the prefrontal cortex (Hermann et al., 2007). There is reason to believe these effects may be even more pronounced in heavy chronic users, as heavy users have been found to have smaller amygdalar volumes as compared to controls (Yücel et al., 2008). ...
... Chronic, heavy marijuana use is also associated with impairments in memory and attention that worsen with increasing years of regular use (Solowij et al., 2002). Human imaging studies indicate that marijuana use may affect executive function via its impact on the prefrontal cortex (Hermann et al., 2007;Quickfall & Crockford, 2006), and heavy marijuana users have been found to have smaller amygdalar volumes (Yücel et al., 2008) as compared to controls. Heavy marijuana users who were abstinent from marijuana for 25 days evidenced persistent neurocognitive and functional brain abnormalities (decreased activity in the dorsolateral prefrontal cortex) and faulty decision-making on the Iowa Gambling Task (Bolla, Eldreth, Matochik, & Cadet, 2005). ...
Thesis
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Marijuana is the most commonly used illicit drug. Ongoing legislation necessitates improved understanding of consequences associated with chronic marijuana use, dependence and deprivation. Altered stress responses to uncertain threats have been documented during drug intoxication and withdrawal in our laboratory. Alterations in reward valuation are also associated with chronic drug use such that drug users devalue distal and/or uncertain rewards; instead preferring rewards most similar to intoxication (i.e., certain and immediate). Both aversion to uncertain threats and biases against uncertain rewards have important implications for addiction, as they encourage drug use (a certain reward). We assessed preferences for Certain vs. Uncertain monetary rewards and stress responses to Uncertain Threat in Deprived and Non-Deprived marijuana users and Non-Smokers. The effect of Deprivation on Uncertain Offer Selection grew as the objective Utility of choosing the Uncertain Offer increased. Consistent with predictions, Deprived Smokers preferred Certain rewards to Uncertain rewards to a greater extent than Non-Deprived Smokers, particularly when it was disadvantageous. Deprivation effects on Uncertain Offer Selection were moderated by marijuana-relevant individual differences in use, dependence, and expectancies. Participants were sensitive to changes in Utility. Males were more sensitive to changes in Utility, selecting the Uncertain Offer at higher rates than females as it became more advantageous. However, Non-Deprived females selected the Uncertain Offer more often relative to Non-Smoker females, performing comparably to males. In contrast with earlier findings, both Deprived and Non-Deprived Smokers evidenced increased startle potentiation to Uncertain Threat as compared to Non-Smokers. We confirm that like other drugs of abuse, chronic marijuana use is associated with alterations in reward valuation and stress response. Deprived marijuana users displayed increased aversion to Uncertain Rewards. All Smokers evidenced increased stress response to Uncertain Threats. Finally, our results join recent research suggesting chronic, ongoing marijuana use has more severe consequences for females.
... There is also evidence that using cannabis with a higher CBD/ THC ratio is associated with a lower risk of psychotic disorders, subthreshold psychotic symptoms, and cognitive changes related to psychosis [3], from both studies analyzing THC and CBD concentrations in hair samples [83,84], and from a study analyzing the content of the cannabis that subjects reported regularly using [85]. Cannabis users have been found to have evidence for neurotoxicity in the prefrontal cortex based on lower levels of N-acetylaspartic acid measured by proton magnetic spectroscopy, which reflects neuronal integrity [86]. A higher ratio of CBD to THC concentrations in hair samples of cannabis users was associated with higher levels of N-acetylaspartic acid in the putamen/globus pallidus region [86], as well as larger hippocampal volume [87,88]. ...
... Cannabis users have been found to have evidence for neurotoxicity in the prefrontal cortex based on lower levels of N-acetylaspartic acid measured by proton magnetic spectroscopy, which reflects neuronal integrity [86]. A higher ratio of CBD to THC concentrations in hair samples of cannabis users was associated with higher levels of N-acetylaspartic acid in the putamen/globus pallidus region [86], as well as larger hippocampal volume [87,88]. ...
Article
A convergence of evidence shows that use of Cannabis sativa is associated with increased risk of developing psychotic disorders, including schizophrenia, and earlier age at which psychotic symptoms first manifest. Cannabis exposure during adolescence is most strongly associated with the onset of psychosis amongst those who are particularly vulnerable, such as those who have been exposed to child abuse and those with family histories of schizophrenia. Schizophrenia that develops after cannabis use may have a unique clinical phenotype, and several genetic polymorphisms may modulate the relationship between cannabis use and psychosis. The endocannabinoid system has been implicated in psychosis both related and unrelated to cannabis exposure, and studying this system holds potential to increase understanding of the pathophysiology of schizophrenia. Anandamide signaling in the central nervous system may be particularly important. Δ(9)-Tetrahydrocannabinol in cannabis can cause symptoms of schizophrenia when acutely administered, and cannabidiol (CBD), another compound in cannabis, can counter many of these effects. CBD may have therapeutic potential for the treatment of psychosis following cannabis use, as well as schizophrenia, possibly with better tolerability than current antipsychotic treatments. CBD may also have anti-inflammatory and neuroprotective properties. Establishing the role of CBD and other CBD-based compounds in treating psychotic disorders will require further human research.
... Given the putative neurotoxic effects of cannabis (Pope et al., 2010), there is interest in the impact of heavy cannabis use on regional levels of N-acetylaspartate (NAA), a proxy marker of neuronal integrity (Moffett et al., 2007). The first MRS study on this subject found that the NAA to total creatine ratio was decreased in the DLPFC of heavy cannabis users versus controls (Hermann et al., 2007). A decrease in NAA to total creatine ratio was since replicated in the neighbouring inferior frontal gyrus of polydrug users, which was negatively correlated with degree of cannabis use only (Cowan et al., 2009), and the mid-frontal anterior cingulate area of methamphetamine and cannabis users versus methamphetamine users alone (Sung et al., 2013). ...
Article
Full-text available
The laws governing cannabis are evolving worldwide and associated with changing patterns of use. The main psychoactive drug in cannabis is Δ9-tetrahydrocannabinol (THC), a partial agonist at the endocannabinoid CB1 receptor. Acutely, cannabis and THC produce a range of effects on several neurocognitive and pharmacological systems. These include effects on executive, emotional, reward and memory processing via direct interactions with the endocannabinoid system and indirect effects on the glutamatergic, GABAergic and dopaminergic systems. Cannabidiol, a non-intoxicating cannabinoid found in some forms of cannabis, may offset some of these acute effects. Heavy repeated cannabis use, particularly during adolescence, has been associated with adverse effects on these systems, which increase the risk of mental illnesses including addiction and psychosis. Here, we provide a comprehensive state of the art review on the acute and chronic neuropsychopharmacology of cannabis by synthesizing the available neuroimaging research in humans. We describe the effects of drug exposure during development, implications for understanding psychosis and cannabis use disorder, and methodological considerations. Greater understanding of the precise mechanisms underlying the effects of cannabis may also give rise to new treatment targets.
... Despite strong evidence for verbal memory impairment among recreational MJ consumers, findings from other areas of memory function, namely associative and visuospatial memory, are less clear. For example, fewer studies note decrements on assessments of visual short-term memory (Hermann et al., 2007;Sneider, Gruber, Rogowska, Silveri, & Yurgelun-Todd, 2013). Working memory, often also considered a core facet of executive function, reflects temporary storage and manipulation of information for problemsolving or mental operations. ...
Article
The neurobiologic effects of cannabis, commonly referred to as ‘marijuana’ (MJ), have been studied for decades. The impact of recreational MJ use on cognition and measures of brain function and structure is outlined, and variables influencing study results are discussed, including age of the consumer, patterns of MJ use, variations in MJ potency, and the presence of additional cannabinoids. Although evidence suggests that chronic, heavy recreational MJ use is related to cognitive decrements and neural changes, particularly when use begins in adolescence, findings from studies of recreational MJ users may not be applicable to medical marijuana (MMJ) patients given differences in demographic variables, product selection, and reasons for use. Although additional research is needed to fully understand the impact of MJ and individual cannabinoids on the brain, current findings are beginning to inform public policy, including considerations for age limits, potential limits for some cannabinoids, and guidelines for use. However, barriers continue to impede researchers’ ability to conduct studies that will guide policy change and provide vital information to consumers and patients regarding best practices and safest methods for use. The need for information is critical, as legalization of MJ for medical and recreational use is increasingly widespread.
... Also, the neuroprotective action of CBD in the human basal ganglia was supported by the strong relationship between N-acetylaspartate/total creatine ratio and CBD in the putamen/globus pallidum found in recreational cannabis users. This could reflect an enhancement of neuronal and axonal integrity in these regions by CBD [37]. ...
... 3.2. Cognition and task-based measures of self-regulation: AUD, cocaine, methamphetamine, and marijuana dependence individually have each been linked to cognitive dysfunction, mainly in learning and memory, working memory, and executive skills (e.g., Hermann et al 2007;Hester and Garavan 2004;Oscar-Berman 2000). Also cigarette smoking in non-clinical cohorts and AUD relates to cognitive deficits and less recovery of cognitive function and neurobiology with abstinence (reviewed in Pennington et al 2013). ...
Chapter
Polysubstance users are the largest group of treatment seekers in the United States and Europe. Although polysubstance use disorders (PSUD) constitute an enormous individual and societal burden, little is known about the neuroadaptations and cognitive deficits associated with concurrent chronic misuse of illicit, psychoactive substances and alcohol, their changes with abstinence, and their influence on the ability of individuals to engage in adaptive, pro-health behavior. Recent research demonstrates that magnetic resonance-based neurobiology, cognition, and self-regulation as well as the ethnic breakdown differ substantially between individuals with PSUD and alcohol use disorders (AUD), who have been extensively studied. These groups appear to represent different treatment-seeking populations and therefore may require different treatment approaches. Furthermore, chronic tobacco use appears to affect neurobiology and cognition with a different pattern than in AUD and drug-free controls. We review these PSUD studies in the context of previous work and point out important new avenues for future research.
... Individuals with a history of tobacco or cannabis use were excluded because of possible confounds with neuronal oxidative damage 26 and/or neurochemical profile alterations. 27 Procedures All procedures were approved by the Institutional Review Board: Human Subjects Committee of the University of Minnesota, and informed consent was obtained from all participants. Volunteers were asked to discontinue antioxidant supplements for 3 weeks before the study given that the most common supplemental antioxidants are eliminated over this time. ...
Article
Objective: To investigate whether early neurochemical abnormalities are detectable by high field magnetic resonance spectroscopy (MRS) in individuals with spinocerebellar ataxias (SCAs) 1, 2, 3 and 6, including patients without manifestation of ataxia. Methods: A cohort of 100 subjects (N=18‐21 in each SCA group, including premanifest mutation carriers; mean score on the Scale for the Assessment and Rating of Ataxia (SARA) <10 for all genotypes, and 22 matched controls) was scanned at 7 tesla to obtain neurochemical profiles of the cerebellum and brainstem. A novel multi‐variate approach (distance‐weighted discrimination) was used to combine regional profiles into an “MRS score”. Results: MRS scores robustly distinguished individuals with SCA from controls, with misclassification rates of 0% (SCA2), 2% (SCA3), 5% (SCA1) and 17% (SCA6). Premanifest mutation carriers with estimated disease onset within 10 years had MRS scores in the range of early manifest SCA subjects. Levels of neuronal and glial markers significantly correlated with SARA and an Activities of Daily Living score in subjects with SCA. Regional neurochemical alterations were different between SCAs at comparable disease severity, with SCA2 displaying the most extensive neurochemical abnormalities, followed by SCA1, SCA3 and SCA6. Interpretation: Neurochemical abnormalities are detectable in individuals prior to manifest disease, which may allow premanifest enrollment in future SCA trials. Correlations with ataxia and quality of life scores show that neurochemical levels can serve as clinically meaningful endpoints in trials. Ranking of SCA types by degree of neurochemical abnormalities indicates that the neurochemistry may reflect synaptic function or density. This article is protected by copyright. All rights reserved.
... That is, it is unclear how lower FA in the corpus callosum would manifest in everyday life. While such white matter changes could, for example, lead to further addictive behavior, altered FA in the corpus callosum has also been associated with a host of other variables such as age (Lebel et al., 2010), gender and handedness (Westerhausen et al., 2004), autism (Hermann et al., 2007), traumatic brain injury (Kumar et al., 2009), schizophrenia (Foong et al., 2000), and bipolar disorder (Barnea-Goraly et al., 2009). Given this, an alternative possible explanation is that some findings were restricted to the most prominent white matter pathways due to the methodological approach. ...
... [15] Recent evidence of diminished neuronal and axonal integrity in the dorsolateral prefrontal cortex indicated by magnetic resonance spectroscopic markers of metabolism (the ratio N-acetylaspartate/total creatine) was reported. [16] Subjects and Methods After being explained about the risk and benefit associated with the study in details in a language they understand properly, patients provided informed consent mentioning their willingness for voluntary participation in the study. ...
Article
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Aims: This study aims to compare the cognitive function of patients having dual diagnosis of bipolar affective disorder and cannabis dependence with those having either diagnosis alone and with healthy controls. Settings and Design: Hospital-based study. Subjects and Methods: Study subjects were selected from patients attending psychiatry outpatient department in the presence of two senior consultant psychiatrists. Among the pool of the patients, only those who meet the inclusion and exclusion criteria were selected for the study. Then the selected patients were administered the semi-structured sociodemographic data sheet, Young Mania Rating Scale, Hamilton Depression Rating Scale, General Health Questionnaire-12, Trail Making Test Part A and Part B, verbal fluency tests, Stroop Neuropsychological Screening Test, clock drawing test. Statistical analysis was done by using appropriate statistical methods. Statistical analysis was done with the help of Statistical Package for Social Science-20 (SPSS-20, International Business Machines Corporation (IBM)). Results: The results of our study showed there was significant impairment of cognitive function of the patients of bipolar with cannabis dependence than the patients of bipolar disorder or cannabis dependence alone. It had been also found that with an increase in age of onset of bipolar disorder, there was decrease in no of episode, decrease current duration, and inter-episodic recovery was better. Conclusions: The significant cognitive function impairment exists in bipolar with cannabis dependence and the severity of bipolar outcome correlate with the extent of cannabis use also. In spite of certain limitations such as small sample size, short follow-up time, absence of Indian version of neuropsychological tests, and referral bias inherent in hospital-based studies; present study provides valuable empirical insight into complex relationship between cannabis dependence, bipolar disorder, and cognitive dysfunction.
... For instance, in contrast to the present results, several studies in recently abstinent (6-36 hours) adult cannabis users showed no differences in working memory abilities compared with infrequent or non-users (Pope and Yurgelun-Todd, 1996;Solowij et al., 2002;Kanayama et al., 2004;Whitlow et al., 2004;Fisk and Montgomery, 2008). Human studies assessing the residual effects of cannabis use on cognitive flexibility are more mixed, with some studies showing impairments (Pope and Yurgulen-Todd, 1996;Solowij et al., 2002) and others showing no deficits (Whitlow et al., 2004;Gruber and Yurgelun-Todd, 2005; Hermann et al., 2007). Consistent with the present findings, associative learning in recently abstinent adolescent and adult users has been shown to be unaffected (Harvey et al., 2007;Fisk and Montgomery, 2008;Jager et al., 2010). ...
Article
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Cannabis-related impairments to cognitive function may represent novel therapeutic targets for cannabis-use disorder, although the nature, persistence, and reversibility of those deficits remain unclear. Adult male rhesus monkeys (N=6) responded in the mornings on tasks designed to assess different cognitive domains using CANTAB touchscreens followed by responding maintained under a fixed-ratio (FR) 10 schedule of food presentation in different operant chambers. First, the acute effects of Δ9-tetrahydrocannabinol (THC; 0.01-0.56 mg/kg, i.v.) on cognitive performance, FR responding and body temperature were determined. Next, THC (1.0-2.0 mg/kg, s.c.) was administered daily after FR10 sessions for 12 weeks during which the residual effects of THC (i.e., 22 hrs after administration) on cognition were examined and the acute effects of THC were redetermined. In a subgroup of monkeys, dopamine D2/D3 receptor availability was assessed after 4 weeks of chronic THC exposure and compared to drug-naive controls using positron emission tomography and [11C]-raclopride (N=4/group). Acute THC pretreatments dose-dependently decreased FR responding and body temperature, while impairment to cognitive performance was task specific. During chronic treatment, THC produced persistent residual impairment only to working memory; tolerance differentially developed to acute cognitive impairments. There was recovery from residual cognitive impairments to working memory within 2 weeks of abstinence. Compared to controls, D2/D3 receptor availability was not altered during chronic THC treatment. In conclusion, THC-induced disruptions in cognition were task-specific, as was tolerance development, and not related to changes in D2/D3 receptor availability. Intervention strategies for cannabis-use disorder that enhance working memory performance may facilitate positive treatment outcomes.
... 8,9 In contrast, cannabidiol (CBD), the second most abundant component of cannabis -less studied than THC -has been shown to have anxiolytic, anti psychotic, antidepressant, and neuroprotective properties. [10][11][12][13] CBD acts on the ECBS as a weak inverse agonist on CB1 receptors, stimulates the TRVP1, and alters the hydrolysis of AEA by inhibiting fatty acid amine hydrolase. [14][15][16] CBD has been shown to be an agonist of 5-HT1a serotoninergic receptors and to regulate stress response and compulsive behaviors. ...
Article
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Drug addiction is a chronically relapsing disorder characterized by the compulsive desire to use drugs and a loss of control over consumption. Cannabidiol (CBD), the second most abundant component of cannabis, is thought to modulate various neuronal circuits involved in drug addiction. The goal of this systematic review is to summarize the available preclinical and clinical data on the impact of CBD on addictive behaviors. MEDLINE and PubMed were searched for English and French language articles published before 2015. In all, 14 studies were found, 9 of which were conducted on animals and the remaining 5 on humans. A limited number of preclinical studies suggest that CBD may have therapeutic properties on opioid, cocaine, and psychostimulant addiction, and some preliminary data suggest that it may be beneficial in cannabis and tobacco addiction in humans. Further studies are clearly necessary to fully evaluate the potential of CBD as an intervention for addictive disorders.
... Cocaine, methamphetamines, and opioids have been demonstrated to increase HIV replication in rodent models and in vitro (Kim et al., 2015;Dhillon et al., 2007;Liang et al., 2008;Schweitzer et al., 1991) thus, supporting a role for drugs of abuse to potentially increase neuroinflammation and neurodegeneration and possibly disrupt brain metabolism. Independently, drugs of abuse have been demonstrated to alter brain metabolism during active use and during periods of abstinence (Lehrmann et al., 2003;Li et al., 2012;Deng et al., 2012;Hermann et al., 2007;Fonseca et al., 2017;Kim et al., 2018;Crocker et al., 2017). Drug use alone is associated with significant microgliosis (Tomlinson et al., 1999). ...
Article
The brain is particularly sensitive to changes in energy supply. Defects in glucose utilization and mitochondrial dysfunction are hallmarks of nearly all neurodegenerative diseases and are also associated with the cognitive decline that occurs as the brain ages. Chronic neuroinflammation driven by glial activation is commonly implicated as a contributing factor to neurodegeneration and cognitive impairment. Human immunodeficiency virus-1 (HIV-1) disrupts normal brain homeostasis and leads to a spectrum of HIV-associated neurocognitive disorders (HAND). HIV-1 activates stress responses in the brain and triggers a state of chronic neuroinflammation. Growing evidence suggests that inflammatory processes and bioenergetics are interconnected in the propagation of neuronal dysfunction. Clinical studies of people living with HIV and basic research support the notion that HIV-1 creates an environment in the CNS that interrupts normal metabolic processes at the cellular level to collectively alter whole brain metabolism. In this review, we highlight reports of abnormal brain metabolism from clinical studies and animal models of HIV-1. We also describe diverse CNS cell-specific changes in bioenergetics associated with HIV-1. Moreover, we propose that attention should be given to adjunctive therapies that combat sources of metabolic dysfunction as a mean to improve and/or prevent neurocognitive impairments.
... 14 As such, this system represents a critical player in the maintenance and modulation of synaptic plasticity. 15 During frequent cannabis use, a series of poorly understood neuroplastic changes occur which can lead to the development of dependence. Early onset of cannabis use has been found to be related to increased risk of development of schizophrenia later in life, and leads to impairments in cognitive processes reliant on the circuitry of the dorsolateral prefrontal cortex (DLPFC). ...
... Reduced NAA/tCr ratios have been reported in diverse cases, such as patients with Alzheimer's disease, euthymic bipolar disorder, or men with recreational cannabis usage [70][71][72]. Interestingly, increased NAA/tCr levels have rarely been reported. ...
Article
Full-text available
To diagnose autism spectrum disorder (ASD), researchers have sought biomarkers whose alterations correlate with the susceptibility to ASD. However, biomarkers closely related to the pathophysiology of ASD are lacking. Even though excitation/inhibition (E/I) imbalance has been suggested as an underlying mechanism of ASD, few studies have investigated the actual ratio of glutamate (Glu) to γ-aminobutyric acid (GABA) concentration in vivo. Moreover, there are controversies in the directions of E/I ratio alterations even in extensively studied ASD animal models. Here, using proton magnetic resonance spectroscopy ( ¹ H-MRS) at 9.4T, we found significant differences in the levels of different metabolites or their ratios in the prefrontal cortex and hippocampus of Cntnap2 −/− mice compared to their wild-type littermates. The Glu/GABA ratio, N-acetylaspartate (NAA)/total creatine (tCr) ratio, and tCr level in the prefrontal cortex were significantly different in Cntnap2 −/− mice compared to those in wild-type mice, and they significantly correlated with the sociability of mice. Moreover, receiver operating characteristic (ROC) analyses indicated high specificity and selectivity of these metabolites in discriminating genotypes. These results suggest that the lowered Glu/GABA ratio in the prefrontal cortex along with the changes in the other metabolites might contribute to the social behavior deficit in Cntnap2 −/− mice. Our results also demonstrate the utility of ¹ H-MRS in investigating the underlying mechanisms or the diagnosis of ASD.
... Prolonged use of Cannabis is related to the decrease of neuronal and axonal integrity in the DLPFC. The results is interesting as the decreased ratio of NAA/tCr in DLPFC and neuropsychological deficits were also reported in schizophrenia (Hermann et al. 2007), breathing-related to CNS as the opioid analgesics have the possibility of combining with other CNS depressants like benzodiazepines which creates problems (Zutler and Holty 2011). There are also reports showing the suppression of apnoea by CBD. ...
Chapter
Sickle cell anemia (SCA) is an inherited disorder in the β-globin chain of hemoglobin that affects millions of people around the world, especially children. This disease prevalently occurs in some Mediterranean and Saharan Africa. For the treatment of SCA patients, a wide range of drugs have been explored by targeting antisickling activity, γ-globulin induction, antiplatelet effect, etc., but hardly a few drugs have shown potential to combat with this complex disease phenomenon. In spite of unprecedented advances in modern system of medicine, people in the disease-prone area have been taking traditional medicinal plants or plant-derived products to increase the life span of patients. Moreover, numerous clinical trials have been going on for the use of natural products under the purview of symptomatic management of SCA. This chapter is focused on the effect of natural products in pure form or characterized phytoconstituents on particularly inhibition of hemoglobin polymerization. This summarized information will be beneficial for further exploration of new therapeutics in the treatment arena of SCA.
... Prolonged use of Cannabis is related to the decrease of neuronal and axonal integrity in the DLPFC. The results is interesting as the decreased ratio of NAA/tCr in DLPFC and neuropsychological deficits were also reported in schizophrenia (Hermann et al. 2007), breathing-related to CNS as the opioid analgesics have the possibility of combining with other CNS depressants like benzodiazepines which creates problems (Zutler and Holty 2011). There are also reports showing the suppression of apnoea by CBD. ...
... By using a rat model of PD generated by unilateral injection of 6-hydroxydopamine into the medial forebrain bundle, it was shown that CBD can attenuate dopamine depletion and tyrosine hydroxylase deficits, which are indicative of the degree of neurodegeneration of nigrostriatal dopaminergic projections [1,7]. The neuroprotective action of CBD in animal models of PD is in accord with the strong positive correlation between the N-acetylaspartate/ total creatine ratio (which is suggestive of increased neurogenesis or synaptogenesis) and CBD levels measured in the putamen/globus pallidus of recreational users of Cannabis [42]. Further studies investigating the mode of action of CBD showed that this plant compound counteracted the decrease in copper-zinc superoxide dismutase (a key enzyme in endogenous defences against oxidative stress) induced by 6-hydroxydopamine in the rat substantia nigra [43]. ...
Article
Delta(9)-tetrahydrocannabinol binds cannabinoid (CB(1) and CB(2)) receptors, which are activated by endogenous compounds (endocannabinoids) and are involved in a wide range of physiopathological processes (e.g. modulation of neurotransmitter release, regulation of pain perception, and of cardiovascular, gastrointestinal and liver functions). The well-known psychotropic effects of Delta(9)-tetra hydrocannabinol, which are mediated by activation of brain CB(1) receptors, have greatly limited its clinical use. However, the plant Cannabis contains many cannabinoids with weak or no psychoactivity that, therapeutically, might be more promising than Delta(9)-tetra hydrocannabinol. Here, we provide an overview of the recent pharmacological advances, novel mechanisms of action, and potential therapeutic applications of such non-psychotropic plant-derived cannabinoids. Special emphasis is given to cannabidiol, the possible applications of which have recently emerged in inflammation, diabetes, cancer, affective and neurodegenerative diseases, and to Delta(9)-tetrahydrocannabivarin, a novel CB(1) antagonist which exerts potentially useful actions in the treatment of epilepsy and obesity.
... Chronic, heavy marijuana use is associated with impairments in memory and attention that worsen with increasing years of regular use (Solowij et al., 2002). Thus, marijuana use may impair decision-making via its impact on the prefrontal cortex (Hermann et al., 2007;Quickfall & Crockford, 2006) and related working memory functions (Fridberg, Gerst, & Finn, 2013). Correspondingly, cognitive enhancement and remediation has been proposed as a promising treatments for marijuana and other drug use disorders (Baskin-Sommers, Curtin, & Newman, 2015;Sofuoglu, Sugarman, & Carroll, 2010). ...
Article
Full-text available
Marijuana is the most commonly used illicit drug in the United States and its use is rising. Nonetheless, scientific efforts to clarify the risk for addiction and other harm associated with marijuana use have been lacking. Maladaptive decision-making is a cardinal feature of addiction that is likely to emerge in heavy users. In particular, distorted subjective reward valuation related to homeostatic or allostatic processes has been implicated for many drugs of abuse. Selective changes in responses to uncertainty have been observed in response to intoxication and deprivation from various drugs of abuse. To assess for these potential neuroadaptive changes in reward valuation associated with marijuana deprivation, we examined the subjective value of uncertain and certain rewards among deprived and non-deprived heavy marijuana users in a behavioral economics decision-making task. Deprived users displayed reduced valuation of uncertain rewards, particularly when these rewards were more objectively valuable. This uncertainty aversion increased with increasing quantity of marijuana use. These results suggest comparable decision-making vulnerability from marijuana use as other drugs of abuse, and highlights targets for intervention.
... Preclinical evidence indicate chronic exposure to THC has short-and long-term effects on glutamate neurotransmission and synaptic plasticity (4,5). Increasing evidence from neuroimaging studies suggest chronic cannabis exposure is also associated with disturbances of glutamate in humans, with reports of reduced glutamate metabolites in striatal, frontal cortical and white matter regions (6)(7)(8)(9)(10). ...
Article
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There is evidence that long-term cannabis use is associated with alterations to glutamate neurotransmission and glial function. In this study, 26 long-term cannabis users (males=65.4%) and 47 non-cannabis using healthy controls (males=44.6%) underwent proton magnetic resonance spectroscopy (1H-MRS) of the anterior cingulate cortex (ACC) in order to characterize neurometabolite alterations in cannabis users and to examine associations between neurometabolites, cannabis exposure, and cannabis use behaviors. Myo-inositol, a marker of glial function, and glutamate metabolites did not differ between healthy controls and cannabis users or cannabis users who met criteria for DSM5 cannabis use disorder (n=17). Lower myo-inositol, a putative marker of glial function, was related to greater problematic drug use (F1,22 = 11.95, p=.002; Cohen’s f=0.59, large effect; Drug Abuse Screening Test) and severity of cannabis dependence (F1,22 = 6.61, p=.17; Cohen’s f=0.44, large effect). Further, past-year cannabis exposure exerted different effects on glutamate and glutamate+glutamine in males and females (glutamate: F1,21 = 6.31, p=.02; glutamate+glutamine: F1,21 = 7.20, p=.014), such that greater past-year cannabis exposure was related to higher concentrations of glutamate metabolites in male cannabis users (glutamate: F1,14 = 25.94, p=.00016; Cohen’s f=1.32, large effect; glutamate+glutamine: F1,14 = 23.24, p=.00027, Cohen’s f=1.24, large effect) but not in female cannabis users (glutamate: F1,6 = 1.37, p=0.78; glutamate+glutamine: F1,6 = 0.001, p=.97). The present results extend existing evidence of altered glial function and glutamate metabolism with cannabis use by providing evidence linking problematic drug use behaviors with glial function as measured with myo-inositol and recent chronic cannabis exposure to alterations in glutamate metabolism. This provides novel directions for the interrogation of the impact of cannabis use on brain neurochemistry.
... For example Chang et al. [71] reported reduced glutamate, choline, and myoinositol concentrations in the basal ganglia of chronic marijuana users. Applying MRS imaging, Hermann et al. [72] identified lower concentrations of N-acetyl aspartate in the dorsolateral prefrontal cortex of adult smokers. Prescot et al. applied recently completed a small pilot study using proton MRS to the anterior cingulate of marijuana smoking and non-smoking adolescents and also found reduced N-acetyl aspartate, as well as reduced glutamate and creatine in marijuana-using individuals [73]. ...
Article
Full-text available
There is extensive research on the safety, toxicology, potency, and therapeutic potential of cannabis. However, uncertainty remains facilitating continued debate on medical and recreational cannabis policies at the state and federal levels. This review will include a brief description of cannabinoids and the endocannabinoid system; a summary of the acute and long-term effects of cannabis; and a discussion of the therapeutic potential of cannabis. The conclusions about safety and efficacy will then be compared with the current social and political climate to suggest future policy directions and general guidelines. Electronic supplementary material The online version of this article (doi:10.1007/s13311-015-0380-8) contains supplementary material, which is available to authorized users.
... 19,20 Furthermore, repeated use of cannabis has been associated with structural changes in frontal areas, as evinced by decreased gray matter volume, [21][22][23] and abnormal concentrations of metabolites including N-acetylaspartate (NAA), myoinositol (mI), and choline-containing compounds (Cho), biochemical markers of neuronal integrity and glial activation. 18,19,[24][25][26][27][28] Taken together, these studies provide evidence that repeated cannabis exposure may lead to alterations in neurotransmission and neuronal health, which underlie the diminished cognitive and behavioral response associated with acute cannabis tolerance. However, to date, the neuroadaptations that may underlie cannabis tolerance have not been systematically assessed. ...
Article
Full-text available
Cannabis is the most commonly used illicit drug in the world. However, because of a changing legal landscape and rising interest in therapeutic utility, there is an increasing trend in (long-term) use and possibly cannabis impairment. Importantly, a growing body of evidence suggests that regular cannabis users develop tolerance to the impairing, as well as the rewarding, effects of the drug. However, the neuroadaptations that may underlie cannabis tolerance remain unclear. Therefore, this double-blind, randomized, placebo-controlled, cross-over study assessed the acute influence of cannabis on the brain and behavioral outcomes in two distinct cannabis user groups. Twelve occasional and 12 chronic cannabis users received acute doses of cannabis (300-μg/kg delta-9-tetrahydrocannabinol) and placebo and underwent ultrahigh field functional magnetic resonance imaging and magnetic resonance spectroscopy. In occasional users, cannabis induced significant neurometabolic alterations in reward circuitry, namely, decrements in functional connectivity and increments in striatal glutamate concentrations, which were associated with increases in subjective high and decreases in performance on a sustained attention task. Such changes were absent in chronic users. The finding that cannabis altered circuitry and distorted behavior in occasional, but not chronic users, suggests reduced responsiveness of the reward circuitry to cannabis intoxication in chronic users. Taken together, the results suggest a pharmacodynamic mechanism for the development of tolerance to cannabis impairment, of which is important to understand in the context of the long-term therapeutic use of cannabis-based medications, as well as in the context of public health and safety of cannabis use when performing day-today operations.
... NAA is an indicator of neuronal health (Chawla et al., 2014); therefore, the lower levels of NAA suggest that CB use may have a toxic effect on neurons. Additionally, Hermann et al. (2007) found that recreational male CB users had lower NAA/tCr than control non-users and Yücel et al. (2016) found lower levels of NAA in the hippocampus in CB users. It should be noted that the reports reviewed measured NAA from different brain regions and often reported NAA as a ratio making replication studies important. ...
Article
Full-text available
With the legalization of recreational cannabis (CB) the characterization of how it may impact brain chemistry is essential. Magnetic resonance spectroscopy (MRS) was used to examine neurometabolite concentrations in the dorsal anterior cingulate (dACC) in chronic CB users (N = 26; 10 females) and controls (N = 24; 10 females). The concentrations of glutamate (Glu), total creatine (tCr), choline (Cho), total N-acetylaspartate (tNAA), and myo-inositol (mI) were estimated using LCModel. The ANCOVAs failed to show significant differences between controls and CB users. Regression analyses were then performed on the CB group to model each neurometabolite to determine its relationship to monthly CB use, sex, the interaction between CB use and sex. tCr was found to be predicted by both monthly CB use and sex. While the regression model was not significant the relationship between monthly CB use and Glu appears to be modulated by sex with the effect of monthly use (dose) being stronger in males. tNAA failed to show an effect of CB use but did reveal an effect of sex with females showing larger tNAA levels. Although the results presented are preliminary due to the small sample size they do guide future research. The results presented provide direction for further studies as they suggest that dose may significantly influence the observance of CB effects and that those effects may be modulated by sex. Studies with significantly larger sample sizes designed specifically to examine individuals with varying usage as well as sex effects are necessary.
... 43 Other studies have reported nonsignificant changes in myoinositol in the frontal white matter 39 in CU or in the temporal region in cannabis and ecstasy users. 44 Studies investigating NAA, a marker of neuronal integrity, 35,45 have reported decreased levels in CU compared with NU in the prefrontal cortex 46 and hippocampus, 47 and inverse relationship between NAA levels and cannabis use in the inferior frontal gyrus. 44 However, not all previous studies in CU have reported the concentration of all of these metabolites in the brain. ...
Article
Cannabis use has been associated with adverse mental health outcomes, the neurochemical underpinnings of which are poorly understood. Although preclinical evidence suggests glutamatergic dysfunction following cannabis exposure in several brain regions including the hippocampus, evidence from human studies have been inconsistent. We investigated the effect of persistent cannabis use on the brain levels of N-acetyl aspartate (NAA) and myoinositol, the metabolite markers of neurons and glia, the site of the main central cannabinoid CB1 receptor, and the levels of glutamate, the neurotransmitter directly affected by CB1 modulation. We investigated cannabis users (CUs) who started using during adolescence, the period of greatest vulnerability to cannabis effects and focused on the hippocampus, where type 1 cannabinoid receptors (CBR1) are expressed in high density and have been linked to altered glutamatergic neurotransmission. Twenty-two adolescent-onset CUs and 21 nonusing controls (NU), completed proton magnetic resonance spectroscopy, to measure hippocampal metabolite concentrations. Glutamate, NAA, and myoinositol levels were compared between CU and NU using separate analyses of covariance. CU had significantly lower myoinositol but not glutamate or NAA levels in the hippocampus compared with NU. Myoinositol levels in CU positively correlated with glutamate levels, whereas this association was absent in NU. Altered myoinositol levels may be a marker of glia dysfunction and is consistent with experimental preclinical evidence that cannabinoid-induced glial dysfunction may underlie cannabinoid-induced memory impairments. Future studies using appropriate imaging techniques such as positron emission tomography should investigate whether glial dysfunction associated with cannabis use underlies hippocampal dysfunction and memory impairment in CUs.
Chapter
This chapter focuses on application of magnetic resonance spectroscopy (MRS) methodologies and their relevance to drug addiction research. It introduces the significant features and characteristics of currently available MRS techniques and summarizes empirical findings. It outlines limitations of current MRS approaches and highlights potential future research directions to provide an enhanced understanding of brain mechanisms that underlie addiction. Functional and structural alterations observed in neuroimaging studies support conclusion that chronic exposure to alcohol results in neurotoxic effects on brain. The chapter reviews a number of MRS studies for neurometabolite quantification and localization in each patient group dependent on different classes of substance. Ongoing and future studies to expand the use of MRS findings as a potential surrogate biomarker have unique clinical benefits.
Article
The endocannabinoid (EC) system, consisting of ECs, their synthesizing and degrading enzymes, specific transmembrane EC transporters and receptors, is located in both excitatory and inhibitory synapses of all the classical neurotransmitter types throughout the central and peripheral nervous systems, where it acts as a retrograde signaling mechanism to inhibit further release of transmitter. This form of synaptic plasticity is a major component of both rapid short-term and sustained long-term adaptive responses that underlie such processes as homeostasis, learning, memory, and extinction. The functional effects on any given pathway can be either inhibitory or excitatory, depending on whether excitatory (e.g., glutamatergic) or inhibitory (e.g., GABAergic) modulation normally predominates in that pathway. However, the dose-effect curves of EC activity are in many instances biphasic, because sustained strong activity leads to EC receptor desensitization and down-regulation, resulting in progressive loss or even reversal of the effect. Therefore the effects of cannabis and exogenous cannabinoids, of both plant and synthetic origin, are in many cases different from, or even opposite to, those of the EC system.
Article
This chapter is aimed at summarizing the existing literature with respect to the subjective and objective cognitive profiles associated with marijuana use. Although subjective reports of marijuana use include feelings of relaxation and increased creativity, the altered state of consciousness and reduced inhibitory and executive cognitive functions may be enough to cause impairment in daily functioning. However, a chronically high level of consumption for an extended period of time is likely to result in increased risk of developing impairments such as affective dysregulation, inefficient cognitive control, underachievement, lower estimated intellectual capacity, and increased potential for additional drug use.
Article
As outlined elsewhere in this book epidemiological, clinical and genetic approaches have linked cannabis to schizophrenia from aetiological, contributory and exacerbating perspectives. These studies implicate cannabis use as deleterious in schizophrenia either in increasing its incidence, precipitating illness onset or worsening its outcomes. This suggests that inhaled or ingested components of cannabis may interact directly with biological systems relevant to schizophrenia. Much work has focussed on the main psychoactive component of cannabis, Δ9-tetrahydrocannabinol (THC), which appears to induce psychotic symptoms in both healthy controls and those with schizophrenia (D’Souza et al., 2005). However, there are at least 60 other bioactive components that could mediate the effects of cannabis in humans (Mechoulam and Hanus, 2000; and see Chapters 2 and 3). Hence, one explanation for the association of cannabis with schizophrenia is that the human endocannabinoid (eCB) system (ECS) may be disrupted in vulnerable individuals, predisposing them to the risk of developing, precipitating or exacerbating schizophrenia when exposed to cannabis. The human ECS is detailed elsewhere (see Chapter 3) and consists of a number of eCBs, their synthetic, degradative and transport pathways and the receptors to which they bind, principally the cannabinoid CB1 and CB2 receptors. The two major endocannabinoids are anandamide and 2-arachidonoyl glycerol (2-AG), with the latter predominating in the human central nervous system (CNS) (Piomelli, 2003). In addition to the CB1 and CB2 receptors, the endocannabinoids also activate other receptors in the CNS, including vanilloid (VR1), peroxisome proliferator-activated receptors, orphan G-protein coupled receptors (e.g. GPR55) and transmitter-gated ion channels (Pertwee, 2010). Although it is possible that any component of the ECS may be altered in individuals vulnerable to developing schizophrenia, methodological constraints have restricted investigation to a number of key elements.
Book
It has been 15 years since the original publication of Neuropsychology of Attention. At the time of its publication, attention was a construct that had long been of theoretical interest in the field of psychology and was receiving increased research by cognitive scientists. Yet, attention was typically viewed as a nuisance variable; a factor that needed to be accounted for when assessing brain function, but of limited importance in its own right. There is a need for a new edition of this book within Neuropsychology to present an updated and integrated review of what is know about attention, the disorders that affect it, and approaches to its clinical assessment and treatment. Such a book will provide perspectives for experimental neuropsychological study of attention and also provide clinicians with insights on how to approach this neuropsychological domain. © Springer Science+Business Media New York 2014. All rights reserved.
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Aim There is increasing concern that cannabinoid exposure during adolescence may disturb brain maturation and produce long-term cognitive deficits. However, studies in human subjects have provided limited evidence for such causality. The present study utilized behavioral and neuroimaging endpoints in female non-human primates to examine the effects of acute and chronic exposure during adolescence to the cannabinoid receptor full agonist, AM2389, on cognitive processing and brain function and chemistry. Materials and methods Adolescent female rhesus macaques were trained on a titrating-delay matching-to-sample (TDMTS) touchscreen task that assays working memory. TDMTS performance was assessed before and during chronic exposure to AM2389, following antagonist (rimonabant) administration, and after discontinuation of the chronic regimen. Resting-state fMRI connectivity and magnetic resonance spectroscopy data were acquired prior to drug treatment, during chronic exposure, and following its discontinuation. Voxels were placed in the medial orbitofrontal cortex (mOFC), a region involved in memory processing that undergoes maturation during adolescence. Results TDMTS performance was dose-dependently disrupted by acute AM2389; however, chronic treatment resulted in tolerance to these effects. TDMTS performance also was disrupted by discontinuation of the chronic regimen but surprisingly, not by rimonabant administration during chronic AM2389 treatment. mOFC N- acetylaspartate/creatine ratio decreased after acute and chronic administration but returned to baseline values following discontinuation of chronic treatment. Finally, intra-network functional connectivity (mOFC) increased during the chronic regimen and returned to baseline values following its discontinuation. Conclusion Neural effects of a cannabinergic drug may persist during chronic exposure, notwithstanding the development of tolerance to behavioral effects. However, such effects dissipate upon discontinuation, reflecting the restorative capacity of affected brain processes.
Article
Background: The most robust neurocognitive effect of marijuana use is memory impairment. Memory deficits are also high among persons living with HIV/AIDS, and marijuana is the most commonly used drug in this population. Yet research examining neurocognitive outcomes resulting from co-occurring marijuana and HIV is limited. Objective: The primary objectives of this comprehensive review are to: (1) examine the literature on memory functioning in HIV-infected individuals; (2) examine the literature on memory functioning in marijuana users; (3) synthesize findings and propose a theoretical framework to guide future research. Method: PubMed was searched for English publications 2000-2013. Twenty-two studies met inclusion criteria in the HIV literature, and 23 studies in the marijuana literature. Results: Among HIV-infected individuals, memory deficits with medium to large effect sizes were observed. Marijuana users also demonstrated memory problems, but results were less consistent due to the diversity of samples. Conclusion: A compensatory hypothesis, based on the cognitive aging literature, is proposed to provide a framework to explore the interaction between marijuana and HIV. There is some evidence that individuals infected with HIV recruit additional brain regions during memory tasks to compensate for HIV-related declines in neurocognitive functioning. Marijuana use causes impairment in similar brain systems, and thus it is hypothesized that the added neural strain of marijuana can exhaust neural resources, resulting in pronounced memory impairment. It will be important to test this hypothesis empirically, and future research priorities are discussed.
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This study examined the relationship between cannabis use, sex, and attentional inhibition in a sample of 325 young Australians (194 women and 131 men) aged 14 to 24 years. Participants completed an online assessment, which included self-report measures of alcohol and other drug use, psychological distress, schizotypy, and location-based negative priming. Participants who had never used cannabis (n = 163) were compared with occasional (n = 118) and frequent (n = 44) cannabis users, with frequent use being defined as having used cannabis at least weekly in the past 6 months. There was a significant interaction between sex and cannabis use, with follow-up analyses indicating that frequent cannabis use was associated with reduced negative priming among females only. This study highlights the role of sex in influencing how cannabis use interacts with cognition and suggests that females who use cannabis frequently may be more likely than males to exhibit deficits in attentional inhibition. (PsycINFO Database Record
Chapter
A little over 20 years ago, the first studies of blood oxygen level-dependent (BOLD) were conducted by several pioneers in burgeoning field of neuroimaging conducted demonstrating that functional magnetic resonance imaging (FMRI) of the brain was possible [1–4]. Soon after this, BOLD was shown to correspond with brain activation during simple sensory, motor, and cognitive operations, with regional patterns of cortical response that corresponded with established functional neuroanatomy [5–16]. These findings complemented parallel research that had been emerging a few years before using radiological methods like positron emission tomography (PET) [17]. Interest in functional neuroimaging surged as the significance of these findings became evident to neuroscientists. Neuroimaging has become a primary method for cognitive neuroscience research over the past 2 decades, providing a powerful tool for studying brain structure and function. Neuroimaging has evolved to the point that many universities now have research-dedicated MR scanners, in many cases located in psychology or neuroscience departments. This reflects the perception that neuroimaging is likely to continue to have a significant influence on the cognitive and behavioral neurosciences in the future.
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Importance There are no effective medications for treating dependence on cannabis. Objective To examine the safety and efficacy of nabiximols in the treatment of patients with cannabis dependence. Design, Setting, and Participants This parallel double-blind randomized clinical trial comparing nabiximols with placebo in a 12-week, multisite outpatient study recruited participants from February 3, 2016, to June 14, 2017, at 4 outpatient specialist alcohol and drug treatment services in New South Wales, Australia. Participants had cannabis dependence (as defined by the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision) and were seeking treatment, were nonresponsive to prior treatment attempts, were 18 to 64 years of age, had no other substance use disorder, had no severe medical or psychiatric conditions, were not pregnant, were not mandated by a court to undergo treatment, and provided informed consent. Results for primary efficacy measures and all secondary outcomes were obtained using a modified intention-to-treat data set. Interventions Participants received 12-week treatment involving weekly clinical reviews, structured counseling, and flexible medication doses—up to 32 sprays daily (tetrahydrocannabinol, 86.4 mg, and cannabidiol, 80 mg), dispensed weekly. Main Outcomes and Measures Primary outcome was self-reported number of days using illicit cannabis during the 12-week period. Other outcomes included alternate cannabis use parameters (periods of abstinence, withdrawal, cravings, and problems), safety parameters (adverse events and aberrant medication use), health status, other substance use, and treatment retention. Results A total of 128 participants (30 women and 98 men; mean [SD] age, 35.0 [10.9] years) were randomized and received at least 1 dose of study medication. Participants had used a mean (SD) of 2.3 (2.1) g of cannabis on a mean (SD) of 25.7 (4.5) days in the past 28 days. Treatment retention was comparable for the 2 groups (placebo, 30 of 67 participants [44.8%]; nabiximols, 30 of 61 participants [49.2%]), and both groups used similar mean (SD) doses (placebo, 18.5 [9.5] sprays daily; nabiximols, 17.6 [9.5] sprays daily, equivalent to a mean [SD] of 47.5 [25.7] mg of tetrahydrocannabinol and 44.0 [23.8] mg of cannabidiol). For the primary end point, the placebo group reported significantly more days using cannabis during the 12 weeks (mean [SD], 53.1 [33.0] days) than the nabiximols group (mean [SD], 35.0 [32.4] days; estimated difference, 18.6 days; 95% CI, 3.5-33.7 days; P = .02). Both groups showed comparable improvements in health status, with no substantial changes in other substance use. Medication was well tolerated with few adverse events. Conclusions and Relevance This study demonstrates that cannabinoid agonist treatment, in this case using nabiximols, in combination with psychosocial interventions is a safe approach for reducing cannabis use among individuals with cannabis dependence who are seeking treatment. Trial Registration anzctr.org.au Identifier: ACTRN12616000103460
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Introduction and aims: The Australian Treatment Outcomes Profile (ATOP) was developed as a clinical tool for monitoring the substance use, health and wellbeing of clients in alcohol and other drug treatment. This is the first psychometric validation of the ATOP in a cannabis-dependent treatment population. Design and methods: A total of 128 individuals with cannabis dependence enrolled in an outpatient randomised controlled trial were administered the ATOP and gold-standard health and wellbeing questionnaires once by clinicians and once by researchers at baseline. Concurrent validity was assessed by testing ATOP Psychological Health, Physical Health and Quality of Life questions against concurrently administered gold-standard questionnaires: the Short Form 36 Health Survey (SF-36), the 21-item Depression, Anxiety and Stress Scale (DASS-21) and the Sheehan Disability Scale (SDS). Interrater reliability was tested by comparing clinician-administered ATOP items at the medical screening interview to the same ATOP items administered by researchers at baseline. Results: ATOP Psychological Health showed moderate to strong correlations with SF-36 Mental Components, SF-36 Mental Health and DASS-21 scores (r = 0.40-0.52) and ATOP Physical Health with SF-36 Physical Components and SF-36 General Health scores (r = 0.36-0.67). The ATOP Quality of Life scale showed moderate agreement with the SDS and six-dimensional health state short form scales (r = 0.38-0.40). ATOP substance use, employment, education and child care items showed good to excellent interrater reliability (Krippendorff's α = 0.62-0.81), and tobacco use, Psychological Health, Physical Health and Quality of Life showed fair to moderate interrater reliability (Krippendorff's α = 0.42-0.53). Discussion and conclusions: The ATOP appears to be valid and reliable when tested in a population with cannabis-dependence, justifying its widespread use in clinical settings.
Article
Proton magnetic resonance spectroscopy (1H-MRS) now is widely used in clinical researches for the measurement of compounds or metabolites in vivo, especially in neuropsychiatric diseases/disorders. Recently, there are many studies on substance use disorders utilizing 1H-MRS to explore the mechanism of brain metabolites. It is found that metabolites levels in substance users are changed compared with healthy controls. Furthermore, these changes also relate to behavior indices, and provide evidence for the impact on neuronal health, energy metabolism and membrane turnover.However, 1H-MRS is not yet a mature detection technology, and it still has many challenges in the application of the neuropsychiatric disorder area. The settings of test parameters and the inconsistency of results across different studies still plague the clinicians and technicians. This article is intended to provide an overview of basic theory and methods of 1H-MRS, and the literature reporting metabolites alterations in substance dependence, as well as the related neuropsychological performance. At last, we will discuss the forthcoming challenges and possible future direction in this area.
Chapter
Cannabis L. belongs to Cannabaceae family known as ‘hemp’ and has been used as a mind-altering drug as described in prehistoric societies of Eurasia and Africa. A total of 100 phytocannabinoids have been reported from Cannabis sativa L. till date, owing to their therapeutic values. The two primary constituents present in Cannabis are non-psychoactive cannabidiol (CBD) and psychoactive Δ9-tetrahydrocannabinol (THC). CBD has enormous potential for the development as a drug candidate as depicted by diverse clinical and preclinical studies for the treatment of various neuropsychiatric disorders, arthritis, cancer and other diseases. Regardless of its therapeutic importance and interaction with the endocannabinoid system (ECS), definite pharmacological mechanism is not clearly established. Apart from medicinal research, there are a number of aspects which should be taken under consideration such as opinion of FDA, legal aspects of cannabis and international scenario during the drug development based on this plant.
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The phytocannabinoids of Cannabis sativa L. have, since ancient times, been proposed as a pharmacological alternative for treating various central nervous system (CNS) disorders. Interestingly, cannabinoid receptors (CBRs) are highly expressed in the basal ganglia (BG) circuit of both animals and humans. The BG are subcortical structures that regulate the initiation, execution, and orientation of movement. CBRs regulate dopaminergic transmission in the nigro-striatal pathway and, thus, the BG circuit also. The functioning of the BG is affected in pathologies related to movement disorders, especially those occurring in Parkinson’s disease (PD), which produces motor and non-motor symptoms that involving GABAergic, glutamatergic, and dopaminergic neural networks. To date, the most effective medication for PD is levodopa (l-DOPA); however, long-term levodopa treatment causes a type of long-term dyskinesias, l-DOPA-induced dyskinesias (LIDs). With neuromodulation offering a novel treatment strategy for PD patients, research has focused on the endocannabinoid system (ECS), as it participates in the physiological neuromodulation of the BG in order to control movement. CBRs have been shown to inhibit neurotransmitter release, while endocannabinoids (eCBs) play a key role in the synaptic regulation of the BG. In the past decade, cannabidiol (CBD), a non-psychotropic phytocannabinoid, has been shown to have compensatory effects both on the ECS and as a neuromodulator and neuroprotector in models such as 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and reserpine, as well as other PD models. Although the CBD-induced neuroprotection observed in animal models of PD has been attributed to the activation of the CB1 receptor, recent research conducted at a molecular level has proposed that CBD is capable of activating other receptors, such as CB2 and the TRPV-1 receptor, both of which are expressed in the dopaminergic neurons of the nigro-striatal pathway. These findings open new lines of scientific inquiry into the effects of CBD at the level of neural communication. Cannabidiol activates the PPARγ, GPR55, GPR3, GPR6, GPR12, and GPR18 receptors, causing a variety of biochemical, molecular, and behavioral effects due to the broad range of receptors it activates in the CNS. Given the low number of pharmacological treatment alternatives for PD currently available, the search for molecules with the therapeutic potential to improve neuronal communication is crucial. Therefore, the investigation of CBD and the mechanisms involved in its function is required in order to ascertain whether receptor activation could be a treatment alternative for both PD and LID.
Article
Many American and Dutch adolescents use marijuana regularly. There is concern that such use may impair cognitive function more in adolescents than adults. We examined effects of regular marijuana use on long-term memory and perseveration among American and Dutch adolescents. We administered Buschke's Selective Reminding Test (BSRT) to assess long-term memory and the Wisconsin Card Sorting Test (WCST) to assess perseveration in male teenagers. Usable test data were obtained for 12 American marijuana users, 13 American controls, 9 Dutch marijuana users, and 12 Dutch controls. In BSRT, users showed lower overall long-term storage than controls (adjusted means ± SE's for numbers of words per trial of 9.4 ± 0.2, 13.4 ± 0.3, 11.7 ± 0.2, and 12.4 ± 0.2 for American users, Dutch users, American controls, and Dutch controls, respectively). Marijuana was associated with memory effects only in American, not Dutch, users. Bivariate Pearson correlations for American and Dutch users combined showed associations of lower total recall with more uses in the previous year and lifetime (r = –0.61 and r = –0.53, respectively); and more perseverative errors with more uses in the previous year (r = 0.55). Some findings were consistent with the possibility that regular adolescent marijuana use causes deficits in cognition, especially memory. However, a causal interpretation cannot be inferred from our findings and is challenging to reconcile with the observation of memory deficits only in American users. Our study was novel in examining the influence of nationality on marijuana's cognitive effects. More studies of this topic should compare effects across nationalities or cultures.
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Importance Substantial shifts in perception and policy regarding cannabis have recently occurred, with use of cannabis increasing while its perceived harm decreases. One possible risk of increased cannabis use is poorer cognitive functioning, especially in youth. Objective To provide the first quantitative synthesis of the literature examining cannabis and cognitive functioning in adolescents and young adults (with a mean age of 26 years and younger). Data Sources PubMed, PsycInfo, Academic Search Premier, Scopus, and bibliographies of relevant reviews were searched for peer-reviewed, English-language studies from the date the databases began through May 2017. Study Selection Consensus criteria were used to determine study inclusion through abstract and manuscript review. Data Extraction and Synthesis This study followed Meta-analysis of Observational Studies in Epidemiology guidelines. Effect size estimates were calculated using multivariate mixed-effects models for cognitive functioning outcomes classified into 10 domains. Main Outcomes and Measures Results from neurocognitive tests administered in cross-sectional studies were primary outcomes, and we examined the influence of a priori explanatory variables on variability in effect size. Results Sixty-nine studies of 2152 cannabis users (mean [SD] age, 20.6 [2.8] years; 1472 [68.4%] male) and 6575 comparison participants with minimal cannabis exposure were included (mean [SD] age, 20.8 [3.4]; 3669 [55.8%] male). Results indicated a small overall effect size (presented as mean d) for reduced cognitive functioning associated with frequent or heavy cannabis use (d, −0.25; 95% CI, −0.32 to −0.17; P < .001). The magnitude of effect sizes did not vary by sample age or age at cannabis use onset. However, studies requiring an abstinence period longer than 72 hours (15 studies; n = 928) had an overall effect size (d, −0.08; 95% CI, −0.22 to 0.07) that was not significantly different from 0 and smaller than studies with less stringent abstinence criteria (54 studies; n = 7799; d, −0.30; 95% CI, −0.37 to −0.22; P = .01). Conclusions and Relevance Associations between cannabis use and cognitive functioning in cross-sectional studies of adolescents and young adults are small and may be of questionable clinical importance for most individuals. Furthermore, abstinence of longer than 72 hours diminishes cognitive deficits associated with cannabis use. Although other outcomes (eg, psychosis) were not examined in the included studies, results indicate that previous studies of cannabis in youth may have overstated the magnitude and persistence of cognitive deficits associated with use. Reported deficits may reflect residual effects from acute use or withdrawal. Future studies should examine individual differences in susceptibility to cannabis-associated cognitive dysfunction.
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Electroconvulsive therapy (ECT) is still the most effective treatment not only for psychotic depression, but also for treatment of resistant or other severe forms of major depressive episodes. Nevertheless, the exact nature of the therapeutic effect of ECT is unknown. Modern theories of depression suggest changes of synaptic plasticity especially within the hippocampus. It was hypothesized that such changes may be reflected in changes of proton magnetic resonance spectroscopy (1 H MRS) detectable signals. The current literature on 1 H MRS studies on ECT effects is small with a large diversity of MRS methods applied, brain regions studied and metabolite changes found. Nevertheless, there is good evidence that changes in neurometabolite concentrations are induced by ECT that can be non invasively monitored by 1 H MRS. There also are pioneering 1 H MRS studies on animal models of depression: the Learned Helplessness model in rats and the chronic social stress model in tree shrews. The proposed review will summarize the current MRS findings in humans and animals and discuss possible interpretations.
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A review and critique of the literature pertaining to the use of cognitive remediation techniques in patients with schizophrenia is presented. The review is organized into three sections, according to the neuropsychological deficit targeted for remediation: 1) executive-function, 2) attention, and 3) memory. With regards to executive-function, despite an initial report suggesting that Wisconsin Card Sorting Test performance cannot be remediated, subsequent studies suggest that performance can be improved on a variety of dependent measures including perseverative errors, categories achieved, and conceptual level responses. These observations were confirmed by a meta-analytic investigation that revealed large mean effects sizes (d + = 0.96) for these studies. Effect sizes were homogenous across discrepant remediation strategies and dependent measures. With regards to attention, serial scanning can be improved with instruction and reinforcement, whereas there is mixed evidence suggesting that practice-based attention drills can improve performance on measures of sustained attention in schizophrenia. With regards to memory, relatively simple semantic and affective elaborate encoding strategies elevates verbal list-learning memory in patients with schizophrenia to levels consistent with controls. A similar encoding procedure, combined with vigilance training, produces substantial improvement in social cue recognition. Avenues for future research are discussed.
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Cognitive correlates of long-term cannabis use have been elusive. We tested the hypothesis that long-term cannabis use is associated with deficits in short term memory, working memory, and attention in a literate, westernized culture (Costa Rica) in which the effects of cannabis use can be isolated. Two cohorts of long-term cannabis users and nonusers were studied. Within each cohort, users and nonusers were comparable in age and socioeconomic status. Polydrug users and users who tested positive for the use of cannabis at the time of cognitive assessment after a 72-hour abstention period were excluded. The older cohort (whose age was approximately 45 years) had consumed cannabis for an average of 34 years, and comprised 17 users and 30 nonusers, who had been recruited in San José, Costa Rica, and had been observed since 1973. The younger cohort (whose age was approximately 28 years) had consumed cannabis for an average of 8 years, and comprised 37 users and 49 nonusers. Short-term memory, working memory, and attentional skills were measured in each subject. Older long-term users performed worse than older nonusers on 2 short-term memory tests involving learning lists of words. In addition, older long-term users performed worse than older nonusers on selective and divided attention tasks associated with working memory. No notable differences were apparent between younger users and nonusers. Long-term cannabis use was associated with disruption of short-term memory, working memory, and attentional skills in older long-term cannabis users.
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To determine which proton magnetic resonance (MR) spectroscopic imaging measures are best for lateralizing the seizure focus in patients who have temporal lobe epilepsy with and in those without hippocampal atrophy on MR images, the extent of contralateral abnormalities, and whether there is a correlation between MR spectroscopic imaging findings and surgical outcome. MR spectroscopic imaging was performed in 16 adult patients with temporal lobe epilepsy and unilateral electroencephalographic findings and in 16 adult control subjects. Eleven patients underwent surgery; all patients underwent MR imaging. Nine patients had hippocampal atrophy on MR images. An ipsilateral decrease in the N-acetylaspartate concentration or the ratio of N-acetylaspartate to the sum of creatine and choline (N-acetylaspartate/ [creatine + choline]) was found in all patients. Decreased contralateral N-acetylaspartate concentration, N-acetylaspartate/(creatine + choline), or N-acetylaspartate concentration and N-acetylaspartate/(creatine + choline) were detected in eight patients (50%), which suggests bilateral abnormalities not detected with MR imaging. In the five patients who underwent surgery and did not show hippocampal atrophy on MR images, successful and unsuccessful outcomes were correctly predicted with N-acetylaspartate concentration. Decreased N-acetylaspartate concentration is not due solely to hippocampal atrophy. Contralateral abnormalities are much more frequent than expected. MR spectroscopic imaging is valuable in the presurgical evaluation of epilepsy.
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Marijuana consumption elicits diverse physiological and psychological effects in humans, including memory loss. Here we report that Delta9-tetrahydrocannabinol (THC), the major psychoactive component of marijuana, is toxic for hippocampal neurons. Treatment of cultured neurons or hippocampal slices with THC caused shrinkage of neuronal cell bodies and nuclei as well as genomic DNA strand breaks, hallmarks of neuronal apoptosis. Neuron death induced by THC was inhibited by nonsteroidal anti-inflammatory drugs, including indomethacin and aspirin, as well as vitamin E and other antioxidants. Furthermore, treatment of neurons with THC stimulated a significant increase in the release of arachidonic acid. We hypothesize that THC neurotoxicity is attributable to activation of the prostanoid synthesis pathway and generation of free radicals by cyclooxygenase. These data suggest that some of the memory deficits caused by cannabinoids may be caused by THC neurotoxicity.
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The neuroprotective actions of cannabidiol and other cannabinoids were examined in rat cortical neuron cultures exposed to toxic levels of the excitatory neurotransmitter glutamate. Glutamate toxicity was reduced by both cannabidiol, a nonpsychoactive constituent of marijuana, and the psychotropic cannabinoid (-)Delta9-tetrahydrocannabinol (THC). Cannabinoids protected equally well against neurotoxicity mediated by N-methyl-D-aspartate receptors, 2-amino-3-(4-butyl-3-hydroxyisoxazol-5-yl)propionic acid receptors, or kainate receptors. N-methyl-D-aspartate receptor-induced toxicity has been shown to be calcium dependent; this study demonstrates that 2-amino-3-(4-butyl-3-hydroxyisoxazol-5-yl)propionic acid/kainate receptor-type neurotoxicity is also calcium-dependent, partly mediated by voltage sensitive calcium channels. The neuroprotection observed with cannabidiol and THC was unaffected by cannabinoid receptor antagonist, indicating it to be cannabinoid receptor independent. Previous studies have shown that glutamate toxicity may be prevented by antioxidants. Cannabidiol, THC and several synthetic cannabinoids all were demonstrated to be antioxidants by cyclic voltametry. Cannabidiol and THC also were shown to prevent hydroperoxide-induced oxidative damage as well as or better than other antioxidants in a chemical (Fenton reaction) system and neuronal cultures. Cannabidiol was more protective against glutamate neurotoxicity than either ascorbate or alpha-tocopherol, indicating it to be a potent antioxidant. These data also suggest that the naturally occurring, nonpsychotropic cannabinoid, cannabidiol, may be a potentially useful therapeutic agent for the treatment of oxidative neurological disorders such as cerebral ischemia.
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Certain cognitive, behavioral, and emotional deficits (so-called negative symptoms) in patients with schizophrenia have often been attributed to prefrontal cortical pathology, but direct evidence for a relationship between prefrontal neuronal pathology and negative symptoms has been lacking. The authors hypothesized that an in vivo measure of prefrontal neuronal pathology (N:-acetylaspartate [NAA] levels) in patients with schizophrenia would predict negative symptoms. Proton magnetic resonance spectroscopic imaging ((1)H-MRSI) and rating scales for negative and positive symptoms were used to study 36 patients with schizophrenia. Magnetic resonance spectra were analyzed as metabolite ratios, and parametric correlations were performed. A regionally selective negative correlation was found between prefrontal NAA-creatine ratio and negative symptom ratings in this group of patients with schizophrenia. Lower prefrontal NAA-and by inference greater neuronal pathology-predicted more severe negative symptoms in patients with schizophrenia. These data demonstrate a relationship between an intraneuronal measure of dorsolateral prefrontal cortex integrity and negative symptoms in vivo and represent further evidence for the involvement of the dorsolateral prefrontal cortex in negative symptoms associated with schizophrenia.
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Using proton magnetic resonance spectroscopic imaging, the authors measured thalamic N-acetylaspartate (NAA) concentrations in patients with schizophrenia. The study included 15 schizophrenic patients on a stable medication regimen and 15 age-matched healthy comparison subjects. Concentrations of NAA, creatine plus phosphocreatine, and choline-containing compounds in bilateral thalamic regions were determined. Previous findings of lower NAA concentration in the left and right mediodorsal region of the thalamus and significant correlations between left and right thalamic NAA measures in patients with schizophrenia were corroborated. Furthermore, the concentrations of choline-containing compounds were significantly lower in the schizophrenic patients. No group differences in creatine plus phosphocreatine were found. There is strong evidence for neuronal dysfunction or loss in the mediodorsal region of the thalamus in patients with schizophrenia.
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Although cannabis is the most widely used illicit drug in the United States, its long-term cognitive effects remain inadequately studied. We recruited individuals aged 30 to 55 years in 3 groups: (1) 63 current heavy users who had smoked cannabis at least 5000 times in their lives and who were smoking daily at study entry; (2) 45 former heavy users who had also smoked at least 5000 times but fewer than 12 times in the last 3 months; and (3) 72 control subjects who had smoked no more than 50 times in their lives. Subjects underwent a 28-day washout from cannabis use, monitored by observed urine samples. On days 0, 1, 7, and 28, we administered a neuropsychological test battery to assess general intellectual function, abstraction ability, sustained attention, verbal fluency, and ability to learn and recall new verbal and visuospatial information. Test results were analyzed by repeated-measures regression analysis, adjusting for potentially confounding variables. At days 0, 1, and 7, current heavy users scored significantly below control subjects on recall of word lists, and this deficit was associated with users' urinary 11-nor-9-carboxy-Delta9-tetrahydrocannabinol concentrations at study entry. By day 28, however, there were virtually no significant differences among the groups on any of the test results, and no significant associations between cumulative lifetime cannabis use and test scores. Some cognitive deficits appear detectable at least 7 days after heavy cannabis use but appear reversible and related to recent cannabis exposure rather than irreversible and related to cumulative lifetime use.
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Traumatic brain injury triggers the accumulation of harmful mediators that may lead to secondary damage. Protective mechanisms to attenuate damage are also set in motion. 2-Arachidonoyl glycerol (2-AG) is an endogenous cannabinoid, identified both in the periphery and in the brain, but its physiological roles have been only partially clarified. Here we show that, after injury to the mouse brain, 2-AG may have a neuroprotective role in which the cannabinoid system is involved. After closed head injury (CHI) in mice, the level of endogenous 2-AG was significantly elevated. We administered synthetic 2-AG to mice after CHI and found significant reduction of brain oedema, better clinical recovery, reduced infarct volume and reduced hippocampal cell death compared with controls. When 2-AG was administered together with additional inactive 2-acyl-glycerols that are normally present in the brain, functional recovery was significantly enhanced. The beneficial effect of 2-AG was dose-dependently attenuated by SR-141761A, an antagonist of the CB1 cannabinoid receptor.
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In recent years the illicit drug ecstasy (MDMA, 3,4-methylenedioxymethamphetamine) has come into widespread use among young people. Despite clear evidence for the neurotoxic potential of MDMA in animals, corresponding evidence in humans is limited to indirect findings. In an exploratory study we compared the hippocampal H-1-MRSI (magnetic resonance spectroscopic imaging) spectra, of five MDMA users with those of controls with no history of substance abuse. Although H-1-MRSI is, sensitive in detecting alterations in neuronal viability in association with diseases leading to neuronal degeneration, we were not able to demonstrate any differences in hippocampal H-1-MRSI between MDMA users and controls.
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Cognitive impairments are associated with long-term cannabis use, but the parameters of use that contribute to impairments and the nature and endurance of cognitive dysfunction remain uncertain. To examine the effects of duration of cannabis use on specific areas of cognitive functioning among users seeking treatment for cannabis dependence. Multisite retrospective cross-sectional neuropsychological study conducted in the United States (Seattle, Wash; Farmington, Conn; and Miami, Fla) between 1997 and 2000 among 102 near-daily cannabis users (51 long-term users: mean, 23.9 years of use; 51 shorter-term users: mean, 10.2 years of use) compared with 33 nonuser controls. Measures from 9 standard neuropsychological tests that assessed attention, memory, and executive functioning, and were administered prior to entry to a treatment program and following a median 17-hour abstinence. Long-term cannabis users performed significantly less well than shorter-term users and controls on tests of memory and attention. On the Rey Auditory Verbal Learning Test, long-term users recalled significantly fewer words than either shorter-term users (P =.001) or controls (P =.005); there was no difference between shorter-term users and controls. Long-term users showed impaired learning (P =.007), retention (P =.003), and retrieval (P =.002) compared with controls. Both user groups performed poorly on a time estimation task (P<.001 vs controls). Performance measures often correlated significantly with the duration of cannabis use, being worse with increasing years of use, but were unrelated to withdrawal symptoms and persisted after controlling for recent cannabis use and other drug use. These results confirm that long-term heavy cannabis users show impairments in memory and attention that endure beyond the period of intoxication and worsen with increasing years of regular cannabis use.
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Literature data related to the merit of hair as a chronological diary of drug exposure, as examined by segmental analysis, are reviewed with emphases on the mechanisms of drug incorporation, physiology of hair growth, and findings resulting from research effort and routine analytical results. In a single anagen strand, a drug dose may be incorporated, within the hair follicle, to a drug-containing zone of approximately 2-5 mm width, which appears at the skin surface 1-5 days after drug exposure and moves regularly away following the strand's growth rate. This process is disturbed by deposition from sweat, sebum, and in rare cases environmental contamination, as well as by elimination during hair care or chemical treatment. In a hair tuft, the time resolution is seriously deteriorated by the presence of 5-15% (or even more) strands in the resting stage, by variability in the growth rate (up to 40%), and by inexact alignment of the strands. Interindividually, the generally accepted medium growth rate of 1.1 ± 0.2 cm/month is only a very rough approximation. When applying to retrospective elucidation of intoxications and control of illegal or therapeutic drug intake cases, correlations ranging from excellent agreement to enormous deviations have been reported. Satisfactory dose-concentration correlation could not be established in both intra- and interindividual studies. Therefore, the domain of routine hair analysis remains the retrospective qualitative detection of drug exposure. Improved time estimation is possible using anagen hair and careful determination of individual growth rate and its variation at the sites of sampling, careful sample handling, and analysis of sufficient segments. Copyright © 1998 Central Police University.
Article
Background We monitored the effect of electroconvulsive therapy (ECT) on the nuclear magnetic resonance–detectable metabolites N-acetylaspartate, creatine and phosphocreatine, and choline-containing compounds in the hippocampus by means of hydrogen 1 magnetic resonance spectroscopic imaging. We hypothesized that if ECT-induced memory deterioration was associated with neuronal loss in the hippocampus, the N-acetylaspartate signal would decrease after ECT and any increased membrane turnover would result in an increase in the signal from choline-containing compounds.Methods Seventeen patients received complete courses of ECT, during which repeated proton magnetic resonance spectroscopic imaging studies of the hippocampal region were performed. Individual changes during the course of ECT were compared with values obtained in 24 healthy control subjects and 6 patients remitted from major depression without ECT.Results No changes in the hippocampal N-acetylaspartate signals were detected after ECT. A significant mean increase of 16% of the signal from choline-containing compounds after 5 or more ECT treatments was observed. Despite the mostly unilateral ECT application (14 of 17 patients), the increase in the choline-containing compound signal was observed bilaterally. Lactate or elevated lipid signals were not detected. All patients showed clinical amelioration of depression after ECT.Conclusions Electroconvulsive therapy is not likely to induce hippocampal atrophy or cell death, which would be reflected by a decrease in the N-acetylaspartate signal. Compared with an age-matched control group, the choline-containing compounds signal in patients with a major depressive episode was significantly lower than normal, before ECT and normalized during ECT.
Article
Context Cognitive impairments are associated with long-term cannabis use, but the parameters of use that contribute to impairments and the nature and endurance of cognitive dysfunction remain uncertain.Objective To examine the effects of duration of cannabis use on specific areas of cognitive functioning among users seeking treatment for cannabis dependence.Design, Setting, and Participants Multisite retrospective cross-sectional neuropsychological study conducted in the United States (Seattle, Wash; Farmington, Conn; and Miami, Fla) between 1997 and 2000 among 102 near-daily cannabis users (51 long-term users: mean, 23.9 years of use; 51 shorter-term users: mean, 10.2 years of use) compared with 33 nonuser controls.Main Outcome Measures Measures from 9 standard neuropsychological tests that assessed attention, memory, and executive functioning, and were administered prior to entry to a treatment program and following a median 17-hour abstinence.Results Long-term cannabis users performed significantly less well than shorter-term users and controls on tests of memory and attention. On the Rey Auditory Verbal Learning Test, long-term users recalled significantly fewer words than either shorter-term users (P = .001) or controls (P = .005); there was no difference between shorter-term users and controls. Long-term users showed impaired learning (P = .007), retention (P = .003), and retrieval (P = .002) compared with controls. Both user groups performed poorly on a time estimation task (P<.001 vs controls). Performance measures often correlated significantly with the duration of cannabis use, being worse with increasing years of use, but were unrelated to withdrawal symptoms and persisted after controlling for recent cannabis use and other drug use.Conclusions These results confirm that long-term heavy cannabis users show impairments in memory and attention that endure beyond the period of intoxication and worsen with increasing years of regular cannabis use.
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Volumetric proton magnetic resonance spectroscopic imaging (MRSI) was used to generate brain metabolite maps in 15 young and 19 elderly adult volunteers. All subjects also had structural MR scans, and a model, which took into account the underlying structural composition of the brain contributing to each metabolite voxel, was developed and used to estimate the concentration of the N-acetyl-moiety (NAc), creatine (Cr), and choline (Cho) in gray matter and white matter. NAc concentration (signal intensity per unit volume of brain) was higher in gray than white matter and did not differ between young and old subjects despite significant gray matter volume deficits in the older subjects. To the extent that NAc is an index of neuronal integrity, the available gray matter appears to be intact in these older healthy adults. Cr concentrations were much higher in gray than white matter and significantly higher in the old than young subjects. Cho concentration in gray matter was also significantly higher in old than young subjects. Independent determination of metabolite values rather than use of ratios is essential for characterizing age-related changes in brain MRS metabolites. Magn Reson Med 41:276–284, 1999. Published 1999 Wiley-Liss, Inc.
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Four tests previously used to determine the presence of brain injury were considered in terms of their comparative advantages, disadvantages, and rationale. These tests were the Wechsler Mental Abilities Scale (Form B or MAS), Shipley-Hartford Retreat Scale for Intellectual Impairment, Hunt-Minnesota Test for Organic Brain Damage, and Rorschach Test. It is suggested that the Rorschach is the most useful for this purpose. The brain injured group consisted of 44 patients who were known to have sustained cerebral damage. The evidence was derived largely from surgeons' reports. In the instances where these were lacking, positive pneumo-encephalograms and/or neurological findings were available. The source of these injuries ranged from high velocity missiles to auto accidents. In regard to the severity and type of injury the neurologist distributed the 44 cases as follows: 11 severe, 21 moderate, and 12 mild; 9 were considered to have focal lesions, 17 were classed as focal-diffuse and 18 were diffuse. The neurotics and normals do not appear to differ in any respect. Although this was suggested by their means, it was considered best to make this test before the two groups were combined into the control group and used averages have been affected by the presence of a few extremely low or high scores. Four of the brain injured cases during the free association period gave stories that bore little relationship to the one that was read to them. However, they retained enough of the original story to receive some credit. In every instance the confabulation had a central idea or theme and was fairly coherent and cohesive, but in each instance elements of circumstantiality, preservation, and pseudo-profundity were present. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
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Abstract  Both spatial working memory deficit and disorganization symptoms have been considered significant components of schizophrenic impairment involved with the dorsolateral prefrontal cortex. The purpose of the present study was to investigate the relationships among spatial working memory, psychiatric symptoms including disorganization symptoms, and social functioning in schizophrenia. Fifty clinically stable patients with schizophrenia and 34 healthy controls participated in the study. Patients were rated with the Brief Psychiatric Rating Scale and the Rehabilitation Evaluation Hall and Baker. The Advanced Trail Making Test was used to evaluate spatial working memory. Patients demonstrated significantly reduced spatial working memory compared to that of healthy controls. Spatial working memory in patients correlated significantly with social functioning such as self-care skills, community skills and speech disturbance, and with disorganization symptoms. Disorganization symptoms also correlated with these aspects of social functioning. In conclusion it is suggested that both spatial working memory deficit and disorganization symptoms, which are impairments involved with the dorsolateral prefrontal cortex dysfunction, can serve as effective predictors of social functioning.
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An automated method for analysis of in vivo proton magnetic resonance (MR) spectra and reconstruction of metabolite distributions from MR spectroscopic imaging (MRSI) data is described. A parametric spectral model using acquisition specific, a priori information is combined with a wavelet-based, nonparametric characterization of baseline signals. For image reconstruction, the initial fit estimates were additionally modified according to a priori spatial constraints. The automated fitting procedure was applied to four different examples of MRS data obtained at 1.5 T and 4.1 T. For analysis of major metabolites at medium TE values, the method was shown to perform reliably even in the presence of large baseline signals and relatively poor signal-to-noise ratios typical of in vivo proton MRSI. identification of additional metabolites was also demonstrated for short TE data. Automated formation of metabolite images will greatly facilitate and expand the clinical applications of MR spectroscopic imaging.
Article
Objective and method: The acute effects of delta9 tetrahydrocannabinol (THC) on cerebral blood flow (CBF) were studied in human subjects. Regional CBF was measured with 15O-water and Positron Emission Tomography (PET) in 32 volunteers with a history of exposure to marijuana. Scans were performed before and after intravenous (I.V.) infusion of either of two doses of THC or a placebo, given under double blind conditions. Results: THC but not placebo increased CBF especially in the frontal regions bilaterally, insula and cingulate gyrus and sub-cortical regions with somewhat greater effects in the right hemisphere. While most regions showed significant change at 60 minutes for the lower dose group, the higher dose group had significant change at 30 and 60 minutes. There was a highly significant change in the anterior/posterior ratio for the two THC groups reflecting minimal change in occipital flow but significant increases in frontal flow. Self ratings of THC intoxication showed significant effects, and regression analysis indicated it correlated most markedly with the right frontal region. Conclusion: Behavioral manifestations of marijuana intoxication may be associated with increased functional activity of the brain especially the frontal cortex, insula and cingulate gyrus.
Article
Metabolic changes in the hippocampus formation can be investigated with in vivo magnetic resonance spectroscopy (MRS). Learned helplessness (LH) is a well validated animal model of depression which we established in Sprague–Dawley rats defining some as “learned helpless” (LH) or not “learned helpless” (NLH). Helpless and non-helpless rats received a course of daily administered electroconvulsive shocks (ECS) for 6 days. MRS measurements were performed on a 4.7 T animal scanner with an average voxel size within the rat hippocampus of 10 μl. In LH rats hippocampal creatine/NAA rose significantly (14%) whereas creatine/NAA of NLH rats showed no increase at all. A possible connection between hippocampal creatine levels and major depressive disorders as a reflection of changes in energy metabolism is discussed.
Article
We investigated the effects of acute i.v. administration of 2 mg of delta 9-tetrahydrocannabinol (THC) on regional brain glucose metabolism using 18F-2-fluoro-2-deoxyglucose and positron emission tomography (PET) in eight normal subjects. Subjects were tested twice: during baseline conditions and 30-40 min after THC administration. Changes in global cerebral glucose metabolism in response to THC were variable: three subjects showed an increase, three showed a decrease, and two showed no change. In contrast, all subjects showed an increase in normalized metabolism in the cerebellum following THC administration. Cerebellar changes were the only significant regional metabolic changes due to THC administration. The increase in metabolic activity in the cerebellum was correlated with the subjective sense of THC intoxication and with plasma THC concentration. Cerebellar localization of metabolic effects due to THC administration corresponds well with the high density of cannabinoid receptors known to be in this area.
Article
The evidence for long-term cognitive impairments associated with chronic use of cannabis has been inconclusive. We report the results of a brain event-related potential (ERP) study of selective attention in long-term cannabis users in the unintoxicated state. Two ERP measures known to reflect distinct components of attention were found to be affected differentially by duration and frequency of cannabis use. The ability to focus attention and filter out irrelevant information, measured by frontal processing negativity to irrelevant stimuli, was impaired progressively with the number of years of use but was unrelated to frequency of use. The speed of information processing, measured by the latency of parietal P300, was delayed significantly with increasing frequency of use but was unaffected by duration of use. The results suggest that a chronic buildup of cannabinoids produces both short- and long-term cognitive impairments.
Article
The purpose of the present study was to investigate the disruptive effects of cannabinoids on working memory as assessed in the eight-arm radial-maze. Systemic administration of delta 9-THC, WIN-55,212-2, and CP-55,940 increased the number of errors committed in the radial-maze. CP-55,940 was the most potent cannabinoid in impairing memory (ED50 = 0.13 mg/kg). delta 9-THC and WIN-55,212-2 disrupted maze-choice accuracy at equipotent doses (ED50 values = 2.1 and 2.2 mg/kg, respectively). In addition, systemic administration of each of these agents retarded completion time. Whereas the doses of delta 9-THC and CP-55,940 required to retard maze performance were higher than those needed to increase error numbers, WIN-55,212-2 was equipotent in both of these measures. On the other hand, neither anandamide, the putative endogenous cannabinoid ligand, nor cannabidiol, an inactive naturally occurring cannabinoid, had any apparent effects on memory. A second aim of this study was to elucidate the neuroanatomical substrates mediating the disruptive effects of cannabinoids on memory. Intrahippocampal injections of CP-55,940 impaired maze performance in a dose-dependent manner (ED50 = 8 micrograms/rat), but did not retard the amount of time required to complete the maze. The effects of intrahippocampal CP-55,940 were apparently specific to cognition because no other cannabinoid pharmacological effects (e.g., antinociception, hypothermia, and catalepsy) were detected. This dissociation between choice accuracy in the radial-maze and other cannabinoid pharmacological effects suggests that the working memory deficits produced by cannabinoids may be mediated by cannabinoid receptors in the hippocampus.