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OBJECTIVE: Clinical investigators in Japan have long suggested that exposure to methamphetamine might cause a persistent schizophrenia-like psychosis. This possibility is discounted in the Western literature. To investigate the relationship between drug use and later schizophrenia, the authors conducted a large-scale cohort study of drug users initially free of persistent psychosis. METHOD: A population-based cohort study was conducted using data from California inpatient hospital discharge records from 1990 through 2000. Patients with methamphetamine-related conditions (N=42,412) and those with other drug use disorders (cannabis, cocaine, alcohol, and opioids) were propensity score-matched to individuals with primary appendicitis who served as a population proxy comparison group; the methamphetamine cohort was also matched to the other drug cohorts. Cox modeling was used to estimate differences between matched groups in the rates of subsequent admission with schizophrenia diagnoses. RESULTS: The methamphetamine cohort had a significantly higher risk of schizophrenia than the appendicitis group (hazard ratio=9.37) and the cocaine, opioid, and alcohol groups (hazard ratios ranging from 1.46 to 2.81), but not significantly different from that of the cannabis group. The risk of schizophrenia was higher in all drug cohorts than in the appendicitis group. CONCLUSIONS: Study limitations include difficulty in confirming schizophrenia diagnoses independent of drug intoxication and the possibility of undetected schizophrenia predating drug exposure. The study's findings suggest that individuals with methamphetamine-related disorders have a higher risk of schizophrenia than those with other drug use disorders, with the exception of cannabis use disorders. The elevated risk in methamphetamine users may be explained by shared etiological mechanisms involved in the development of schizophrenia. [ABSTRACT FROM AUTHOR]

Animal data indicate that the recreational drug ecstasy (3,4-methylenedioxymethamphetamine) can damage brain serotonin neurons. However, human neuroimaging measurements of serotonin transporter binding, a serotonin neuron marker, remain contradictory, especially regarding brain areas affected; and the possibility that structural brain differences might account for serotonin transporter binding changes has not been explored. We measured brain serotonin transporter binding using [(11)C] N,N-dimethyl-2-(2-amino-4-cyanophenylthio) benzylamine in 50 control subjects and in 49 chronic (mean 4 years) ecstasy users (typically one to two tablets bi-monthly) withdrawn from the drug (mean 45 days). A magnetic resonance image for positron emission tomography image co-registration and structural analyses was acquired. Hair toxicology confirmed group allocation but also indicated use of other psychoactive drugs in most users. Serotonin transporter binding in ecstasy users was significantly decreased throughout all cerebral cortices (range -19 to -46%) and hippocampus (-21%) and related to the extent of drug use (years, maximum dose), but was normal in basal ganglia and midbrain. Substantial overlap was observed between control and user values except for insular cortex, in which 51% of ecstasy user values fell below the lower limit of the control range. Voxel-based analyses confirmed a caudorostral gradient of cortical serotonin transporter binding loss with occipital cortex most severely affected. Magnetic resonance image measurement revealed no overall regional volume differences between groups; however, a slight left-hemispheric biased cortical thinning was detected in methamphetamine-using ecstasy users. The serotonin transporter binding loss was not related to structural changes or partial volume effect, use of other stimulant drugs, blood testosterone or oestradiol levels, major serotonin transporter gene promoter polymorphisms, gender, psychiatric status, or self-reported hyperthermia or tolerance. The ecstasy group, although 'grossly behaviourally normal', reported subnormal mood and demonstrated generally modest deficits on some tests of attention, executive function and memory, with the latter associated with serotonin transporter decrease. Our findings suggest that the 'typical'/low dose (one to two tablets/session) chronic ecstasy-polydrug user might display a highly selective mild to marked loss of serotonin transporter in cerebral cortex/hippocampus in the range of that observed in Parkinson's disease, which is not gender-specific or completely accounted for by structural brain changes, recent use of other drugs (as assessed by hair analyses) or other potential confounds that we could address. The striking sparing of serotonin transporter-rich striatum (although possibly affected in 'heavier' users) suggests that serotonergic neurons innervating cerebral cortex are more susceptible, for unknown reasons, to ecstasy than those innervating subcortical regions and that behavioural problems in some ecstasy users during abstinence might be related to serotonin transporter changes limited to cortical regions. [ABSTRACT FROM AUTHOR]

The D(3) dopamine (DA) receptor is a member of the D(2)-like DA receptor family. While the D(2) receptor is abundant especially in motor-regions of the striatum, the D(3) receptor shows a relative abundance in limbic regions and globus pallidus. This receptor is of current interest in neurology because of its potential involvement in psychiatric and motor complications in Parkinson's disease and the possibility that dopamine D(3)-preferring agonist therapy might delay progression of the disorder. Preclinical data indicate that striatal levels of the D(3) (but not the D(2)) DA receptor are decreased following lesion of nigrostriatal DA neurons; at present, there are no in vivo data on this receptor subtype in Parkinson's disease. The objective of this positron emission tomography study was to compare [(11)C]-(+)-PHNO (D(3) versus D(2) preferring) and [(11)C]raclopride (D(3) = D(2)) binding in brain of non-depressed, non-demented, dopaminergic drug-naïve patients with early-stage Parkinson's disease (n = 10), relative to matched-controls (n = 9). Parkinson's disease was associated with a trend for bilaterally decreased [(11)C]-(+)-PHNO (but not [(11)C]raclopride) binding in the D(3)-rich ventral striatum (-11%, P = 0.07) and significantly decreased binding in globus pallidus (-42%, P = 0.02). In contrast, in the primarily D(2)-populated putamen, both [(11)C]-(+)-PHNO (25%, P = 0.02) and [(11)C]raclopride (25%, P < 0.01) binding were similarly increased, especially on the side contra-lateral to the symptoms. In the midbrain, presumably containing D(3) receptors localized to the substantia nigra, [(11)C]-(+)-PHNO binding was normal. Decreased [(11)C]-(+)-PHNO to [(11)C]raclopride ratio correlated with motor deficits and lowered-mood (P < 0.02). Our imaging data suggest that brain DA neuron loss in the human causes region-specific differential changes in DA D(2) and D(3) receptors with D(3) receptor 'downregulation' possibly related to some motor and mood problems in Parkinson disease. D(3) receptor levels might be a determinant vulnerability factor underlying side-effects associated with treatment; hence, these initial findings provide valuable baseline information to understand the role of D(3) receptors in response to Parkinson's disease medication. [ABSTRACT FROM AUTHOR]

This study investigated whether abnormalities in serotonin transporter binding occur in Parkinson's disease (PD) patients with concurrent depression. We estimated serotonin transporter levels in seven clinically depressed early-stage PD patients and in seven healthy matched-control subjects during a single positron emission tomography (PET) scan with the serotonin transporter radioligand, [(11)C]DASB. Depressed PD patients displayed a wide-spread increase (8-68%) in [(11)C]DASB specific binding outside of the striatum, which was significant in dorsolateral (37%) and prefrontal (68%) cortices. Elevated [(11)C]DASB binding was positively correlated with depressive symptoms but not with disease severity or duration. Compatible with recent PET/[(11)C]DASB findings in major depression, the present preliminary data suggest that increased [(11)C]DASB binding, possibly reflecting greater serotonin transporter density (up-regulation), might be a pathological feature of depression in Parkinson's disease-and possibly a characteristic of depressive illness in general. [ABSTRACT FROM AUTHOR]

BACKGROUND: Since methamphetamine and other amphetamine-type stimulants (meth/amphetamine) can damage dopaminergic neurons, researchers have long speculated that these drugs may predispose users to develop Parkinson's disease (PD), a dopamine deficiency neurological disorder. METHODS: We employed a retrospective population-based cohort study using all linked statewide California inpatient hospital episodes and death records from January 1, 1990 through December 31, 2005. Patients at least 30 years of age were followed for up to 16 years. Competing risks analysis was used to determine whether the meth/amphetamine cohort had elevated risk of developing PD (ICD-9 332.0; ICD-10 G20) in comparison to a matched population-proxy appendicitis group and a matched cocaine drug control group. Individuals admitted to hospital with meth/amphetamine-related conditions (n=40,472; ICD-9 codes 304.4, 305.7, 969.7, E854.2) were matched on age, race, sex, date of index admission, and patterns of hospital admission with patients with appendicitis conditions (n=207,831; ICD-9 codes 540-542) and also individuals with cocaine-use disorders (n=35,335; ICD-9 codes 304.2, 305.6, 968.5). RESULTS: The meth/amphetamine cohort showed increased risk of PD compared to both that of the matched appendicitis group [hazard ratio (HR)=1.76, 95% CI: 1.12-2.75, p=0.017] and the matched cocaine group [HR=2.44, 95% CI: 1.32-4.41, p=0.004]. The cocaine group did not show elevated hazard of PD compared to the matched appendicitis group [HR=1.04, 95% CI: 0.56-1.93, p=0.80]. CONCLUSION: These data provide evidence that meth/amphetamine users have above-normal risk for developing PD. [ABSTRACT FROM AUTHOR]

Phospholipids are essential components of cell membranes which may also function to mediate some of the behavioural effects of dopamine receptor stimulation caused by psychostimulant drugs. Neuroimaging and pharmacological data suggest that abnormal brain metabolism of phospholipids might explain some of the consequences of chronic exposure to drugs of abuse including drug craving. We previously reported decreased activity of calcium-stimulated phospholipase A(2) (Ca-PLA(2)) in autopsied putamen of human cocaine users. To establish the specificity of this change in phospholipid metabolism and whether decreased Ca-PLA(2) might be a general feature of all abused drugs which enhance dopaminergic neurotransmission, we measured activity of 11 major phospholipid metabolic enzymes in dopamine-rich (putamen) and poor brain areas of chronic users of cocaine and of methamphetamine. Enzyme changes were restricted to the putamen which showed decreased (-21%, as compared with the control subjects) Ca-PLA(2) activity in users of methamphetamine and reduced (-31%) activity of phosphocholine cytidylyltransferase (PCCT), the rate-limiting enzyme of phosphatidylcholine synthesis, in the cocaine users. We suggest that chronic exposure to psychostimulant drugs might cause a compensatory downregulation of Ca-PLA(2) in dopamine-rich brain areas due to excessive dopamine-related stimulation of the enzyme. Decreased striatal Ca-PLA(2) and/or PCCT activity in cocaine users might also help to explain why CDP choline, which enhances phospholipid synthesis, reduces craving in some users of the drug cocaine. [ABSTRACT FROM AUTHOR]

Background: After acute COVID-19, five percent of people experience persistent depressive symptoms and reduced cognitive function (COVID-DC). Theoretical models propose that astrogliosis is important in long COVID but measures primarily indicative of astrogliosis have not been studied in the brain of long COVID or COVID-DC. The objective is to measure [ 11 C]SL25.1188 total distribution volume ([ 11 C]SL25.1188 V T ), index of monoamine oxidase B (MAO-B) density and marker of astrogliosis with PET in COVID-DC and compare to healthy controls., Methods: In 21 COVID-DC cases and 21 healthy controls, [ 11 C]SL25.1188 V T was measured in prefrontal cortex, anterior cingulate cortex, hippocampus, dorsal putamen, and ventral striatum. Depressive symptoms were measured with the Beck Depression Inventory-II and cognitive symptoms were measured with neuropsychological tests., Results: [ 11 C]SL25.1188 V T was higher in COVID-DC in prefrontal cortex, anterior cingulate cortex, hippocampus, dorsal putamen, and ventral striatum compared to healthy controls. Depressive symptom severity correlated negatively with [ 11 C]SL25.1188 V T across prioritized brain regions. More recent acute COVID-19 correlated positively with [ 11 C]SL25.1188 V T , reflecting higher values since predominance of the omicron variant. Exploratory analyses found greater [ 11 C]SL25.1188 V T in hippocampus, dorsal putamen, and ventral striatum compared to major depressive episode controls with no history of COVID-19; and no relationship to cognitive testing in prioritized regions., Conclusions: Results strongly support the presence of MAO-B labelled astrogliosis in COVID-DC throughout the regions assessed although the association of greater astrogliosis with less symptoms raises the possibility of a protective role. Magnitude of astrogliosis in COVID-DC is greater since emergence of omicron variant., (Copyright © 2024. Published by Elsevier Inc.)

Background: We previously reported that the 2018 Canadian Cannabis Act, allowing youth to possess up to 5 g dried cannabis or equivalent for personal use/sharing, was associated with short-term (76 days) post-legalization reduction in police-reported cannabis-related crimes among youth. To establish whether the change might be sustained, we now estimate this association during a much longer time period by including an additional three years of post-legalization data., Methods: Using national daily police-reported criminal incident data from January 1, 2015-December 31, 2021 from the Canadian Uniform Crime Reporting Survey (UCR-2), the study employed Seasonal Autoregressive Integrated Moving Average (SARIMA) time series models to assess the associations between legalization and youth (12-17 years) cannabis-related offenses (male, n = 34,508; female, n = 9529)., Results: Legalization was associated with significant reductions in both male and female police-reported cannabis-related offenses: females, 4.04 daily incidents [95% confidence interval (CI), 3.08; 5.01], a 62.1% decrease [standard error (se), 34.3%]; males, 12.42 daily offenses (95% CI, 8.99; 15.86), a reduction of 53.0% (se, 22.7%). There was no evidence of associations between cannabis legalization and patterns of property or violent crimes., Conclusions: Results suggest that the impact of the Cannabis Act on reducing cannabis-related youth crimes is sustained, supporting the Act's objectives to reduce cannabis-related criminalization among youth and associated effects on the Canadian criminal justice system., Competing Interests: Declaration of Competing Interest This research was supported in part by a Canadian Institutes of Health Research (CIHR) Project Grant (PJT 180292) awarded to the first author (RCC). In relation to the manuscript, the authors have no competing interests to declare., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Traumatic brain injury (TBI) is common but little is known why up to a third of patients have persisting symptoms. Astrogliosis, a pathophysiological response to brain injury, may be a potential therapeutic target, but demonstration of astrogliosis in the brain of humans with TBI and persistent symptoms is lacking. Astroglial marker monoamine oxidase B (MAO-B) total distribution volume (11C-SL25.1188 VT), an index of MAO-B density, was measured in 29 TBI and 29 similarly aged healthy control cases with 11C-SL25.1188 PET, prioritizing prefrontal cortex (PFC) and cortex proximal to cortical convexity. Correlations of PFC 11C-SL25.1188 VT with psychomotor and processing speed; and serum blood measures implicated in astrogliosis were determined. 11C-SL25.1188 VT was greater in TBI in PFC (P = 0.00064) and cortex (P = 0.00038). PFC 11C-SL25.1188 VT inversely correlated with Comprehensive Trail Making Test psychomotor and processing speed (r = -0.48, P = 0.01). In participants scanned within 2 years of last TBI, PFC 11C-SL25.1188 VT correlated with serum glial fibrillary acid protein (r = 0.51, P = 0.037) and total tau (r = 0.74, P = 0.001). Elevated 11C-SL25.1188 VT argues strongly for astrogliosis and therapeutics modifying astrogliosis towards curative phenotypes should be tested in TBI with persistent symptoms. Given substantive effect size, astrogliosis PET markers should be applied to stratify cases and/or assess target engagement for putative therapeutics targeting astrogliosis., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background and Aim: A central goal of the Cannabis Act (October 17, 2018) - Canada's national cannabis legalization framework - aimed to reduce cannabis-related criminalization and consequent impact on the Canadian criminal justice system. We assessed whether Canada's cannabis legalization was associated with changes in adult police-reported cannabis-related, property, or violent criminal incidents., Design: Seasonal Autoregressive Integrated Moving Average (SARIMA) time series models evaluated relations between legalization and adult cannabis-related, property, and violent crimes, using criminal incident data from the Canadian Uniform Crime Reporting Survey (UCR-2; January 1, 2015-December 31, 2021)., Primary Sample: National police-reported adult cannabis-related offenses (n = 247,249), property crimes (n = 2,299,777), and violent crimes (n = 1,903,762)., Findings: Implementation of the Cannabis Act was associated with decreases in adult police-reported cannabis-related offenses: females, -13.2 daily incidents (95% CI, -16.4; -10.1; p < 0.001) - a reduction of 73.9% [standard error (se), 30.6%]; males, -69.4 daily offenses (95% CI, -81.5; -57.2; p < 0.001) - a drop of 83.2% (se, 21.2%). Legalization was not associated with significant changes in the adult property-crime or violent-crime series., Conclusions: Our findings suggest that Canada's cannabis legalization was successful in reducing cannabis-related criminalization among adults. There was also a lack of evidence for spillover effects of cannabis legalization on adult property or violent crimes., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Endocannabinoids and related N-acylethanolamines (NAEs) are bioactive lipids with important physiological functions and putative roles in mental health and addictions. Although chronic cannabis use is associated with endocannabinoid system changes, the status of circulating endocannabinoids and related NAEs in people with cannabis use disorder (CUD) is uncertain., Methods: Eleven individuals with CUD and 54 healthy non-cannabis using control participants (HC) provided plasma for measurement by high-performance liquid chromatography-mass spectrometry of endocannabinoids (2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (AEA)) and related NAE fatty acids (N-docosahexaenoylethanolamine (DHEA) and N-oleoylethanolamine (OEA)). Participants were genotyped for the functional gene variant of FAAH (rs324420, C385A) which may affect concentrations of AEA as well as other NAEs (OEA, DHEA)., Results: In overnight abstinent CUD, AEA, OEA and DHEA concentrations were significantly higher (31-40%; p < 0.05) and concentrations of the endocannabinoid 2-AG were marginally elevated (55%, p = 0.13) relative to HC. There were no significant correlations between endocannabinoids/NAE concentrations and cannabis analytes, self-reported cannabis use frequency or withdrawal symptoms. DHEA concentration was inversely related with marijuana craving ( r = -0.86; p = 0.001). Genotype had no significant effect on plasma endocannabinoids/NAE concentrations., Conclusions: Our preliminary findings, requiring replication, might suggest that activity of the endocannabinoid system is elevated in chronic cannabis users. It is unclear whether this elevation is a compensatory response or a predating state. Studies examining endocannabinoids and NAEs during prolonged abstinence as well as the potential role of DHEA in craving are warranted.

Background: Reductions in fatty acid amide hydrolase (FAAH), the catabolic enzyme for the endocannabinoid anandamide, may play a role in drinking behavior and risk for alcohol use disorder. We tested the hypotheses that lower brain FAAH levels in heavy-drinking youth are related to increased alcohol intake, hazardous drinking, and differential response to alcohol., Methods: FAAH levels in the striatum, prefrontal cortex, and whole brain were determined using positron emission tomography imaging of [ 11 C]CURB in heavy-drinking youth (N = 31; 19-25 years of age). C385A FAAH genotype (rs324420) was determined. Behavioral (n = 29) and cardiovascular (n = 22) responses to alcohol were measured during a controlled intravenous alcohol infusion., Results: Lower [ 11 C]CURB binding was not significantly related to frequency of use but was positively associated with hazardous drinking and reduced sensitivity to the negative effects of alcohol. During alcohol infusion, lower [ 11 C]CURB binding related to greater self-reported stimulation and urges and lower sedation (p < .05). Lower heart rate variability was related to both greater alcohol-induced stimulation and lower [ 11 C]CURB binding (p < .05). Family history of alcohol use disorder (n = 14) did not relate to [ 11 C]CURB binding., Conclusions: In line with preclinical studies, lower FAAH in the brain was related to a dampened response to the negative, impairing effects of alcohol, increased drinking urges, and alcohol-induced arousal. Lower FAAH might alter positive or negative effects of alcohol and increase urges to drink, thereby contributing to the addiction process. Determining whether FAAH influences motivation to drink through increased positive/arousing effects of alcohol or greater tolerance should be investigated., (Copyright © 2022 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Importance: Persistent depressive symptoms, often accompanied by cognitive symptoms, commonly occur after COVID-19 illness (hereinafter termed COVID-DC, DC for depressive and/or cognitive symptoms). In patients with COVID-DC, gliosis, an inflammatory change, was suspected, but measurements of gliosis had not been studied in the brain for this condition., Objective: To determine whether translocator protein total distribution volume (TSPO VT), a marker of gliosis that is quantifiable with positron emission tomography (PET), is elevated in the dorsal putamen, ventral striatum, prefrontal cortex, anterior cingulate cortex, and hippocampus of persons with COVID-DC., Design, Setting, and Participants: This case-control study conducted at a tertiary care psychiatric hospital in Canada from April 1, 2021, to June 30, 2022, compared TSPO VT of specific brain regions in 20 participants with COVID-DC with that in 20 healthy controls. The TSPO VT was measured with fluorine F 18-labeled N-(2-(2-fluoroethoxy)benzyl)-N-(4-phenoxypyridin-3-yl)acetamide ([18F]FEPPA) PET., Main Outcomes and Measures: The TSPO VT was measured in the dorsal putamen, ventral striatum, prefrontal cortex, anterior cingulate cortex, and hippocampus. Symptoms were measured with neuropsychological and psychological tests, prioritizing outcomes related to striatal function., Results: The study population included 40 participants (mean [SD] age, 32.9 [12.3] years). The TSPO VT across the regions of interest was greater in persons with COVID-DC (mean [SD] age, 32.7 [11.4] years; 12 [60%] women) compared with healthy control participants (mean [SD] age, 33.3 [13.9] years; 11 [55%] women): mean (SD) difference, 1.51 (4.47); 95% CI, 0.04-2.98; 1.51 divided by 9.20 (17%). The difference was most prominent in the ventral striatum (mean [SD] difference, 1.97 [4.88]; 95% CI, 0.36-3.58; 1.97 divided by 8.87 [22%]) and dorsal putamen (mean difference, 1.70 [4.25]; 95% CI, 0.34-3.06; 1.70 divided by 8.37 [20%]). Motor speed on the finger-tapping test negatively correlated with dorsal putamen TSPO VT (r, -0.53; 95% CI, -0.79 to -0.09), and the 10 persons with the slowest speed among those with COVID-DC had higher dorsal putamen TSPO VT than healthy persons by 2.3 (2.30 divided by 8.37 [27%]; SD, 2.46; 95% CI, 0.92-3.68)., Conclusions and Relevance: In this case-control study, TSPO VT was higher in patients with COVID-DC. Greater TSPO VT is evidence for an inflammatory change of elevated gliosis in the brain of an individual with COVID-DC. Gliosis may be consequent to inflammation, injury, or both, particularly in the ventral striatum and dorsal putamen, which may explain some persistent depressive and cognitive symptoms, including slowed motor speed, low motivation or energy, and anhedonia, after initially mild to moderate COVID-19 illness.

Introduction: Although there is momentum towards legalising adult recreational cannabis use worldwide, the extent of youth cannabis-related harm associated with legalisation is still uncertain. The current study aimed to assess whether the initial implementation of Canada's cannabis legalisation (via the Cannabis Act) on 17 October 2018 might be associated with youth harm, as assessed by emergency department visits for cannabis-related disorders/poisoning., Methods: We used Ontario and Alberta, Canada emergency department data from 1 April 2015 to 31 December 2019. We identified all cannabis-related disorders/poisoning (ICD-10 CA: F12.X, T40.7) emergency department visits of youth (n = 13,615), defined as patients younger than the minimum legal cannabis sales age (18 years, Alberta; 19 years, Ontario). Seasonal Autoregressive Integrated Moving Average (SARIMA) models were employed to assess the impact of legalisation on weekly counts of cannabis-related harms., Results: The final SARIMA intervention (step) parameter indicated a post-legalisation increase of 14.7 (95% confidence interval [CI] 5.0; 24.3, p < 0.01) weekly youth cannabis-related disorder/poisoning presentations to Ontario/Alberta emergency department settings, equivalent to an increase of 20.0% (95% CI 6.2%; 33.9%). There was no evidence of associations between cannabis legalisation and comparison series of youth alcohol, opioid or appendicitis emergency department episodes., Discussion/conclusion: Our findings require replication and extension but are consistent with the possibility that the implementation of the Cannabis Act was associated with an increase in youth cannabis-related presentations to Ontario/Alberta emergency departments., (© 2023 Australasian Professional Society on Alcohol and other Drugs.)

Introduction: Oxidative stress has been implicated in psychiatric disorders, including posttraumatic stress disorder (PTSD). Currently, the status of glutathione (GSH), the brain's most abundant antioxidant, in PTSD remains uncertain. Therefore, the current study investigated brain concentrations of GSH and peripheral concentrations of blood markers in individuals with PTSD vs. Healthy Controls (HC)., Methods: GSH spectra was acquired in the anterior cingulate cortex (ACC) and dorsolateral prefrontal cortex (DLPFC) using MEGA-PRESS, a J-difference-editing acquisition method. Peripheral blood samples were analyzed for concentrations of metalloproteinase (MMP)-9, tissue inhibitors of MMP (TIMP)-1,2, and myeloperoxidase (MPO)., Results: There was no difference in GSH between PTSD and HC in the ACC ( n = 30 PTSD, n = 20 HC) or DLPFC ( n = 14 PTSD, n = 18 HC). There were no group differences between peripheral blood markers ( P > 0.3) except for (non-significantly) lower TIMP-2 in PTSD. Additionally, TIMP-2 and GSH in the ACC were positively related in those with PTSD. Finally, MPO and MMP-9 were negatively associated with duration of PTSD., Conclusions: We do not report altered GSH concentrations in the ACC or DLPFC in PTSD, however, systemic MMPs and MPO might be implicated in central processes and progression of PTSD. Future research should investigate these relationships in larger sample sizes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Watling, Rhind, Warsh, Green, McCluskey, Tong, Truong, Chavez, Richardson, Kish and Boileau.)

Microglia are immune brain cells implicated in stress-related mental illnesses including posttraumatic stress disorder (PTSD). Their role in the pathophysiology of PTSD, and on neurobiological systems that regulate stress, is not completely understood. We tested the hypothesis that microglia activation, in fronto-limbic brain regions involved in PTSD, would be elevated in participants with occupation-related PTSD. We also explored the relationship between cortisol and microglia activation. Twenty participants with PTSD and 23 healthy controls (HC) completed positron emission tomography (PET) scanning of the 18-kDa translocator protein (TSPO), a putative biomarker of microglia activation using the probe [ 18 F]FEPPA, and blood samples for measurement of cortisol. [ 18 F]FEPPA V T was non-significantly elevated (6.5-30%) in fronto-limbic regions in PTSD participants. [ 18 F]FEPPA V T was significantly higher in PTSD participants reporting frequent cannabis use compared to PTSD non-users (44%, p = 0.047). Male participants with PTSD (21%, p = 0.094) and a history of early childhood trauma (33%, p = 0.116) had non-significantly higher [ 18 F]FEPPA V T . Average fronto-limbic [ 18 F]FEPPA V T was positively related to cortisol (r = 0.530, p = 0.028) in the PTSD group only. Although we did not find a significant abnormality in TSPO binding in PTSD, findings suggest microglial activation might have occurred in a subgroup who reported frequent cannabis use. The relationship between cortisol and TSPO binding suggests a potential link between hypothalamic-pituitary-adrenal-axis dysregulation and central immune response to trauma which warrants further study., (© 2023. The Author(s).)

Introduction: Preclinical data suggest methamphetamine (MA), a widely used stimulant drug, can harm the brain by causing oxidative stress and inflammation, but only limited information is available in humans. We tested the hypothesis that levels of glutathione (GSH), a major antioxidant, would be lower in the brains of chronic human MA preferring polysubstance users. We also explored if concentrations of peripheral immunoinflammatory blood biomarkers were related with brain GSH concentrations., Methods: 20 healthy controls (HC) (33 years; 11 M) and 14 MA users (40 years; 9 M) completed a magnetic resonance spectroscopy (MRS) scan, with GSH spectra obtained by the interleaved J-difference editing MEGA-PRESS method in anterior cingulate cortex (ACC) and left dorsolateral prefrontal cortex (DLPFC). Peripheral blood samples were drawn for measurements of immunoinflammatory biomarkers. Independent samples t -tests evaluated MA vs. HC differences in GSH., Results: GSH levels did not differ between HC and MA users (ACC p = 0.30; DLPFC p = 0.85). A total of 17 of 25 immunoinflammatory biomarkers were significantly elevated in MA users and matrix metalloproteinase (MMP)-2 ( r = 0.577, p = 0.039), myeloperoxidase (MPO) ( r = -0.556, p = 0.049), and MMP-9 ( r = 0.660, p = 0.038) were correlated with brain levels of GSH., Conclusion: Normal brain GSH in living brain of chronic MA users is consistent with our previous postmortem brain finding and suggests that any oxidative stress caused by MA, at the doses used by our participants, might not be sufficient to cause either a compensatory increase in, or substantial overutilization of, this antioxidant. Additionally, more research is required to understand how oxidative stress and inflammatory processes are related and potentially dysregulated in MA use., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Watling, Jagasar, McCluskey, Warsh, Rhind, Truong, Chavez, Houle, Tong, Kish and Boileau.)

Objective: Cannabis legalization in many jurisdictions worldwide has raised concerns that such legislation might increase the burden of transient and persistent psychotic illnesses in society. Our study aimed to address this issue., Methods: Drawing upon emergency department (ED) presentations aggregated across Alberta and Ontario, Canada records (April 1, 2015-December 31, 2019), we employed Seasonal Autoregressive Integrated Moving Average (SARIMA) models to assess associations between Canada's cannabis legalization (via the Cannabis Act implemented on October 17, 2018) and weekly ED presentation counts of the following ICD-10-CA-defined target series of cannabis-induced psychosis (F12.5; n  = 5832) and schizophrenia and related conditions ("schizophrenia"; F20-F29; n  = 211,661), as well as two comparison series of amphetamine-induced psychosis (F15.5; n  = 10,829) and alcohol-induced psychosis (F10.5; n  = 1,884)., Results: ED presentations for cannabis-induced psychosis doubled between April 2015 and December 2019. However, across all four SARIMA models, there was no evidence of significant step-function effects associated with cannabis legalization on post-legalization weekly ED counts of: (1) cannabis-induced psychosis [0.34 (95% CI -4.1; 4.8; P  = 0.88)]; (2) schizophrenia [24.34 (95% CI -18.3; 67.0; P  = 0.26)]; (3) alcohol-induced psychosis [0.61 (95% CI -0.6; 1.8; P  = 0.31); or (4) amphetamine-induced psychosis [1.93 (95% CI -2.8; 6.7; P  = 0.43)]., Conclusion: Implementation of Canada's cannabis legalization framework was not associated with evidence of significant changes in cannabis-induced psychosis or schizophrenia ED presentations. Given the potentially idiosyncratic rollout of Canada's cannabis legalization, further research will be required to establish whether study results generalize to other settings.

Background: Preclinical evidence suggests that increasing levels of the major endocannabinoid anandamide decreases anxiety and fear responses potentially through its effects in the amygdala. Here we used neuroimaging to test the hypothesis that lower fatty acid amide hydrolase (FAAH), the main catabolic enzyme for anandamide, is associated with a blunted amygdala response to threat., Methods: Twenty-eight healthy participants completed a positron emission tomography (PET) scan with the radiotracer for FAAH, [ 11 C]CURB, as well as a block-design functional magnetic resonance imaging session during which angry and fearful faces meant to activate the amygdala were presented., Results: [ 11 C]CURB binding in the amygdala as well as in the medial prefrontal cortex, cingulate and hippocampus correlated positively with blood-oxygen-level-dependent (BOLD) signal during processing of angry and fearful faces (p FWE < 0.05)., Conclusion: Our finding that lower levels of FAAH in amygdala, medial prefrontal cortex, cingulate and hippocampus was associated with a dampened amygdala response to a threatening social cue aligns with preclinical and neuroimaging studies in humans and suggests the involvement of FAAH in modulating stress and anxiety in humans. The current neuroimaging study also lends support for the potential use of FAAH inhibitors to control amygdala hyperactivity, which is known to be involved in the pathophysiology of anxiety and trauma-related disorders., (© 2022 The Authors.)

Posttraumatic stress disorder (PTSD) is a debilitating mental health condition that results from exposure to traumatic event(s). Decreased astrocyte-related proteins (e.g., glial fibrillary acidic protein, GFAP) and atrophic astrocytes in corticolimbic brain areas implicated in PTSD have been reported in experimental models suggesting that astrocyte pathology may be a feature of this disorder. We used positron emission tomography (PET) of the monoamine oxidase (MAO)-B probe [ 11 C]SL25.1188 to test the hypothesis that levels of MAO-B, an index of astrocyte levels is decreased in PTSD. MAO-B availability ([ 11 C]SL25.1188 distribution volume) was measured in 13 participants with PTSD (∼39 years, 6F) and 17 healthy controls (HC) (∼31 years, 9F). A magnetic resonance image was acquired to delineate 6 cortiolimbic brain regions. PTSD was associated with a trending reduction in [ 11 C]SL25.1188 availability across regions (8-17%; p = 0.067) implicating the ventral striatum (p uncorrected = 0.015) and medial prefrontal cortex (p uncorrected = 0.060). [ 11 C]SL25.1188 availability was ∼30% lower in corticolimbic regions in PTSD with co-morbid major depressive disorder (MDD) (n = 4) vs HC (p = 0.001) and vs PTSD without MDD (p = 0.005). Our preliminary results do not suggest astrogliosis (inferred from elevated availability) in PTSD, but rather point to a loss of astrocytes or an independent downregulation of MAO-B in PTSD with more severe negative affect. These exploratory findings, which are partly in line with preclinical literature and recent PET observations of decreased microglia marker, Translocator Protein, in PTSD, warrant replication in a larger PTSD cohort., Competing Interests: Declaration of Competing Interest All authors declare no conflict of interest., (Copyright © 2021. Published by Elsevier B.V.)

Aims: Canada's 2018 Cannabis Act allows youth (age 12-17 years) to possess up to 5 g of dried cannabis (or equivalent) for personal consumption/sharing. This study assessed whether the Cannabis Act was associated with changes in police-reported cannabis offences among youth in Canada., Design: Time series model using national daily criminal incident data from January 1, 2015-December 31, 2018 from the Canadian Uniform Crime Reporting Survey (UCR-2). Seasonal autoregressive integrated moving average time series models, stratified by sex, assessed the relations between legalization and youth cannabis-related offences., Setting: Canada, 2015-2018., Cases: Police-reported cannabis-related offenses among youth age 12-17 years (male, n = 32 178; female, n = 9001)., Measurements: Outcomes: police-reported cannabis-related crimes, property crimes, and violent crimes. Covariate: calendar-month., Findings: For females, legalization was associated with a step-effect decrease of 4.56 (95% confidence interval [CI] = 3.32, 5.81; P < 0.001) police-reported cannabis-related criminal offences per day, an effect equivalent to a 64.6% (standard error [SE] = 33.5%) reduction. For males, legalization was associated with a drop of 12.73 (95% CI = 8.82, 16.64; P < 0.001) cannabis-related offences per day, equaling a decrease of 57.7% (SE = 22.6%). Results were inconclusive as to whether there were associations between cannabis legalization and patterns of property crimes or violent crimes., Conclusions: Implementation of the Cannabis Act in Canada in 2018 appears to have been associated with decreases of 55%-65% in cannabis-related crimes among male and female youth., (© 2021 Society for the Study of Addiction.)

Background: Worldwide momentum toward legalization of recreational cannabis use has raised a common concern that such policies might increase cannabis-impaired driving and consequent traffic-related harms, especially among youth. The current study evaluated this issue in Canada., Methods: Utilizing provincial emergency department (ED) records (April 1, 2015-December 31, 2019) from Alberta and Ontario, Canada, we employed Seasonal Autoregressive Integrated Moving Average (SARIMA) models to assess associations between Canada's cannabis legalization (via the Cannabis Act implemented on October 17, 2018) and weekly provincial counts of ICD-10-CA-defined traffic-injury ED presentations. For each province (Alberta/Ontario), SARIMA models were developed on two driver groups: all drivers, and youth drivers (aged 14-17 years in Alberta; 16-18 years, Ontario)., Results: There was no evidence of significant changes associated with cannabis legalization on post-legalization weekly counts of drivers' traffic-injury ED visits in: (1) Alberta, all drivers (n = 52,752 traffic-injury presentations), an increase of 9.17 visits (95 % CI -18.85; 37.20; p = 0.52); (2) Alberta, youth drivers (n = 3265 presentations), a decrease of 0.66 visits (95 % CI -2.26; 0.94; p = 0.42); (3) Ontario, all drivers (n = 186,921 presentations), an increase of 28.93 visits (95 % CI -26.32; 84.19; p = 0.30); and (4) Ontario, youth drivers (n = 4565), an increase of 0.09 visits (95 % CI -6.25; 6.42; p = 0.98)., Conclusions: Implementation of the Cannabis Act was not associated with evidence of significant post-legalization changes in traffic-injury ED visits in Ontario or Alberta among all drivers or youth drivers, in particular., (Copyright © 2021. Published by Elsevier B.V.)

Objective: To establish in an exploratory neuroimaging study whether γ-hydroxybutyrate (sodium oxybate [SO]), a sedative, anti-narcoleptic drug with abuse potential, transiently inhibits striatal dopamine release in the human., Methods: Ten healthy participants (30 years; 6M, 4F) and one participant with narcolepsy received a baseline positron emission tomography scan of [C-11]raclopride, a D2/3 dopamine receptor radioligand sensitive to dopamine occupancy, followed approximately one week later by an oral sedative 3g dose of SO and two [C-11]raclopride scans (1 h, 7 h post SO). Plasma SO levels and drowsiness duration were assessed., Results: No significant changes were detected in [C-11]raclopride binding in striatum overall 1 or 7 h after SO, but a small non-significant increase in [C-11]raclopride binding, implying decreased dopamine occupancy, was noted in limbic striatal subdivision at one hour (+6.5%; p uncorrected = 0.045; +13.2%, narcolepsy participant), returning to baseline at 7 h. A positive correlation was observed between drowsiness duration and percent change in [C-11]raclopride binding in limbic striatum (r = 0.73; p = 0.017)., Conclusions: We did not find evidence in this sample of human subjects of a robust striatal dopamine change, as was reported in non-human primates. Our preliminary data, requiring extension, suggest that a 3g sedative SO dose might cause slight transient inhibition of dopamine release in limbic striatum., (© 2021 John Wiley & Sons Ltd.)

Gliosis is implicated in the pathophysiology of many neuropsychiatric diseases, including treatment-resistant major depressive disorder (TRD). Translocator protein total distribution volume (TSPO V T ), a brain marker mainly reflective of gliosis in disease, can be measured using positron emission tomography (PET). Minocycline reduces gliosis and translocator protein binding in rodents, but this is not established in humans. Here, the ability of oral minocycline to reduce TSPO V T was assessed in TRD. To determine whether oral minocycline, as compared to placebo, can reduce prefrontal cortex (PFC), anterior cingulate cortex (ACC), and insula TSPO V T in TRD, twenty-one TRD participants underwent two [ 18 F]FEPPA PET scans to measure TSPO V T . These were completed before and after either oral minocycline 100 mg bid or placebo which was administered in a randomized double-blinded fashion for 8 weeks. There was no significant difference between the minocycline and placebo groups on change in TSPO V T within the PFC, ACC, and insula (repeated measures ANOVA, effect of group interaction, PFC: F 1,19  = 0.28, P = 0.60; ACC: F 1,19  = 0.54, P = 0.47; insula F 1,19  = 1.6, P = 0.22). Oral minocycline had no significant effect on TSPO V T which suggests that this dosage is insufficient to reduce gliosis in TRD. To target gliosis in TRD either alternative therapeutics or intravenous formulations of minocycline should be investigated. These results also suggest that across neuropsychiatric diseases in humans, it should be assumed that oral minocycline will not reduce TSPO V T or gliosis unless empirically demonstrated.

Background: Upregulation of the endocannabinoid enzyme fatty acid amide hydrolase (FAAH) has been linked to abnormal activity in frontoamygdalar circuits, a hallmark of posttraumatic stress disorder. We tested the hypothesis that FAAH levels in the amygdala were negatively correlated with functional connectivity between the amygdala and prefrontal cortex, subserving stress and affect control., Methods: Thirty-one healthy participants completed positron emission tomography (PET) imaging with the FAAH probe [C-11]CURB, and resting-state functional MRI scans. Participants were genotyped for the FAAH polymorphism rs324420, and trait neuroticism was assessed. We calculated amygdala functional connectivity using predetermined regions of interest (including the subgenual ventromedial prefrontal cortex [sgvmPFC] and the dorsal anterior cingulate cortex [dACC]) and a seed-to-voxel approach. We conducted correlation analyses on functional connectivity, with amygdala [C-11]CURB binding as a variable of interest., Results: The strength of amygdala functional connectivity with the sgvmPFC and dACC was negatively correlated with [C-11]CURB binding in the amygdala (sgvmPFC: r = -0.38, q = 0.04; dACC: r = -0.44; q = 0.03). Findings were partly replicated using the seed-to-voxel approach, which showed a cluster in the ventromedial prefrontal cortex, including voxels in the dACC but not the sgvmPFC (cluster-level, family-wise error rate corrected p < 0.05)., Limitations: We did not replicate earlier findings of a relationship between an FAAH polymorphism (rs324420) and amygdala functional connectivity., Conclusion: Our data provide preliminary evidence that lower levels of FAAH in the amygdala relate to increased frontoamygdalar functional coupling. Our findings were consistent with the role of FAAH in regulating brain circuits that underlie fear and emotion processing in humans., Competing Interests: M. Hill has served on scientific advisory boards for Lundbeck and Sophren Therapeutics. R. Tyndale has consulted for Quinn Emanuel and Ethismos on unrelated topics. No other competing interests declared., (© 2021 Joule Inc. or its licensors.)

Background: Reduced function of fatty acid amide hydrolase, the catabolic enzyme for the endocannabinoid anandamide, can be inherited through a functional genetic polymorphism (FAAH rs324420, C385A, P129T). The minor (A) allele has been associated with reduced FAAH enzyme activity and increased risk for substance use disorders in adults. Whether this inherited difference in endocannabinoid metabolism relates to alcohol use disorder etiology and patterns of alcohol use in youth is unknown., Methods: To examine this question, heavy-drinking youth (n = 302; mean age = 19.74 ± 1.18) were genotyped for FAAH C385A. All subjects completed a comprehensive interview assessing alcohol use patterns including the Timeline Follow-back Method, Alcohol Use Disorders Identification Test (AUDIT), and Drinking Motives Questionnaire. Analyses of Covariance (ANCOVAs) were conducted to assess differences in drinking patterns and drinking motives between genotype groups, and mediation analyses investigated whether drinking motives accounted for indirect associations of genotype with alcohol use severity., Results: Youth with the FAAH minor allele (AC or AA genotype) reported significantly more drinking days (p = 0.045), significantly more frequent heavy episodic drinking (p = 0.003), and significantly higher alcohol-related problems and consumption patterns (AUDIT score p = 0.045, AUDIT-C score p = 0.02). Mediation analyses showed that the association of FAAH C385A with drinking outcomes was mediated by coping motives., Conclusions: These findings extend previous studies by suggesting that reduced endocannabinoid metabolism may be related to heavier use of alcohol in youth, prior to the onset of chronic drinking problems. Furthermore, differences in negative reinforcement-related drinking could account in part for this association., (© 2021 by the Research Society on Alcoholism.)

Activation of brain microglial cells, microgliosis, has been linked to methamphetamine (MA)-seeking behavior, suggesting that microglia could be a new therapeutic target for MA use disorder. Animal data show marked brain microglial activation following acute high-dose MA, but microglial status in human MA users is uncertain, with one positron emission tomography (PET) investigation reporting massively and globally increased translocator protein 18 kDa (TSPO; [C-11](R)-PK11195) binding, a biomarker for microgliosis, in MA users. Our aim was to measure binding of a second-generation TSPO radioligand, [F-18]FEPPA, in brain of human chronic MA users. Regional total volume of distribution (V T ) of [F-18]FEPPA was estimated with a two-tissue compartment model with arterial plasma input function for 10 regions of interest in 11 actively using MA users and 26 controls. A RM-ANOVA corrected for TSPO rs6971 polymorphism was employed to test significance. There was no main effect of group on [F-18]FEPPA V T (P = .81). No significant correlations between [F-18]FEPPA V T and MA use duration, weekly dosage, blood MA concentrations, regional brain volumes, and self-reported craving were observed. Our preliminary findings, consistent with our earlier postmortem data, do not suggest substantial brain microgliosis in MA use disorder but do not rule out microglia as a therapeutic target in MA addiction. Absence of increased [F-18]FEPPA TSPO binding might be related to insufficient MA dose or blunting of microglial response following repeated MA exposure, as suggested by some animal data., (© 2020 Society for the Study of Addiction.)

Background: In almost all of the literature examining the relation between cannabis use and cannabis-related harms, researchers have neglected to include quantity measures of cannabis use. The study aims to assess whether cannabis: (1) quantity predicts harms; and (2) quantity might interact with other key variables (age, gender, and frequency of use) vis-à-vis the outcomes., Method: Using the 2012-2013 National Epidemiologic Survey on Alcohol and Related Conditions-III (NESARC-III), the current study (n = 36,309; n = 3,339 past-year cannabis users) employed a logistic-regression approach to assess the cross-sectional relations between the continuous variables of cannabis-use quantity and frequency and two Alcohol Use Disorder and Associated Disabilities Interview Schedule-5 (AUDADIS-5) DSM-5-based outcomes: past-year cannabis-use disorder (CUD) and past-year cannabis-related problems (CRP)., Results: In the CUD model, the key variables log quantity [OR = 1.98 (95 % CI, 1.64;2.39), p < 0.001], log frequency [OR = 1.78 (95 % CI, 1.62;1.96), p < 0.001] and the log-quantity-by-log-frequency interaction [OR = 0.83 (95 % CI, 0.75;0.93), p = 0.002] were statistically significant. The final CRP model included the following main predictors: log quantity [OR = 2.13 (95 % CI, 1.70;2.66), p = <0.001], log frequency [OR = 1.50 (95 % CI, 1.36;1.65), p = <0.001], and a log-quantity-by-log-frequency interaction [OR = 0.82 (95 % CI, 0.73;0.93), p = 0.002]., Conclusions: The quantity-by-frequency interactions in both models showed that the relative effect of quantity on cannabis-use disorders and cannabis-related problems decreased as frequency increased, and vice versa., (Copyright © 2020. Published by Elsevier B.V.)

Background: Gliosis is common among neuropsychiatric diseases, but the relationship between gliosis and response to therapeutics targeting effects of gliosis is largely unknown. Translocator protein total distribution volume (TSPO V T ), measured with positron emission tomography, mainly reflects gliosis in neuropsychiatric disease. Here, the primary objective was to determine whether TSPO V T in the prefrontal cortex (PFC) and anterior cingulate cortex (ACC) predicts reduction of depressive symptoms following open-label celecoxib administration in treatment-resistant major depressive disorder., Methods: A total of 41 subjects with treatment-resistant major depressive disorder underwent one [ 18 F]FEPPA positron emission tomography scan to measure PFC and ACC TSPO V T . Open-label oral celecoxib (200 mg, twice daily) was administered for 8 weeks. Change in symptoms was measured with the 17-item Hamilton Depression Rating Scale (HDRS)., Results: Cumulative mean change in HDRS scores between 0 and 8 weeks of treatment was plotted against PFC and ACC TSPO V T , showing a significant nonlinear relationship. At low TSPO V T values, there was no reduction in HDRS scores, but as TSPO V T values increased, there was a reduction in HDRS scores that then plateaued. This was modeled with a 4-parameter sigmoidal model in which PFC and ACC TSPO V T accounted for 84% and 92% of the variance, respectively., Conclusions: Celecoxib administration in the presence of gliosis labeled by TSPO V T is associated with greater reduction of symptoms. Given the predictiveness of TSPO V T on symptom reduction, this personalized medicine approach of matching a marker of gliosis to medication targeting effects of gliosis should be applied in early development of novel therapeutics, in particular for treatment-resistant major depressive disorder., (Copyright © 2020 Society of Biological Psychiatry. All rights reserved.)

Rationale: The long-held speculation that the brain serotonin system mediates some behavioral effects of the psychostimulant cocaine is supported in part by the high affinity of cocaine for the serotonin transporter (SERT) and by reports that the serotonin transporter (SERT), estimated by SERT binding, is increased in brain of human chronic cocaine users. Excessive SERT activity and consequent synaptic serotonin deficiency might cause a behavioral (e.g., mood) abnormality in chronic users of the drug., Objective and Methods: Previous studies focused on changes in SERT binding, which might not necessarily reflect changes in SERT protein. Therefore, we compared levels of SERT protein, using a quantitative Western blot procedure, in autopsied brain (striatum, cerebral cortices) of chronic human cocaine users (n = 9), who all tested positive for the drug/metabolite in brain, to those in control subjects (n = 15) and, as a separate drug of abuse group, in chronic heroin users (n = 11)., Results: We found no significant difference in protein levels of SERT or the serotonin synthesizing enzyme tryptophan hydroxylase-2 among the control and drug abuse groups. In the cocaine users, no significant correlations were observed between SERT and brain levels of cocaine plus metabolites, or with levels of serotonin or its metabolite 5-hydroxyindoleacetic acid., Conclusion: Our postmortem data suggest that a robust increase in striatal/cerebral cortical SERT protein is not a common characteristic of chronic, human cocaine users.

The endocannabinoid enzyme, fatty acid amide hydrolase (FAAH), has been proposed as a therapeutic target for alcohol use disorder (AUD) and co-morbid psychiatric illnesses. Investigating this target in the living human brain and its relationship to clinical outcome is a critical step of informed drug development. Our objective was to establish whether brain FAAH levels are low in individuals with AUD and related to drinking behavior. In this pilot study, treatment-seeking patients with AUD completed two PET scans with the FAAH radiotracer [C-11]CURB after 3-7 days (n = 14) and 2-4 weeks (n = 9) of monitored abstinence. Healthy controls (n = 25) completed one scan. FAAH genetic polymorphism (rs324420) and blood concentrations of anandamide and other N-acylethanolamines metabolized by FAAH were determined and AUD symptoms assessed. In AUD, brain FAAH levels were globally lower than controls during early abstinence (F(1,36) = 5.447; p = 0.025)) and FAAH substrates (anandamide, oleoylethanolamide, and N-docosahexaenoylethanolamide) were significantly elevated (30-67%). No significant differences in FAAH or FAAH substrates were noted after 2-4 weeks abstinence. FAAH levels negatively correlated with drinks per week (r = -0.57, p = 0.032) and plasma concentrations of the three FAAH substrates (r > 0.57; p < 0.04)). Our findings suggest that early abstinence from alcohol in AUD is associated with transiently low brain FAAH levels, which are inversely related to heavier alcohol use and elevated plasma levels of FAAH substrates. Whether low FAAH is an adaptive beneficial response to chronic alcohol is unknown. Therapeutic strategies focusing on FAAH inhibition should consider the possibility that low FAAH during early abstinence may be related to drinking.

Positron emission tomography (PET) imaging of the translocator protein (TSPO) is widely used as a biomarker of microglial activation. However, TSPO protein concentration in human brain has not been optimally quantified nor has its regional distribution been compared to TSPO binding. We determined TSPO protein concentration, change with age, and regional distribution by quantitative immunoblotting in autopsied human brain. Brain TSPO protein concentration (>0.1 ng/µg protein) was higher than those reported by in vitro binding assays by at least 2 to 70 fold. TSPO protein distributed widely in both gray and white matter regions, with distribution in major gray matter areas ranked generally similar to that of PET binding in second-generation radiotracer studies. TSPO protein concentration in frontal cortex was high at birth, declined precipitously during the first three months, and increased modestly during adulthood/senescence (10%/decade; vs. 30% for comparison astrocytic marker GFAP). As expected, TSPO protein levels were significantly increased (+114%) in degenerating putamen in multiple system atrophy, providing further circumstantial support for TSPO as a gliosis marker. Overall, findings show some similarities between TSPO protein and PET binding characteristics in the human brain but also suggest that part of the TSPO protein pool might be less available for radioligand binding.

The endocannabinoid and dopaminergic systems have independently been implicated in substance use disorder and obesity. We investigated a potential interaction between genetically inherited variation in fatty acid amide hydrolase (FAAH, C385A), which metabolizes the cannabis-like endocannabinoid anandamide, and dopaminergic system, measured by dopamine receptor levels and mRNA. Binding of the dopamine D3 preferring probe [C-11]-(+)-PHNO was measured with positron emission tomography (PET) in 79 human subjects genotyped for the FAAH C385A polymorphism (36/79 AC + AA). Autoradiography with [H-3]-(+)-PHNO and in situ hybridization with a D3-specific S-35 riboprobe were carried out in 30 knock-in mice with the FAAH C385A polymorphism (20/30 AC + AA). We found that the FAAH genetic variant C385A was associated with significantly higher (+)-PHNO binding in both humans and in knock-in mice, and this effect was restricted to D3 selective brain regions (limbic striatum, globus pallidus, and ventral pallidum (9-14%; p < 0.04) in humans and Islands of Calleja (28%; p = 0.036) in mice). In situ hybridization with a D3-specific S-35 riboprobe in FAAH knock-in C385A mice confirmed significantly increased D3 receptor mRNA across examined regions (7-44%; p < 0.02). The association of reduced FAAH function with higher dopamine D3 receptors in human and mouse brain provide a mechanistic link between two brain systems that have been implicated in addiction-risk. This may explain the greater vulnerability for addiction and obesity in individuals with C385A genetic variant and by extension, suggest that a D3 antagonism strategy in substance use disorders should consider FAAH C385A polymorphism.

Aim: To establish whether the population-level pattern of cannabis use by quantity is similar to the distributions previously reported for alcohol, in which a small subset of drinkers accounts for a majority of total population alcohol consumption., Method: The current study pooled Waves 1-3 of the 2018 National Cannabis Survey (n = 18,900; 2584 past-three-month cannabis users), a set of stratified, population-based surveys designed to assess cannabis consumption and related behaviors in Canada. Each survey systematically measured self-reported cannabis consumption by quantity across seven of the major cannabis-product types. In order to enable the conversion of self-reported consumption of non-flower cannabis products into a standard joint equivalent (SJE: equal to 0.5 g of dried cannabis), we created conversion metrics for physical production equivalencies across cannabis products., Results: Similar to the findings in the alcohol literature, study results show that cannabis consumption is highly concentrated in a small subset of users: the upper 10% of cannabis users accounted for approximately two-thirds of all cannabis consumed in the country. Males reported consuming more cannabis by volume than females (approximately 60% versus 40%), with young males (15-34 years old) being disproportionately represented in the heaviest-using subgroups., Conclusions: Most of the cannabis used in Canada is consumed by a relatively small population of very heavy cannabis users. Future research should attempt to identify the characteristics of the heaviest-using groups, as well as how population-level cannabis consumption patterns relate to the calculus of cannabis-related harms in society., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Importance: Monoamine oxidase B (MAO-B) is an important, high-density enzyme in the brain that generates oxidative stress by hydrogen peroxide production, alters mitochondrial function, and metabolizes nonserotonergic monoamines. Recent advances in positron emission tomography radioligand development for MAO-B in humans enable highly quantitative measurement of MAO-B distribution volume (MAO-B VT), an index of MAO-B density. To date, this is the first investigation of MAO-B in the brain of major depressive disorder that evaluates regions beyond the raphe and amygdala., Objective: To investigate whether MAO-B VT is elevated in the prefrontal cortex in major depressive episodes (MDEs) of major depressive disorder., Design, Setting, and Participants: This case-control study was performed at a tertiary care psychiatric hospital from April 1, 2014, to August 30, 2018. Twenty patients with MDEs without current psychiatric comorbidities and 20 age-matched controls underwent carbon 11-labeled [11C]SL25.1188 positron emission tomography scanning to measure MAO-B VT. All participants were drug and medication free, nonsmoking, and otherwise healthy., Main Outcomes and Measures: The MAO-B VT in the prefrontal cortex (PFC). The second main outcome was to evaluate the association between MAO-B VT in the PFC and duration of major depressive disorder illness., Results: Twenty patients with MDEs (mean [SD] age, 34.2 [13.2] years; 11 women) and 20 healthy controls (mean [SD] age, 33.7 [13.1] years; 10 women) were recruited. Patients with MDEs had significantly greater MAO-B VT in the PFC (mean, 26%; analysis of variance, F1,38 = 19.6, P < .001). In individuals with MDEs, duration of illness covaried positively with MAO-B VT in the PFC (analysis of covariance, F1,18 = 15.2, P = .001), as well as most other cortex regions and the thalamus., Conclusions and Relevance: Fifty percent (10 of 20) of patients with MDEs had MAO-B VT values in the PFC exceeding those of healthy controls. Greater MAO-B VT is an index of MAO-B overexpression, which may contribute to pathologies of mitochondrial dysfunction, elevated synthesis of neurotoxic products, and increased metabolism of nonserotonergic monoamines. Hence, this study identifies a common pathological marker associated with downstream consequences poorly targeted by the common selective serotonin reuptake inhibitor treatments. It is also recommended that the highly selective MAO-B inhibitor medications that are compatible for use with other antidepressants and have low risk for hypertensive crisis should be developed or repurposed as adjunctive treatment for MDEs.

Background: Animal studies suggest that exposure to either of the two widely used drugs of abuse, heroin or cocaine, causes depletion of the antioxidant, reduced glutathione, a hallmark of oxidative stress, in the brain. However, the relevance of the animal findings to the human is uncertain and clinical trials with the antioxidant GSH precursor n-acetylcysteine have produced mixed results in cocaine dependence., Methods: Our major objective was to compare glutathione levels, determined by an HPLC-coulometric procedure, in autopsied brain of chronic heroin (n = 11) and cocaine users (n = 9), who were positive for the drugs in the brain, to those of matched controls (n = 16). Six brain regions were examined, including caudate, hippocampus, thalamus and frontal, temporal and insular cortices., Results: In contrast to experimental animal findings, we found no statistically significant difference between mean levels of reduced or oxidized glutathione in the drug user vs. control groups. Moreover, no correlation was found between levels of drugs in the brain and those of glutathione., Conclusions: Acknowledging the many generic limitations of an autopsied human brain study and the preliminary nature of the findings, our data nevertheless suggest that any oxidative stress caused by heroin or cocaine in chronic users of the drugs might not be sufficient to cause substantial loss of stores of glutathione in the human brain, at least during early withdrawal. These findings, requiring replication, might also have some relevance to future clinical trials employing glutathione supplement therapy as an anti-oxidative strategy in chronic users of the two abused drugs., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: It is assumed that recreational use of methamphetamine can trigger acute myocardial infarction (AMI) events, but estimates of longitudinal hazards of AMI among methamphetamine users are lacking., Methods: Retrospective cohort study: Competing-risks analysis was used to estimate time-to-AMI patterns in methamphetamine versus matched appendicitis (population-proxy) and matched cocaine (drug-control) groups. Cohorts were propensity-score-matched using demographic and clinical variables., Setting: California, 1990-2005., Participants: Cohorts of individuals with no prior or concurrent history of AMI hospitalized with methamphetamine- (n = 73,056), cocaine- (n = 47,726), or appendicitis-related conditions (n = 330,109)., Measurements: ICD-9/ICD-10 indications of AMI (ICD-9 410.X; ICD-10 I21.X) in death records or inpatient hospital data., Results: Patients in methamphetamine cohort were more likely to develop subsequent AMI in comparison to those in matched appendicitis cohort [Hazard ratio (HR): 1.41; 95% CI, 1.23-1.62, p < 0.0001], with increased risk most marked in young methamphetamine users (age 15-34 years; HR: 2.04; 95% CI, 1.63-2.57, p = 0. 0001). Risk was slightly increased vs. that in matched cocaine group (HR: 1.19; 95% CI, 1.02-1.39, p = 0. 029). Individuals in cocaine cohort were also more likely to experience AMI outcome vs. appendicitis cohort (HR: 1.25; 95% CI, 1.08-1.45, p = 0. 0023)., Conclusion: Our longitudinal data support results of earlier epidemiological studies suggesting that persons with methamphetamine- (or cocaine-) use disorders might have increased AMI risk. However, because of potential study limitations and the unexpectedly modest magnitude of the observed increased AMI hazard, these findings must be considered preliminary and require replication., (Copyright © 2018. Published by Elsevier B.V.)

Background: A key component of alcohol dependence (AD), a severe form of alcohol use disorder, is the negative emotional state during withdrawal. Monoamine oxidase A (MAO-A) is an important enzyme that metabolizes monoamines and creates oxidative stress. Elevations in MAO-A level, especially in the prefrontal and anterior cingulate cortex (PFC and ACC), are associated with low mood states, including the dysphoria of early alcohol withdrawal in humans. The aim of the present study was to determine whether chronic alcohol vapor exposure causes an upregulation of MAO-A activity or level in the PFC and ACC of rodents during acute withdrawal., Methods: Sprague-Dawley rats were exposed to ethanol vapor or control condition for 17 h per day for 8 weeks. MAO-A activity and protein levels were measured immediately after exposure, acute withdrawal (24 h), protracted withdrawal (4 day), and protracted abstinence (3 weeks) (n = 16/group; 8 alcohol exposed, 8 control)., Results: Chronic ethanol vapor exposure significantly elevated MAO-A activity and protein levels in the PFC and ACC at 24-h withdrawal (multivariate analysis of variance (MANOVA), activity: F 2,13  = 3.82, p = .05, protein: F 2,13  = 5.13, p = .02). There were no significant changes in MAO-A level or activity at other timepoints., Conclusions: The results of this study suggest a causal relationship between acute alcohol withdrawal and elevated MAO-A levels and activity, clarifying the observation of greater MAO-A binding in human alcohol withdrawal. This has important implications for developing methods of targeting MAO-A and/or sequelae of its dysregulation in alcohol dependence., (Copyright © 2018 Elsevier B.V. All rights reserved.)

In a recent clinical trial, the drug BIA 10-2474, a putative fatty acid amide hydrolase(FAAH) inhibitor, was responsible for severe adverse events (SAEs), including one death. To date, there has been little reliable information divulged about the potency of BIA 10-2474 at FAAH in the central nervous system. We synthesised BIA 10-2474 and determined its ability to inhibit FAAH ex vivo in rat brain using a FAAH selective radiotracer. BIA 10-2474 proved to be a potent FAAH inhibitor with IC 50 s of 50-70 µg/kg (i.p.) in various brain regions. This information may be useful for determining the cause of the SAEs.