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There is emerging evidence that the endocannabinoid system (ECS) plays a significant role in the pathophysiology of many psychiatric disorders, including attention deficit hyperactivity disorder (ADHD). Increasing evidence suggests that a number of neurobiological correlates between endogenous cannabinoid function and cognitive dysfunction are seen in ADHD, making the ECS a possible target for therapeutic interventions. Cannabis use and cannabis use disorder are more prevalent in individuals with ADHD, compared to the general population, and there is growing popular perception that cannabis is therapeutic for ADHD. However, the relationship between cannabis use and ADHD symptomology is poorly understood. Further understanding of the role of the ECS in ADHD pathophysiology and the molecular alterations that may be a target for treatment is needed. To further the science on this emerging area of research, this scoping review describes the preclinical and clinical evidence seeking to understand the relationship between the ECS and ADHD., (© 2024 The Author(s). Developmental Psychobiology published by Wiley Periodicals LLC.)

Alcohol and cannabis use disorder (AUD/CUD) are two of the most common addictive disorders. While studies are beginning to understand the neural changes related to acute and chronic use, few studies have examined the independent effects of AUD and CUD on neural oscillatory activity. We examined 45 adults who reported current use of both cannabis and alcohol. Participants underwent the SCID-V to determine whether they met criteria for AUD and/or CUD. Participants also completed a visual-spatial processing task while undergoing magnetoencephalography (MEG). ANCOVA with a 2 × 2 design was then used to identify the main effects of AUD and CUD on source-level oscillatory activity. Of the 45 adults, 17 met criteria for AUD, and 26 met criteria for CUD. All participants, including comparison groups, reported use of both cannabis and alcohol. Statistical analyses showed a main effect of AUD, such that participants with AUD displayed a blunted occipital alpha (8-16 Hz) response. Post-hoc testing showed this decreased alpha response was related to increased AUD symptoms, above and beyond amount of use. No effects of AUD or CUD were identified in visual theta or gamma activity. In conclusion, AUD was associated with reduced alpha responses and scaled with increasing severity, independent of CUD. These findings indicate that alpha oscillatory activity may play an integral part in networks affected by alcohol addiction., (© 2021. The Author(s).)

Cannabis use during pregnancy has continued to rise, particularly in developed countries, as a result of the trend towards legalization and lack of consistent, evidence-based knowledge on the matter. While there is conflicting data regarding whether cannabis use during pregnancy leads to adverse outcomes such as stillbirth, preterm birth, low birthweight, or increased admission to neonatal intensive care units, investigations into long-term effects on the offspring's health are limited. Historically, studies have focused on the neurobehavioral effects of prenatal cannabis exposure on the offspring. The effects of cannabis on other physiological aspects of the developing fetus have received less attention. Importantly, our knowledge about cannabinoid signaling in the placenta is also limited. The endocannabinoid system (ECS) is present at early stages of development and represents a potential target for exogenous cannabinoids in utero. The ECS is expressed in a broad range of tissues and influences a spectrum of cellular functions. The aim of this review is to explore the current evidence surrounding the effects of prenatal exposure to cannabinoids and the role of the ECS in the placenta and the developing fetus.

The brain's endocannabinoid system plays a crucial role in reward processes by mediating appetitive learning and encoding the reinforcing properties of substances. Evidence also suggests that endocannabinoids are an important constituent of neuronal substrates involved in emotional responses to stress. Thus, it is critical to understand how the endocannabinoid system and stress may affect reward processes given their importance in substance use disorders. We examined the relationship between factors that regulate endocannabinoid system signaling (i.e., cannabinoid receptor genes and prolonged cannabis exposure) and stress on fMRI BOLD response to reward cues using multivariate statistical analysis. We found that proxies for endocannabinoid system signaling (i.e., endocannabinoid genes and chronic exposure to cannabis) and stress have differential effects on neural response to cannabis cues. Specifically, a single nucleotide polymorphism (SNP) variant in the cannabinoid receptor 1 (CNR1) gene, early life stress, and current perceived stress modulated reward responsivity in long-term, heavy cannabis users, while a variant in the fatty acid amide hydrolase (FAAH) gene and current perceived stress modulated cue-elicited response in non-using controls. These associations were related to distinct neural responses to cannabis-related cues compared to natural reward cues. Understanding the contributions of endocannabinoid system factors and stress that lead to downstream effects on neural mechanisms underlying sensitivity to rewards, such as cannabis, will contribute towards a better understanding of endocannabinoid-targeted therapies as well as individual risks for cannabis use disorder., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Cannabis is one of the most widely used substances across the globe and its use has a substantial heritable component. However, the heritability of cannabis use varies according to substance use phenotype, suggesting that a unique profile of gene variants may contribute to the different stages of use, such as age of use onset, lifetime use, cannabis use disorder, and withdrawal and craving during abstinence. Herein, we review a subset of genes identified by candidate gene, family-based linkage, and genome-wide association studies related to these cannabis use phenotypes. We also describe their relationships with other substances, and their functions at the neurobiological, cognitive, and behavioral levels to hypothesize the role of these genes in cannabis use risk. Delineating genetic risk factors in the various stages of cannabis use will provide insight into the biological mechanisms related to cannabis use and highlight points of intervention prior to and following the development of dependence, as well as identify targets to aid drug development for treating problematic cannabis use., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Impulse control deficits are often found to co-occur with substance use disorders (SUDs). On the one hand, it is well known that chronic intake of drugs of abuse remodels the brain with significant consequences for a range of cognitive behaviors. On the other hand, individual variation in impulse control may contribute to differences in susceptibility to SUDs. Both of these relationships have been described, thus leading to a "chicken or the egg" debate which remains to be fully resolved. Does impulsivity precede drug use or does it manifest as a function of problematic drug usage? The link between impulsivity and SUDs has been most strongly established for cocaine and alcohol use disorders using both preclinical models and clinical data. Much less is known about the potential link between impulsivity and cannabis use disorder (CUD) or the directionality of this relationship. The initiation of cannabis use occurs most often during adolescence prior to the brain's maturation, which is recognized as a critical period of development. The long-term effects of chronic cannabis use on the brain and behavior have started to be explored. In this review we will summarize these observations, especially as they pertain to the relationship between impulsivity and CUD, from both a psychological and biological perspective. We will discuss impulsivity as a multi-dimensional construct and attempt to reconcile the results obtained across modalities. Finally, we will discuss possible avenues for future research with emerging longitudinal data., (Copyright © 2020 Elsevier Inc. All rights reserved.)

For thousands of years, Cannabis sativa has been utilized as a medicine and for recreational and spiritual purposes. Phytocannabinoids are a family of compounds that are found in the cannabis plant, which is known for its psychotogenic and euphoric effects; the main psychotropic constituent of cannabis is Δ9-tetrahydrocannabinol (Δ9-THC). The pharmacological effects of cannabinoids are a result of interactions between those compounds and cannabinoid receptors, CB1 and CB2, located in many parts of the human body. Cannabis is used as a therapeutic agent for treating pain and emesis. Some cannabinoids are clinically applied for treating chronic pain, particularly cancer and multiple sclerosis-associated pain, for appetite stimulation and anti-emesis in HIV/AIDS and cancer patients, and for spasticity treatment in multiple sclerosis and epilepsy patients. Medical cannabis varies from recreational cannabis in the chemical content of THC and cannabidiol (CBD), modes of administration, and safety. Despite the therapeutic effects of cannabis, exposure to high concentrations of THC, the main compound that is responsible for most of the intoxicating effects experienced by users, could lead to psychological events and adverse effects that affect almost all body systems, such as neurological (dizziness, drowsiness, seizures, coma, and others), ophthalmological (mydriasis and conjunctival hyperemia), cardiovascular (tachycardia and arterial hypertension), and gastrointestinal (nausea, vomiting, and thirst), mainly associated with recreational use. Cannabis toxicity in children is more concerning and can cause serious adverse effects such as acute neurological symptoms (stupor), lethargy, seizures, and even coma. More countries are legalizing the commercial production and sale of cannabis for medicinal use, and some for recreational use as well. Liberalization of cannabis laws has led to increased incidence of toxicity, hyperemesis syndrome, lung disease cardiovascular disease, reduced fertility, tolerance, and dependence with chronic prolonged use. This review focuses on the potential therapeutic effects of cannabis and cannabinoids, as well as the acute and chronic toxic effects of cannabis use on various body systems.

Cannabis sativa, like all known drugs of abuse, leads to increased dopamine activation within the mesolimbic pathway. Consequent dopamine release within terminal regions of the striatum is a powerful mediator of reward and reinforcement and patterned dopamine release is critical for associative learning processes that are fundamentally involved in addiction. The endocannabinoid system modulates dopamine release at multiple sites, and the receptors, endogenous ligands, and synthetic and metabolic enzymes of the endocannabinoid system may provide key targets for pharmacotherapies to treat disorders of motivation including addiction. Disrupting endocannabinoid signaling decreases drug-induced increases in dopamine release as well those dopamine events evoked by conditioned stimuli during reward seeking. Advances in recording techniques for dopamine are allowing unprecedented examinations of these two interacting systems and elucidating the mechanisms of endocannabinoid modulation of dopamine release in reward and addiction., (Copyright © 2021 Cold Spring Harbor Laboratory Press; all rights reserved.)

Background: The effect of concomitant cocaine and cannabis use on monocyte activation and inflammation in patients with alcohol use disorder (AUD) is unknown., Methods: To analyze the impact of cocaine and cannabis use on levels of markers of monocyte activation (sCD163 and sCD14) and systemic inflammation (interleukin-6 [IL-6]) in AUD patients admitted for hospital treatment between 2013 and 2018. Clinical and laboratory parameters were obtained upon admission. IL-6, sCD163, and sCD14 were measured in frozen plasma samples. We performed logistic regression to detect associations between cocaine and cannabis use and markers of monocyte activation and inflammation in the highest quartile., Results: A total of 289 patients (77.5 % male) were included (median age = 50 years). The median alcohol intake upon admission was 142 g/day. The median duration of AUD was 20 years. Of the 289 patients with AUD, 76 % were active smokers, 23.1 % and 22.1 % concomitantly used cocaine and cannabis, respectively The median levels of IL-6, sCD163, and sCD14 were 4.37 pg/mL, 759 ng/mL, and 1.68 × 10 6 pg/mL, respectively. We did not detect associations between cocaine use and inflammation or monocyte activation. Cannabis use was associated with a higher odds of having sCD163 levels in the highest quartile (adjusted odds ratio = 2.34, 95 % confidence interval = 1.07-5.15, p = 0.03). Cannabis use was not associated with inflammation., Conclusion: In this series of AUD patients the concomitant use of cannabis use was associated with sCD163 levels that were in the highest quartile, consistent with monocyte activation., (Copyright © 2020 Elsevier B.V. All rights reserved.)

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., (© 2019 Society for the Study of Addiction.)

Stress and cannabis use are risk factors for the development of psychosis. We have previously shown that subjects at clinical high risk for psychosis (CHR) exhibit a higher striatal dopamine response to stress compared with healthy volunteers (HV), with chronic cannabis use blunting this response. However, it is unknown if this abnormal dopamine response extends to the prefrontal cortex (PFC). Here, we investigated dorsolateral PFC (dlPFC) and medial PFC (mPFC) dopamine release using [ 11 C]FLB457 positron emission tomography (PET) and a validated stress task. Thirty-three participants completed two PET scans (14 CHR without cannabis use, eight CHR regular cannabis users [CHR-CUs] and 11 HV) while performing a Sensory Motor Control Task (control scan) and the Montreal Imaging Stress Task (stress scan). Stress-induced dopamine release (ΔBP ND ) was defined as percent change in D 2/3 receptor binding potential between both scans using a novel correction for injected mass of [ 11 C]FLB457. ΔBP ND was significantly different between groups in mPFC (F(2,30) = 5.40, .010), with CHR-CUs exhibiting lower ΔBP ND compared with CHR (.008). Similarly, salivary cortisol response (ΔAUC I ) was significantly lower in CHR-CU compared with CHR (F(2,29) = 5.08, .013; post hoc .018) and positively associated with ΔBP ND . Furthermore, CHR-CUs had higher attenuated psychotic symptoms than CHR following the stress task, which were negatively associated with ΔBP ND . Length of cannabis use was negatively associated with ΔBP ND in mPFC when controlling for current cannabis use. Given the global trend to legalize cannabis, this study is important as it highlights the effects of regular cannabis use on cortical dopamine function in high-risk youth., (© 2019 Society for the Study of Addiction.)

Purpose: Drug use during pregnancy is a critical global challenge, capable of severe impacts on neonatal development. However, the consumption of cannabis and synthetic cannabinoids is on the rise in pregnant women. Obstetric complications with increased risks of miscarriage, fetal growth restriction, and brain development impairment have been associated with perinatal cannabis exposure, but data on synthetic cannabinoid use during pregnancy are limited., Methods: We reviewed studies that investigated the risks associated with cannabis and synthetic cannabinoid use and those that reported the concentrations of cannabinoids and synthetic cannabinoids in maternal (breast milk) and neonatal (placenta, umbilical cord, meconium, and hair) matrices during human pregnancy. A MEDLINE and EMBASE literature search to identify all relevant articles published in English from January 1998 to April 2019 was performed., Results: Cannabis use during pregnancy is associated with increased risks of adverse obstetrical outcomes, although neurobehavioral effects are still unclear. Analyses of cannabinoids in meconium are well documented, but further research on other unconventional matrices is needed. Adverse effects due to perinatal synthetic cannabinoid exposure are still unknown, and analytical data are scarce., Conclusions: Awareness of the hazards of drug use during pregnancy should be improved to encourage health care providers to urge pregnant women to abstain from cannabis and, if cannabis-dependent, seek treatment. Moreover, substances used throughout pregnancy should be monitored as a deterrent to cannabis use, and potential cannabis-dependent women should be identified, so as to limit cannabis-fetal exposure during gestation, and provided appropriate treatment.

Importance: Cannabis is the most commonly used illicit drug in the world. Cannabinoids have been shown to modulate immune responses; however, the association of cannabis with neuroimmune function has never been investigated in vivo in the human brain., Objective: To investigate neuroimmune activation or 18-kDa translocator protein (TSPO) levels in long-term cannabis users, and to evaluate the association of brain TSPO levels with behavioral measures and inflammatory blood biomarkers., Design, Setting, and Participants: This cross-sectional study based in Toronto, Ontario, recruited individuals from January 1, 2015, to October 30, 2018. Participants included long-term cannabis users (n = 24) and non-cannabis-using controls (n = 27). Cannabis users were included if they had a positive urine drug screen for only cannabis and if they used cannabis at least 4 times per week for the past 12 months and/or met the criteria for cannabis use disorder. All participants underwent a positron emission tomography scan with [18F]FEPPA, or fluorine F 18-labeled N-(2-(2-fluoroethoxy)benzyl)-N-(4-phenoxypyridin-3-yl)acetamide., Main Outcomes and Measures: Total distribution volume was quantified across regions of interest. Stress and anxiety as well as peripheral measures of inflammatory cytokines and C-reactive protein levels were also measured., Results: In total, 24 long-term cannabis users (mean [SD] age, 23.1 [3.8] years; 15 men [63%]) and 27 non-cannabis-using controls (mean [SD] age, 23.6 [4.2] years; 18 women [67%]) were included and completed all study procedures. Compared with the controls, cannabis users had higher [18F]FEPPA total distribution volume (main group effect: F1,48 = 6.5 [P = .01]; ROI effect: F1,200 = 28.4 [P < .001]; Cohen d = 0.6; 23.3% higher), with a more prominent implication for the cannabis use disorder subgroup (n = 15; main group effect: F1,39 = 8.5 [P = .006]; ROI effect: F1,164 = 19.3 [P < .001]; Cohen d = 0.8; 31.5% higher). Greater TSPO levels in the brain were associated with stress and anxiety and with higher circulating C-reactive protein levels in cannabis users., Conclusions and Relevance: The results of this study suggest that TSPO levels in cannabis users, particularly in those with cannabis use disorder, are higher than those in non-cannabis-using controls. The findings emphasize the need for more complementary preclinical systems for a better understanding of the role of cannabinoids and TSPO in neuroimmune signaling.

Marijuana is listed as a Schedule I substance under the American Controlled Substances Act of 1970. As more U.S. states and countries beyond the U.S. seek legalization, demands grow for identifying individuals driving under the influence (DUI) of marijuana. Currently no roadside DUI test exists for determining marijuana impairment, thus the merit lies in detecting the primary and the most sought psychoactive compound tetrahydrocannabinol (THC) in marijuana. Salivary THC levels are correlated to blood THC levels making it a non-invasive medium for rapid THC testing. Affinity biosensing is leveraged for THC biomarker detection through the chemical reaction between target THC and THC specific antibody to a measure signal output related to the concentration of the targeted biomarker. Here, we propose a novel, rapid, electrochemical biosensor for the detection of THC in saliva as a marijuana roadside DUI test with a lower detection limit of 100 pg/ml and a dynamic range of 100 pg/ml - 100 ng/ml in human saliva. The developed biosensor is the first of its kind to utilize affinity-based detection through impedimetric measurements with a rapid detection time of less than a minute. Fourier transform infrared spectroscopy analysis confirmed the successful immobilization of the THC immobilization assay on the biosensing platform. Zeta potential studies provided information regarding the stability and the electrochemical behavior of THC immunoassay in varying salivary pH buffers. We have demonstrated stable, dose dependent biosensing in varying salivary pH's. A binary classification system demonstrating a high general performance (AUC = 0.95) was employed to predict the presence of THC in human saliva. The biosensor on integration with low-power electronics and a portable saliva swab serves as a roadside DUI hand-held platform for rapid identification of THC in saliva samples obtained from human subjects.

Recreational and chronic cannabis use has been associated with a range of acute and chronic effects including; anti-nociceptive actions, anxiety, depression, psychotic symptoms and neurocognitive impairments. The mechanisms underlying cannabinoid-based drugs effects are not fully known but given the neuro-modulatory functions of the endocannabinoid system, it seems likely that agonistic activity at the cannabinoid type-1 receptors (CB 1 ) might modulate the functions of other neurotransmitter systems. The present review has summarized the currently available pre-clinical and clinical data on the interactions of CB 1 and cannabinoid type-2 receptors (CB 2 ) with the central neurotransmitters; dopamine, serotonin, noradrenaline, GABA, glutamate and opioids. Acute and chronic exposures to cannabinoids exert pharmacological alterations in the mammalian brain that have profound implications for our understanding of the neuropharmacology of cannabinoid-based drugs and their effects on mental health and the brain. A recent emergence uses of cannabis for medical purpose together with legalization and decriminalization of cannabis and increasing use of highly potent synthetic cannabinoids raise a growing concern over the effects of cannabinoids and their interaction with other neurotransmitters on physical and mental health., (© 2019 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Background: Changes in cannabis regulation globally make it increasingly important to determine what predicts an individual's risk of experiencing adverse drug effects. Relevant studies have used diverse self-report measures of cannabis use, and few include multiple biological measures. Here we aimed to determine which biological and self-report measures of cannabis use predict cannabis dependency and acute psychotic-like symptoms., Method: In a naturalistic study, 410 young cannabis users were assessed once when intoxicated with their own cannabis and once when drug-free in counterbalanced order. Biological measures of cannabinoids [(Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), cannabinol (CBN) and their metabolites)] were derived from three samples: each participant's own cannabis (THC, CBD), a sample of their hair (THC, THC-OH, THC-COOH, CBN, CBD) and their urine (THC-COOH/creatinine). Comprehensive self-report measures were also obtained. Self-reported and clinician-rated assessments were taken for cannabis dependency [Severity of Dependence Scale (SDS), DSM-IV-TR] and acute psychotic-like symptoms [Psychotomimetic State Inventory (PSI) and Brief Psychiatric Rating Scale (BPRS)]., Results: Cannabis dependency was positively associated with days per month of cannabis use on both measures, and with urinary THC-COOH/creatinine for the SDS. Acute psychotic-like symptoms were positively associated with age of first cannabis use and negatively with urinary THC-COOH/creatinine; no predictors emerged for BPRS., Conclusions: Levels of THC exposure are positively associated with both cannabis dependency and tolerance to the acute psychotic-like effects of cannabis. Combining urinary and self-report assessments (use frequency; age first used) enhances the measurement of cannabis use and its association with adverse outcomes.

Use of alcohol, cannabis and opioids is highly prevalent and is associated with global disease burden and high economic costs. The exact pathophysiology of abuse or addiction associated with these sedative substances is not completely understood, but previous research implicates the important role of the striatal dopamine system in the addiction process. Multiple studies investigated changes in the striatal dopamine systems of users of sedative substances, but currently these results are very heterogeneous. Therefore, we conducted a meta-analysis of in vivo neuroimaging studies investigating dopaminergic alterations in the striatum of users of alcohol, opioids or cannabis. Analyses for each substance were conducted separately for the availability of D2/D3 dopamine receptors, dopamine transporters and dopamine synthesis capacity. In total, 723 substance users and 752 healthy controls were included. The results indicated a significant lower striatal D2/D3 receptor availability in alcohol users compared to controls (g = 0.46) but no difference in dopamine transporter availability or dopamine synthesis capacity. Our analysis indicated that changes of dopamine receptors and transporters are moderated by the duration of abstinence. Comparing opioid users with controls revealed a significant lower D2/D3 receptor availability (g = 1.17) and a significantly lower transporter availability (g = 1.55) in opioid users. For cannabis users, there was no significant difference in receptor availability compared to controls and too few studies provided information on dopamine transporter availability or synthesis capacity. Our analysis provides strong evidence for a central role of the striatal dopamine system in use of alcohol or opioids. Further studies are needed to clarify the impact of the dopamine system in cannabis users.

Cannabis, the most widely used illicit drug worldwide, produces psychoactive effects through its component cannabinoids, which act on the endocannabinoid system. Research on how cannabinoid exposure affects the endocannabinoid system is limited. Substantial evidence indicates cannabis use as a risk factor for psychosis, and the mechanism(s) by which this is occurring is/are currently unknown. Here, we conduct the first review of the effects of exogenous cannabinoids on the endocannabinoid system in humans with and without psychotic disorders. The most well established finding is the down-regulation of cannabinoid CB1 receptors (CB1R) after chronic and recent cannabis exposure, but it remains uncertain whether this effect is present in cannabis users with schizophrenia. We highlight where cannabis exposure affects the endocannabinoid system in a pattern that may mirror what is seen in psychosis, and how further research can push this field forward. In these times of changing cannabis legislation, research highlighting the biological effects of cannabinoids is greatly needed., (Copyright © 2018. Published by Elsevier B.V.)

Although epidemiological data suggest that repeated use of cannabis during adolescence may increase the risk for psychosis, its precise molecular mechanisms remain undetermined. In this study, we examined whether brain-derived neurotrophic factor (BDNF) and its receptor TrkB signaling plays a role in the risk for psychosis after exposure of cannabinoid (CB) receptor agonist during adolescence. Repeated administration of the CB receptor agonist WIN55,212-2 (2 mg/kg/day) during adolescence (P35 - P45) significantly increased methamphetamine (METH: 1 mg/kg)-induced hyperlocomotion in adulthood (P70 - P74) compared with vehicle-treated mice. Western blot analysis showed that BDNF-TrkB signaling in the nucleus accumbens (NAc) of WIN55,212-2-treated mice were significantly higher than that of vehicle-treated mice. Interestingly, an increase in the METH-induced locomotion in WIN55,212-2-treated mice was significantly attenuated by subsequent repeated administration of the TrkB antagonist ANA-12 (0.5 mg/kg/day from P70 to P83). Furthermore, increased BDNF-TrkB signaling in the NAc from WIN55,212-2-treated mice was also significantly attenuated after subsequent repeated administration of ANA-12. These findings suggest that increased BDNF-TrkB signaling in the NAc plays an important role in the increase in METH-induced locomotion in adulthood after repeated WIN55,212-2 administration during adolescence. Therefore, TrkB antagonists would be potential prophylactic and therapeutic drugs for psychosis in adult with cannabis use during adolescence., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: In rodent models, chronic exposure to cannabis' psychoactive ingredient, Δ9-tetrahydrocannabinol, during adolescence leads to abnormal behavior in adulthood. In female rats, this maladaptive behavior is characterized by endophenotypes for depressive-like and psychotic-like disorders as well as cognitive deficits. We recently reported that most depressive-like behaviors triggered by adolescent Δ9-tetrahydrocannabinol exposure can be rescued by manipulating endocannabinoid signaling in adulthood with the anandamide-inactivating enzyme FAAH inhibitor, URB597. However, the molecular mechanisms underlying URB597's antidepressant-like properties remain to be established., Methods: Here we examined the impact of adult URB597 treatment on the cellular and functional neuroadaptations that occurred in the prefrontal cortex and dentate gyrus of the hippocampus upon Δ9-tetrahydrocannabinol during adolescence through biochemical, morphofunctional, and electrophysiological studies., Results: We found that the positive action of URB597 is associated with the rescue of Δ9-tetrahydrocannabinol-induced deficits in endocannabinoid-mediated signaling and synaptic plasticity in the prefrontal cortex and the recovery of functional neurogenesis in the dentate gyrus of the hippocampus. Moreover, the rescue property of URB597 on depressive-like behavior requires the activity of the CB1 cannabinoid receptor., Conclusions: By providing novel insights into the cellular and molecular mechanisms of URB597 at defined cortical and hippocampal circuits, our results highlight that positive modulation of endocannabinoid-signaling could be a strategy for treating mood alterations secondary to adolescent cannabis use.

The recent legalization of recreational marijuana use in some parts of the world, the discovery of new indications for the clinical application of cannabis, and the acceptance of the use of cannabis in practice has been paralleled by extensive research on the active components of cannabis and the endocannabinoid system within the human body. In this review, we evaluate the available evidence on cannabis and its constituents and the application of this evidence in clinical practice, focusing particularly on the liver and liver diseases. Constituents of cannabis, such as cannabidiol and Δ-tetrahydrocannabinol, have shown anti-inflammatory, antioxidant, and hepatoprotective effects both in in vitro and clinical studies, and appear to have potential in the symptom management and treatment of various liver diseases that were previously considered difficult to manage conservatively. In addition, the manipulation of the inherent endocannabinoid response system has found favor in many clinical fields and has generated considerable research and clinical interest. Moreover, evidence with regard to the adverse effects of marijuana use in liver diseases is weak, which has led to raise a question on the prior rules, with regard to a denial of liver transplantation to marijuana users. All in all, the recent trends in research, clinical experiences, as well as the legislature, has opened up new avenues towards the widespread clinical application of cannabis and its derivatives as well as modifiers of the components of the endocannabinoid system. More research is required to fully exploit these new evidences.

Dysregulation of the endogenous lipid mediators endocannabinoids and their G-protein-coupled cannabinoid receptors 1 and 2 (CB 1 R and CB 2 R) has been implicated in a variety of cardiovascular pathologies. Activation of CB 1 R facilitates the development of cardiometabolic disease, whereas activation of CB 2 R (expressed primarily in immune cells) exerts anti-inflammatory effects. The psychoactive constituent of marijuana, Δ 9 -tetrahydrocannabinol (THC), is an agonist of both CB 1 R and CB 2 R, and exerts its psychoactive and adverse cardiovascular effects through the activation of CB 1 R in the central nervous and cardiovascular systems. The past decade has seen a nearly tenfold increase in the THC content of marijuana as well as the increased availability of highly potent synthetic cannabinoids for recreational use. These changes have been accompanied by the emergence of serious adverse cardiovascular events, including myocardial infarction, cardiomyopathy, arrhythmias, stroke, and cardiac arrest. In this Review, we summarize the role of the endocannabinoid system in cardiovascular disease, and critically discuss the cardiovascular consequences of marijuana and synthetic cannabinoid use. With the legalization of marijuana for medicinal purposes and/or recreational use in many countries, physicians should be alert to the possibility that the use of marijuana or its potent synthetic analogues might be the underlying cause of severe cardiovascular events and pathologies.

Given the known vascular effects of cannabis, this study examined the neurophysiological factors that may affect studies of brain activity in cannabis users. We conducted a systematic evaluation in 72 h abstinent, chronic cannabis users (N=74) and nonusing controls (N=101) to determine the association between prolonged cannabis use and the following neurophysiological indicators: (1) global and regional resting cerebral blood flow (CBF), (2) oxygen extraction fraction (OEF), and (3) cerebral metabolic rate of oxygen (CMRO 2 ). We found that cannabis users had greater global OEF and CMRO 2 compared with nonusers. Regionally, we found higher CBF in the right pallidum/putamen of the cannabis users compared with nonusers. Global resting CBF and regional CBF of right superior frontal cortex correlated positively with creatinine-normalized Δ9-tetrahydrocannabinol (THC) levels. These findings demonstrate residual effects of cannabis use whereby global and regional brain metabolism are altered in those with prolonged cannabis exposure. These neurophysiological alterations should be considered in both research and clinical applications.

Cannabis misuse during pregnancy is associated with severe impacts on the mother and baby health, such as newborn low birth weight, growth restriction, pre-term birth, neurobehavioral and developmental deficits. In most of the cases, drug abuse is omitted or denied by the mothers. Thus, toxicological analyzes using maternal-fetal matrices takes place as a suitable tool to assess drug use. Herein, meconium was the chosen matrix to evaluate cannabis exposure through identification and quantification of 11-nor-Δ9-tetrahydrocannabinol-9-carboxylic (THCCOOH). Accelerated solvent extraction (ASE) was applied for sample preparation technique to simultaneously extract and hydrolyze conjugated THCCOOH from meconium, followed by a solid-phase extraction (SPE) procedure. The method was developed and validated for gas chromatography-mass spectrometry (GC-MS), reaching hydrolysis efficiency of 98%. Limits of detection (LOD) and quantification (LOQ) were, respectively, 5 and 10 ng/g. The range of linearity was LOQ to 500 ng/g. Inter and intra-batch coefficients of variation were <8.4% for all concentration levels. Accuracy was in 101.7-108.9% range. Recovery was on average 60.3%. Carryover effect was not observed. The procedure was applied in six meconium samples from babies whose mothers were drug users and showed satisfactory performance to confirm fetal cannabis exposure., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Understanding cannabis and synthetic cannabinoid intake history is vital for treating drug dependence, investigating cannabinoid effects, and providing information to healthcare personnel, medical examiners, and public health officials; this is particularly relevant today with cannabis medicalization and legalization. Required information includes identifying exposure, time of use, frequency of use, relapse, withdrawal, and predicting cannabinoid effects. Recent controlled cannabinoid administration studies enable the development of models and markers to better identify patterns of intake and exposure. Future challenges include developing behavioral markers of cannabis impairment, bringing to market breathalyzers for cannabinoid detection, and identifying markers of recent cannabis intake in diverse biological matrices. We posit that biological monitoring of cannabinoids and metabolites will improve the characterization of cannabis and synthetic cannabinoid intake history., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

An association between marijuana use and schizophrenia has been noted for decades, and the recent emergence of high-efficacy synthetic cannabinoids (SCBs) as drugs of abuse has lead to a growing number of clinical reports of persistent psychotic effects in users of these substances. The mechanisms underlying SCB-elicited pro-psychotic effects is unknown, but given the ubiquitous neuromodulatory functions of the endocannabinoid system, it seems likely that agonist actions at cannabinoid type-1 receptors (CB1Rs) might modulate the functions of other neurotransmitter systems known to be involved in schizophrenia. The present review surveys what is currently known about the interactions of CB1Rs with dopamine, serotonin, and glutamate systems, because all three of those neurotransmitters are well-established in the pathophysiology of schizophrenia and psychosis. Identification of molecular mechanisms underlying the pro-psychotic effects of SCB drugs of abuse may establish certain classes of these substances as particularly dangerous, guiding regulations to control availability of these drugs. Likewise, an understanding of the pharmacological interactions which lead to schizophrenia and psychosis subsequent to SCB exposure might guide the development of novel therapies to treat afflicted users.

In utero exposure to marijuana may cause various short- and long-term health problems, such as stillbirth, low birth weight and decreased cognitive function. Detection of in utero marijuana exposure with a relatively new specimen type, umbilical cord tissue, can be used to plan treatment and guide social management. In this study, a liquid chromatography-tandem mass spectrometry (LC-MS-MS) assay was developed for the simultaneous identification of four cannabinoids in umbilical cord tissue, including ∆9-tetrahydrocannabinol (THC), 11-nor-9-carboxy-∆9--THC (THC-COOH), 11-hydroxy-∆9-THC (11-OH-THC) and cannabinol (CBN). Within- and between-run imprecision, accuracy, linearity, sensitivity, carryover, recovery, matrix effects and specificity were evaluated using drug-free umbilical cord tissue spiked with non-deuterated and deuterated standards. Calibration curves were reproducible and linear (r > 0.995) for all four analytes in the range of 0.2 ng/g lower limit of quantitation (LLOQ) and 30 ng/g upper limit of quantitation (ULOQ). Total imprecisions (% coefficient of variation) were 7.8% (THC), 13.3% (THC-COOH), 11.8% (11-OH-THC) and 10.6% (CBN) at low QC (n = 15, 0.25 ng/g), and were 7.2% (THC), 10.0% (THC-COOH), 9.5% (11-OH-THC) and 5.8% (CBN) at high QC (n = 15, 4 ng/g), respectively. No interfering substances were identified, and no carryover was observed. The average accuracies (N = 25) were 94-95%. The average recoveries observed for THC, THC-COOH, 11-OH-THC and CBN were 74, 82, 58 and 86%, respectively. By analyzing authentic clinical specimens that had been previously tested for cannabinoids by enzyme-linked immunoassay, positive and negative result agreements were 100 and 53.8%. In summary, the presented method can be used for the assessment of in utero exposure to four common cannabinoids.

Cannabis, or the dried leaves, stems, and seeds of the hemp plant Cannabis sativa, is the most widely used illicit drug in America. Typically smoked, vaporized or ingested orally, cannabis is used primarily for recreational purposes, though a few synthetic cannabinoids have been approved for medicinal treatments. Psychoactive cannabinoids, or the pharmacologically active compounds within cannabis, are responsible for producing the infamous "high" sensation, characterized by feelings of euphoria and relaxation, though can also provoke hallucinations, paranoia and anxiety. Cannabinoids act on G-protein coupled receptors in the brain, primarilyCB1 receptors, that typically decrease neural activity and modulate transmitter release. Compared to other drugs of abuse, cannabis use has minimal health risks and almost no potential for fatal overdose, though the trademark method of administration (smoking) has detrimental consequences. Chronic heavy use can also lead to changes in memory, cognitive deficits, psychosis and dependence. Up to 9% of users can develop a cannabis dependence, characterized by a characteristic withdrawal syndrome. The growing prevalence of cannabis use has spurred the development of animals models to research the neurobehavioral basis of cannabis use. Traditional animal models of drug abuse (i.e., conditioned place preference (CPP) and self-administration) have historically struggled to establish rewarding or reinforcing effects of individual cannabinoid molecules. Decades of research have been needed to reveal the appropriate dosage and conditions to promote reward and reinforcement in animal models. While the field has made great strides in elucidating the mechanisms involved in behavioral pharmacology cannabinoids, the social aspects of cannabis use remains underrepresented in animal models. Social interactions are vital to the initiation and continuation of cannabis use in humans, and this component has yet to be accurately captured in current animal models., (© 2018 Elsevier Inc. All rights reserved.)

Rationale: Recent studies have shown that cannabis may disrupt glutamate (Glu) signaling depressing Glu tone in frequent users. Current evidence have also consistently reported lower Glu-levels in various brain regions, particularly in the medial prefrontal cortex (mPFC) of chronic schizophrenia patients, while findings in early psychosis (EP) are not conclusive. Since cannabis may alter Glu synaptic plasticity and its use is a known risk factor for psychosis, studies focusing on Glu signaling in EP with or without a concomitant cannabis-usage seem crucial., Objective: We investigate the effect of cannabis use on prefrontal Glu-levels in EP users vs. both EP non-users and healthy controls (HC)., Methods: Magnetic resonance spectroscopy was used to measure [Glu mPFC ] of 35 EP subjects (18 of whom were cannabis users) and 33 HC. For correlative analysis, neuropsychological performances were scored by the MATRICS-consensus cognitive battery., Results: [Glu mPFC ] was lower in EP users comparing to both HC and EP non-users (p < 0.001 and p = 0.01, respectively), while no differences were observed between EP non-users and HC. A greater [Glu mPFC ]-decline with age was observed in EP users (r = -.46; p = 0.04), but not in EP non-users or HC. Among neuropsychological outcomes, working memory was the only domain that differentiates patients depending on their cannabis use, with users having poorer performances., Conclusions: Cannabis use is associated with reduced prefrontal [Glu mPFC ] and with a stronger Glu-levels decline with age. Glutamatergic abnormalities might influence the cognitive impairment observed in users and have some relevance for the progression of the disease.

Cannabis use has become increasingly accepted socially and legally, for both recreational and medicinal purposes. Without reliable information about the effects of cannabis, people cannot make informed decisions regarding its use. Like alcohol and tobacco, cannabis can have serious adverse effects on health, and some people have difficulty discontinuing their use of the drug. Many cannabis users progress to using and becoming addicted to other drugs, but the reasons for this progression are unclear. The natural cannabinoid system of the brain is complex and involved in many functions, including brain development, reward, emotion, and cognition. Animal research provides an objective and controlled means of obtaining information about: (1) how cannabis affects the brain and behavior, (2) whether medications can be developed to treat cannabis use disorder, and (3) whether cannabis might produce lasting changes in the brain that increase the likelihood of becoming addicted to other drugs. This review explains the tactics used to address these issues, evaluates the progress that has been made, and offers some directions for future research.

In this review, we provide an overview of the relationship between cannabis use and the development of schizophrenia, using both animal and human studies. We further discuss the potential neural mechanism that may mediate the relationship between cannabis use and schizophrenia symptoms. We finally provide clinical implications and future studies that can further elucidate the relationship between cannabis and schizophrenia.

The use of cannabis during pregnancy and lactation is widely recognized as a health concern. The placenta is one of the several biological matrices that can be used to detect in utero drug exposure with the distinct advantage of easy and noninvasive collection. We conducted a PubMed search of selected literature published to June 30, 2016 to investigate the pharmacokinetics of cannabinoids, the active constituent of cannabis, in the placenta. The majority of the selected twelve papers was before 1990 and concerned animals at term gestation with great variability of experimental conditions. Only three were about human population and two of them reported equivocal findings on pre- term placenta. Our systematic review confirms that placental cannabis pharmacokinetics has been scarcely investigated and that further research is needed to determine advantages and disadvantages for monitoring maternal THC use or the degree of in utero exposure., (Copyright © 2017 Elsevier Inc. All rights reserved.)

In the past years, a significant volume of research has implicated the appetitive hormone ghrelin in the mechanisms underlying drug use and addiction. From a neuroscientific standpoint, ghrelin modulates both reward and stress pathways, two key drivers of substance use behaviors. Previous investigations support a connection between the ghrelin system and alcohol, stimulants, and tobacco use in both animals and humans, while the research on opioids and cannabis is scarce. In general, upregulation of the ghrelin system seems to enhance craving for drugs as well as substances use. On the other hand, acute and chronic exposure to drugs of abuse influences the ghrelin system at different levels. This chapter summarizes the literature on the relationship between the ghrelin system and substance-related behaviors. We also review recent work investigating the ghrelin system as a potential pharmacological target for treating substance use disorders and discuss the need for additional research., (2017 Published by Elsevier Inc.)

Most drugs of abuse lead to a general blunting of dopamine release in the chronic phase of dependence, which contributes to poor outcome. To test whether cannabis dependence is associated with a similar dopaminergic deficit, we examined striatal and extrastriatal dopamine release in severely cannabis-dependent participants (CD), free of any comorbid conditions, including nicotine use. Eleven CD and 12 healthy controls (HC) completed two positron emission tomography scans with [ 11 C]-(+)-PHNO, before and after oral administration of d-amphetamine. CD stayed inpatient for 5-7 days prior to the scans to standardize abstinence. Magnetic resonance spectroscopy (MRS) measures of glutamate in the striatum and hippocampus were obtained in the same subjects. Percent change in [ 11 C]-(+)-PHNO-binding potential (ΔBP ND ) was compared between groups and correlations with MRS glutamate, subclinical psychopathological and neurocognitive parameters were examined. CD had significantly lower ΔBP ND in the striatum (P=0.002, effect size (ES)=1.48), including the associative striatum (P=0.003, ES=1.39), sensorimotor striatum (P=0.003, ES=1.41) and the pallidus (P=0.012, ES=1.16). Lower dopamine release in the associative striatum correlated with inattention and negative symptoms in CD, and with poorer working memory and probabilistic category learning performance in both CD and HC. No relationships to MRS glutamate and amphetamine-induced subclinical positive symptoms were detected. In conclusion, this study provides evidence that severe cannabis dependence-without the confounds of any comorbidity-is associated with a deficit in striatal dopamine release. This deficit extends to other extrastriatal areas and predicts subclinical psychopathology., Competing Interests: Dr. Haney has received partial salary support for investigator-initiated studies from Insys Therapeutics Inc, and Lifeloc Technologies and has served as a consultant to Aelis Farma and Health Advances LLC. Dr. Kegeles has received research support from Amgen. Dr. Slifstein has received research support from Forest Laboratories, Pierre-Fabre, CHDI, and Otsuka and has provided consultation for Amgen. Dr. Abi-Dargham has received research support from Takeda and Forest Pharmaceuticals and has served on advisory boards for Roche, Forum, and Otsuka. Drs. Van de Giessen, Weinstein, Cassidy, Dong, Ghazzaoui, Ojeil, Xu, Vadhan and Volkow report no competing interests.

Background: Cannabis is a widely used drug associated with increased risk for psychosis. The dopamine hypothesis of psychosis postulates that altered salience processing leads to psychosis. We therefore tested the hypothesis that cannabis users exhibit aberrant salience and explored the relationship between aberrant salience and dopamine synthesis capacity., Method: We tested 17 cannabis users and 17 age- and sex-matched non-user controls using the Salience Attribution Test, a probabilistic reward-learning task. Within users, cannabis-induced psychotic symptoms were measured with the Psychotomimetic States Inventory. Dopamine synthesis capacity, indexed as the influx rate constant K i cer , was measured in 10 users and six controls with 3,4-dihydroxy-6-[18F]fluoro-l-phenylalanine positron emission tomography., Results: There was no significant difference in aberrant salience between the groups [F 1,32 = 1.12, p = 0.30 (implicit); F 1,32 = 1.09, p = 0.30 (explicit)]. Within users there was a significant positive relationship between cannabis-induced psychotic symptom severity and explicit aberrant salience scores (r = 0.61, p = 0.04) and there was a significant association between cannabis dependency/abuse status and high implicit aberrant salience scores (F 1,15 = 5.8, p = 0.03). Within controls, implicit aberrant salience was inversely correlated with whole striatal dopamine synthesis capacity (r = -0.91, p = 0.01), whereas this relationship was non-significant within users (difference between correlations: Z = -2.05, p = 0.04)., Conclusions: Aberrant salience is positively associated with cannabis-induced psychotic symptom severity, but is not seen in cannabis users overall. This is consistent with the hypothesis that the link between cannabis use and psychosis involves alterations in salience processing. Longitudinal studies are needed to determine whether these cognitive abnormalities are pre-existing or caused by long-term cannabis use.

Background: One of the major mechanisms for terminating the actions of the endocannabinoid anandamide is hydrolysis by fatty acid amide hydrolase (FAAH), and inhibitors of the enzyme were suggested as potential treatment for human cannabis dependence. However, the status of brain FAAH in cannabis use disorder is unknown., Methods: Brain FAAH binding was measured with positron emission tomography and [ 11 C]CURB in 22 healthy control subjects and ten chronic cannabis users during early abstinence. The FAAH genetic polymorphism (rs324420) and blood, urine, and hair levels of cannabinoids and metabolites were determined., Results: In cannabis users, FAAH binding was significantly lower by 14%-20% across the brain regions examined than in matched control subjects (overall Cohen's d = 0.96). Lower binding was negatively correlated with cannabinoid concentrations in blood and urine and was associated with higher trait impulsiveness., Conclusions: Lower FAAH binding levels in the brain may be a consequence of chronic and recent cannabis exposure and could contribute to cannabis withdrawal. This effect should be considered in the development of novel treatment strategies for cannabis use disorder that target FAAH and endocannabinoids. Further studies are needed to examine possible changes in FAAH binding during prolonged cannabis abstinence and whether lower FAAH binding predates drug use., Competing Interests: Financial Disclosures All authors report no biomedical financial interests or potential conflicts of interest., (Copyright © 2016 Society of Biological Psychiatry. All rights reserved.)

Cannabis consumption has radically changed over the last several decades. Tetrahydrcannbidiol concentrations are rising, cannabidiol concentrations falling and cannabis is becoming legalized in several regions of the globe. Concerns have been raised as to the impact of increased cannabis exposure within the general population on public health. One of the more serious concerns is the potential relationship between cannabis consumption and psychosis. Research has shown a relationship between increasing cannabis use and increasing psychosis risk. This risk is moderated by other factors such as stress and a family history of psychosis. Within this context, it is important to determine potential markers for future psychosis risk. Genetic and epigenetic research in cannabis and psychosis is in its early stages. One common denominator between cannabis use disorder and psychosis is dopamine dysfunction. Research has begun to link heightened dopamine reactivity with the psychotomimetic effects of cannabis. Studies in COMT and DRD2 polymorphisms have failed to show greater associations with transition to psychosis. Studies of AKT1 have shown slightly more promising results. Genome-wide association studies have recently been published some indicating novel polymorphisms. These may pave the way to alternate hypotheses to explain the missing links between cannabis use and increased risk of psychosis. Such knowledge may eventually lead to new pharmacotherapies in addition to the means of screening patients for psychosis risk., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Marijuana is the most popular illegal drug worldwide. Recent trends indicate that this may soon change; not due to decreased marijuana use, but to an amendment in marijuana's illegal status. The cannabinoid type 1 (CB1) receptor mediates marijuana's psychoactive and reinforcing properties. CB1 receptors are also part of the brain endocannabinoid (eCB) system and support numerous forms of learning and memory, including the conditioned reinforcing properties of cues predicting reward or punishment. This is accomplished via eCB-dependent alterations in mesolimbic dopamine function, which plays an obligatory role in reward learning and motivation. Presynaptic CB1 receptors control midbrain dopamine neuron activity and thereby shape phasic dopamine release in target regions, particularly the nucleus accumbens (NAc). By also regulating synaptic input to the NAc, CB1 receptors modulate NAc output onto downstream neurons of the basal ganglia motor circuit, and thereby support goal-directed behaviors. Abused drugs promote short- and long-term adaptations in eCB-regulation of mesolimbic dopamine function, and thereby hijack neural systems related to the pursuit of rewards to promote drug abuse. By pharmacologically targeting the CB1 receptors, marijuana has preferential access to this neuronal system and can potently alter eCB-dependent processing of reward-related stimuli. As marijuana legalization progresses, greater access to this drug should increase the utility of marijuana as a research tool to better understand the eCB system, which has the potential to advance cannabinoid-based treatments for drug addiction., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Psychological maturation continues into young adulthood when substance abuse and several psychiatric disorders often emerge. Marijuana is the most common illicit drug abused by youths, typically preceding other illicit substances. We aimed to evaluate the complex and poorly studied relationships between marijuana use, psychiatric symptoms, and cortisol levels in young marijuana users. Psychiatric symptoms and salivary cortisol were measured in 122 youths (13-23 years old) with and without marijuana use. Psychiatric symptoms were evaluated using the Symptom-Checklist-90-R and Brief Psychiatric Rating Scale. Mid-day salivary cortisol levels were measured. Additionally, salivary cytokine levels were measured in a subset of participants. Although the cortisol levels and salivary cytokine levels were similar, the young marijuana users had more self-reported and clinician rated psychiatric symptoms than controls, especially anxiety-associated symptoms. Moreover, marijuana users with earlier age of first use had more symptoms, while those with longer abstinence had fewer symptoms. Greater cumulative lifetime marijuana use was also associated with greater psychiatric symptoms. The discordant anxiety (feeling stressed or anxious despite normal cortisol) in the marijuana users, as well as symptom exacerbations with early and continued marijuana use in young marijuana users suggest that marijuana use may contribute to an aberrant relationship between stress response and psychiatric symptoms. The greater symptomatology, especially in those with earlier initiation and greater marijuana usage, emphasize the need to intervene for substance use and perceived anxiety in this population.

Δ(9) -Tetrahydrocannabinol, the main psychoactive component of cannabis, exerts its central effects through activation of the cerebral type 1 cannabinoid (CB1 ) receptor. Pre-clinical studies have provided evidence that chronic cannabis exposure is linked to decreased CB1 receptor expression and this is thought to be a component underlying drug tolerance and dependence. In this study, we make first use of the selective high-affinity positron emission tomography (PET) ligand [(18) F]MK-9470 to obtain in vivo measurements of cerebral CB1 receptor availability in 10 chronic cannabis users (age = 26.0 ± 4.1 years). Each patient underwent [(18) F]MK-9470 PET within the first week following the last cannabis consumption. A population of 10 age-matched healthy subjects (age = 23.0 ± 2.9 years) was used as control group. Parametric modified standardized uptake value images, reflecting CB1 receptor availability, were calculated. Statistical parametric mapping and volume-of-interest (VOI) analyses of CB1 receptor availability were performed. Compared with controls, cannabis users showed a global decrease in CB1 receptor availability (-11.7 percent). VOI-based analysis demonstrated that the CB1 receptor decrease was significant in the temporal lobe (-12.7 percent), anterior (-12.6 percent) and posterior cingulate cortex (-13.5 percent) and nucleus accumbens (-11.2 percent). Voxel-based analysis confirmed this decrease and regional pattern in CB1 receptor availability in cannabis users. These findings revealed that chronic cannabis use may alter specific regional CB1 receptor expression through neuroadaptive changes in CB1 receptor availability, opening the way for the examination of specific CB1 -cannabis addiction interactions which may predict future cannabis-related treatment outcome., (© 2013 Society for the Study of Addiction.)

Moves to legalize marijuana highlight the urgency to investigate effects of chronic marijuana in the human brain. Here, we challenged 48 participants (24 controls and 24 marijuana abusers) with methylphenidate (MP), a drug that elevates extracellular dopamine (DA) as a surrogate for probing the reactivity of the brain to DA stimulation. We compared the subjective, cardiovascular, and brain DA responses (measured with PET and [(11)C]raclopride) to MP between controls and marijuana abusers. Although baseline (placebo) measures of striatal DA D2 receptor availability did not differ between groups, the marijuana abusers showed markedly blunted responses when challenged with MP. Specifically, compared with controls, marijuana abusers had significantly attenuated behavioral ("self-reports" for high, drug effects, anxiety, and restlessness), cardiovascular (pulse rate and diastolic blood pressure), and brain DA [reduced decreases in distribution volumes (DVs) of [(11)C]raclopride, although normal reductions in striatal nondisplaceable binding potential (BPND)] responses to MP. In ventral striatum (key brain reward region), MP-induced reductions in DVs and BPND (reflecting DA increases) were inversely correlated with scores of negative emotionality, which were significantly higher for marijuana abusers than controls. In marijuana abusers, DA responses in ventral striatum were also inversely correlated with addiction severity and craving. The attenuated responses to MP, including reduced decreases in striatal DVs, are consistent with decreased brain reactivity to the DA stimulation in marijuana abusers that might contribute to their negative emotionality (increased stress reactivity and irritability) and addictive behaviors.

Research on the environmental risk factors for schizophrenia has focused on either psychosocial stress or drug exposure, with limited investigation of their interaction. A heightened dopaminergic stress response in patients with schizophrenia and individuals at clinical high risk (CHR) supports the dopaminergic sensitization hypothesis. Cannabis is believed to contribute to the development of schizophrenia, possibly through a cross-sensitization with stress. Twelve CHR and 12 cannabis-using CHR (CHR-CU, 11 dependent) subjects underwent [(11)C]-(+)-PHNO positron emission tomography scans, while performing a Sensorimotor Control Task (SMCT) and a stress condition (Montreal Imaging Stress task). The simplified reference tissue model was used to obtain binding potential relative to non-displaceable binding (BPND) in the whole striatum, its functional subdivisions (limbic striatum (LST), associative striatum (AST), and sensorimotor striatum (SMST)), globus pallidus (GP), and substantia nigra (SN). Changes in BPND, reflecting alterations in synaptic dopamine (DA) levels, were tested with analysis of variance. SMCT BPND was not significantly different between groups in any brain region (p>0.21). Although stress elicited a significant reduction in BPND in the CHR group, CHR-CU group exhibited an increase in BPND. Stress-induced changes in regional BPND between CHR-CU and CHR were significantly different in AST (p<0.001), LST (p=0.007), SMST (p=0.002), SN (p=0.021), and whole striatum (p=0.001), with trend level in the GP (p=0.099). All subjects experienced an increase in positive (attenuated) psychotic symptoms (p=0.001) following the stress task. Our results suggest altered DA stress reactivity in CHR subjects who concurrently use cannabis, as compared with CHR subjects. Our finding does not support the cross-sensitization hypothesis, which posits greater dopaminergic reactivity to stress in CHR cannabis users, but adds to the growing body of literature showing reduced DA (stress) response in addiction.

Background: Cannabis is the most widely used illicit drug globally, and users are at increased risk of mental illnesses including psychotic disorders such as schizophrenia. Substance dependence and schizophrenia are both associated with dopaminergic dysfunction. It has been proposed, although never directly tested, that the link between cannabis use and schizophrenia is mediated by altered dopaminergic function., Methods: We compared dopamine synthesis capacity in 19 regular cannabis users who experienced psychotic-like symptoms when they consumed cannabis with 19 nonuser sex- and age-matched control subjects. Dopamine synthesis capacity (indexed as the influx rate constant [Formula: see text] ) was measured with positron emission tomography and 3,4-dihydroxy-6-[(18)F]-fluoro-l-phenylalanine ([(18)F]-DOPA)., Results: Cannabis users had reduced dopamine synthesis capacity in the striatum (effect size: .85; t36 = 2.54, p = .016) and its associative (effect size: .85; t36 = 2.54, p = .015) and limbic subdivisions (effect size: .74; t36 = 2.23, p = .032) compared with control subjects. The group difference in dopamine synthesis capacity in cannabis users compared with control subjects was driven by those users meeting cannabis abuse or dependence criteria. Dopamine synthesis capacity was negatively associated with higher levels of cannabis use (r = -.77, p < .001) and positively associated with age of onset of cannabis use (r = .51, p = .027) but was not associated with cannabis-induced psychotic-like symptoms (r = .32, p = .19)., Conclusions: These findings indicate that chronic cannabis use is associated with reduced dopamine synthesis capacity and question the hypothesis that cannabis increases the risk of psychotic disorders by inducing the same dopaminergic alterations seen in schizophrenia., (Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Cannabis use is associated with the development of psychotic symptoms and increased risk for schizophrenia. The mismatch negativity (MMN) is a brain event-related potential marker of change detection thought to index glutamatergic N-methyl-D-aspartate receptor-mediated neurotransmission, which is known to be deficient in schizophrenia. This study examined auditory MMN in otherwise healthy chronic cannabis users compared with nonuser control subjects., Methods: Forty-two chronic cannabis users and 44 nonuser healthy control subjects completed a multi-feature MMN paradigm, which included duration, frequency, and intensity deviants (deviants 6%; standards 82%). The MMN was compared between users and control subjects as well as between long- and short-term users and age- and gender-matched control subjects. Associations between MMN, cannabis use measures, and symptoms were examined., Results: The MMN amplitude was significantly reduced to frequency but not duration or intensity deviants in overall cannabis users relative to control subjects. Frequency MMN was similarly attenuated in short- and long-term users relative to control subjects. Long-term users also exhibited reduced duration MMN relative to control subjects and short-term users and this was correlated with increased duration of exposure to cannabis and increased psychotic-like experiences during intoxication. In short-term users, a younger age of onset of regular cannabis use and greater frequency of use were associated with greater psychotic-like experiences and symptomatic distress., Conclusions: These results suggest impaired sensory memory that might reflect N-methyl-D-aspartate receptor dysfunction in chronic cannabis users. The pattern of MMN alterations in cannabis users differed from that typically observed in patients with schizophrenia, indicating overlapping but distinct underlying pathology., (Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Cannabis is the most widely used illicit drug in the world. Although there is a high prevalence of users who seek treatment for cannabis dependence, no accepted pharmacologic treatment is available to facilitate and maintain abstinence. The hypocretin/orexin system plays a critical role in drug addiction, but the potential participation of this system in the addictive properties of cannabinoids is unknown., Methods: We investigated the effects of hypocretins in the intravenous self-administration of the synthetic cannabinoid agonist WIN55,212-2 using hypocretin receptor-1 (Hcrtr-1) and hypocretin receptor-2 antagonists and Hcrtr-1 knockout mice. Additional groups of mice were trained to obtain water to rule out operant responding impairments. Activation of hypocretin neurons was analyzed by using double-label immunofluorescence of FosB/ΔFosB with hypocretin-1. Microdialysis studies were performed to evaluate dopamine extracellular levels in the nucleus accumbens after acute Δ(9)-tetrahydrocannabinol administration., Results: Systemic administration of the Hcrtr-1 antagonist SB334867 reduced intravenous self-administration of WIN55,212-2, as well as the maximum effort to obtain a WIN55,212-2 infusion, as revealed under a progressive ratio schedule. This role of Hcrtr-1 in the reinforcing and motivational properties of WIN55,212-2 was confirmed in Hcrtr-1 knockout mice. Contingent, but not noncontingent, WIN55,212-2 self-administration increased the percentage of hypocretin cells expressing FosB/ΔFosB in the lateral hypothalamus. The enhancement in dopamine extracellular levels in the nucleus accumbens induced by Δ(9)-tetrahydrocannabinol was blocked in mice lacking the Hcrtr-1., Conclusions: These findings demonstrate that Hcrtr-1 modulates the reinforcing properties of cannabinoids, which could have a clear therapeutic interest., (Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: Bipolar and cannabis use disorders commonly co-occur during adolescence, and neurochemical studies may help clarify the pathophysiology underlying this co-occurrence. This study compared metabolite concentrations in the left ventral lateral prefrontal cortex among adolescents with bipolar disorder (bipolar group; n = 14), adolescents with a cannabis use disorder (cannabis use group; n = 13), adolescents with cannabis use and bipolar disorders (bipolar and cannabis group; n = 25), and healthy adolescents (healthy controls; n = 15). We hypothesized that adolescents with bipolar disorder (with or without cannabis use disorder) would have decreased N-acetyl aspartate levels in the ventral lateral prefrontal cortex compared to the other groups and that the bipolar and cannabis group would have the lowest N-acetyl aspartate levels of all groups., Methods: N-acetyl aspartate concentrations in the left ventral lateral prefrontal cortex were obtained using proton magnetic resonance spectroscopy., Results: Adolescents with bipolar disorder showed significantly lower left ventral lateral prefrontal cortex N-acetyl aspartate levels, but post hoc analyses indicated that this was primarily due to increased N-acetyl aspartate levels in the cannabis group. The cannabis use disorder group had significantly higher N-acetyl aspartate levels compared to the bipolar disorder and the bipolar and cannabis groups (p = .0002 and p = .0002, respectively). Pearson correlations revealed a significant positive correlation between amount of cannabis used and N-acetyl aspartate concentrations., Conclusions: Adolescents with cannabis use disorder showed higher levels of N-acetyl aspartate concentrations that were significantly positively associated with the amount of cannabis used; however, this finding was not present in adolescents with comorbid bipolar disorder.

Introduction: The relation between schizophrenia and cannabis abuse has been widely discussed from etiopathogenetic, psychopathological and neurometabolic points of view. Relatively little has been written about the differences between schizophrenia with co-occurrent cannabis abuse and substance-induced psychotic disorder (SIPD). Given these premises, our study aims to investigate the psychopathological and neurometabolic features of these clinical entities., Methods: We enrolled patients experiencing an acute psychotic episode, affected either by schizophrenia with or without cannabis abuse (SCZ +/- CA; n = 5 and n = 5, respectively) with recent onset (<5 years of illness) or by SIPD (n = 6), as diagnosed by the Structured Clinical Interview for DSM-IV Axis I. Patients affected by SIPD were all cannabis abusers. All patients were assessed with the PANSS (Positive and Negative Scale for Schizophrenia), urinary toxicological tests and brain 18-FDG-PET scanning in resting condition. Statistical analysis (ANOVA) was performed with Statistical Parametric Mapping SPM8 and Scenium software., Results: Bilateral hypermetabolism in the posterior cingulum and the precuneus (p < 0.001) was observed in SIPD patients compared to patients with schizophrenia, with or without cannabis abuse., Conclusions: Our preliminary PET findings suggest that substance abuse may cause increased brain metabolism in patients with induced psychosis but not in those with schizophrenia. These differences in brain metabolism were found in the posterior cingulum and precuneus, which are two core regions of the default mode network in humans., (© 2014 S. Karger AG, Basel.)

Much progress has been made in the last decade in the understanding the neural substrates of drug addiction, transmitters involved, epigenetic background and their relation to learning and memory but much remains to be elucidated and strong effort is necessary to integrate the rich information at the molecular, cellular systems, and behavioral levels to further clarify the mechanisms and therapy of this complex disease. The aim of this review is to collect and interpret the latest opinions in the development, the underlying mechanisms and therapy of addiction as a disease of central nervous system. The neurocircuitry, the transmitters and the epigenetics of addiction are discussed.