Chronic Cannabis Exposure Research Articles

A review of the effects of acute and chronic cannabinoid exposure on the stress response

While cannabis has been used for centuries for its stress-alleviating properties, the effects of acute and chronic cannabinoid exposure on responses to stress remain poorly understood. This review provides an overview of studies that measured stress-related endpoints following acute or chronic cannabinoid exposure in humans and animals. Acute cannabinoid exposure increases basal concentrations of stress hormones in rodents and humans and has dose-dependent effects on stress reactivity in humans and anxiety-like behavior in rodents. Chronic cannabis exposure is associated with dampened stress reactivity, a blunted cortisol awakening response (CAR), and flattened diurnal cortisol slope in humans. Sex differences in these effects remain underexamined, with limited evidence for sex differences in effects of cannabinoids on stress reactivity in rodents. Future research is needed to better understand sex differences in the effects of cannabis on the stress response, as well as downstream impacts on mental health and stress-related disorders.

Urinary Cannabis Metabolite Concentrations in Cannabis Hyperemesis Syndrome.

Cannabis Hyperemesis Syndrome (CHS) is characterized by recurrent episodes of intractable emesis associated with heavy use of cannabis. Recognition of CHS can be problematic due to the lack of specific biomarkers, which can point the clinician to the diagnosis. We present, retrospectively, a series of adolescent/young adult patients who presented to a pediatric gastroenterology (GI) service with acute on chronic nausea and vomiting, subsequently found to have CHS with associated elevated urinary cannabis metabolite concentrations. We describe 15 patients referred to our pediatric GI division for intractable emesis with spot urinary cannabis metabolite carboxy-THC (THC-COOH) concentrations from January 1, 2018 through April 20, 2019. Urinary testing was performed using gas chromatography mass-spectrometry (GC-MS) in a manner consistent with Clinical Laboratory Improvement Amendments (CLIA) requirements at Mayo Clinic laboratory (Rochester, MN). The laboratory cutoffs were 3.0 ng/mL. Data was extracted via chart review and analyzed via online statistical application. Fifteen patients (seven females, eight males) were studied with an average age of 17.7 years. All patients reported frequent cannabis use for at least 1 month and exhibited intractable, non-bilious emesis for at least 2 weeks. Twelve patients also reported weight loss. Two patients had underlying gastrointestinal disease (one with Crohn disease and one with irritable bowel syndrome). All patients had essentially normal GI workup including laboratory tests, imaging studies and endoscopies.Fourteen of 15 patients had urinary THC-COOH concentrations >100 ng/mL, with seven individuals exhibiting levels >500 ng/mL. One patient had a urinary TCH-COOH concentration level under 100 ng/mL had not used cannabis for 2 weeks. Most other patients had used cannabis within 2 days of providing a urine sample. The Binomial test for CHS patients with urinary THC-COOH levels over 100 ng/mL was significant with a P-value of <0.0005 (one tail test). CHS is associated with an elevated urinary THC-COOH level usually exceeding 100 ng/mL, which is indicative of significant chronic cannabis exposure. In patients with a history consistent with CHS, urine THC-COOH testing may help guide the diagnostic evaluation of these patients and decrease the need for further workup.

Evidence That Cannabis Exposure, Abuse, and Dependence Are Related to Glutamate Metabolism and Glial Function in the Anterior Cingulate Cortex: A 1H-Magnetic Resonance Spectroscopy Study.

There is evidence that long-term cannabis use is associated with alterations to glutamate neurotransmission and glial function. In this study, 26 long-term cannabis users (males=65.4%) and 47 non-cannabis using healthy controls (males=44.6%) underwent proton magnetic resonance spectroscopy (1H-MRS) of the anterior cingulate cortex (ACC) in order to characterize neurometabolite alterations in cannabis users and to examine associations between neurometabolites, cannabis exposure, and cannabis use behaviors. Myo-inositol, a marker of glial function, and glutamate metabolites did not differ between healthy controls and cannabis users or cannabis users who met criteria for DSM5 cannabis use disorder (n=17). Lower myo-inositol, a putative marker of glial function, was related to greater problematic drug use (F1,22 = 11.95, p=.002; Cohen’s f=0.59, large effect; Drug Abuse Screening Test) and severity of cannabis dependence (F1,22 = 6.61, p=.17; Cohen’s f=0.44, large effect). Further, past-year cannabis exposure exerted different effects on glutamate and glutamate+glutamine in males and females (glutamate: F1,21 = 6.31, p=.02; glutamate+glutamine: F1,21 = 7.20, p=.014), such that greater past-year cannabis exposure was related to higher concentrations of glutamate metabolites in male cannabis users (glutamate: F1,14 = 25.94, p=.00016; Cohen’s f=1.32, large effect; glutamate+glutamine: F1,14 = 23.24, p=.00027, Cohen’s f=1.24, large effect) but not in female cannabis users (glutamate: F1,6 = 1.37, p=0.78; glutamate+glutamine: F1,6 = 0.001, p=.97). The present results extend existing evidence of altered glial function and glutamate metabolism with cannabis use by providing evidence linking problematic drug use behaviors with glial function as measured with myo-inositol and recent chronic cannabis exposure to alterations in glutamate metabolism. This provides novel directions for the interrogation of the impact of cannabis use on brain neurochemistry.

Cerebellar thickness changes associated with heavy cannabis use: A 3-year longitudinal study.

Cannabis is the most frequently used illicit drug in the world. Cross-sectional neuroimaging studies have revealed that chronic cannabis exposure and the development of cannabis use disorders may affect cerebllar morphology. However, cross-sectional studies cannot make a conclusive distinction between causes and consequences, and there is a lack of longitudinal neuroimaging studies. In the current study, we used longitudinal neuroimaging data to explore whether persistent cannabis use and higher levels of cannabis exposure in young adults are related to cerebellar thickness alterations. Twenty heavy cannabis users (CBs) and 22 non-cannabis-using controls (HCs) completed a comprehensive psychological assessment and a T1-structural MRI scan at baseline and a 3-year follow-up. Except for lobuleVIIB, all cerebellar subregions showed significant effects of age in both the CB and HC groups. Both VI and CrusI had higher rates of increase in CBs than in HCs. In addition, we examined the relationship between changes in cerebellar thickness and cannabis use characteristics. We found that alterations in lobule VI and CrusI were related to the age at onset first cannabis use but not the age at onset frequent cannabis use. The changes in lobule VI and CrusI were associated with the CUDIT score, even when controlling for the AUDIT score. The results indicated that an increased rate of cerebellar thickness is a risk factor for heavy cannabis use in early adulthood. Cannabis use affects the cerebellar structure, and monitoring cerebellar structural alterations that could be used as biomarkers may help guide the development of clinical tools.

Cannabinoid toxicity in pediatrics.

The advent of legalized cannabis in multiple regions of the United States has rendered the drug more accessible to pediatric patients. Pediatricians and Pediatric Emergency Medicine Providers face new challenges in counseling both patients and their parents, diagnosing exploratory ingestions of cannabinoids in toddlers, and managing complications of prolonged, heavy cannabis use in adolescents. The purpose of this review article is to provide clinicians a succinct summary of recent literature regarding tetrahydrocannabinol (THC) pharmacokinetics, pharmacodynamics, impacts on development, as well as presentations of acute and chronic toxicity. Many young children being admitted to the hospital for cannabis toxicity have been exposed to high concentration products, such as edibles, resins, or vaping fluid. These products contain extremely high concentrations of cannabinoids, and lead to sedation, respiratory depression, and other adverse effects. Chronic toxicity associated with cannabis consumption includes neurocognitive changes and cannabinoid hyperemesis syndrome. Clinicians should provide guidance for pediatric patients and their caregivers to reduce the risk of accidental cannabis exposure, particularly with high concentration products. In addition, clinicians should consider chronic cannabis exposure when evaluating certain complaints, such as chronic vomiting or educational performance at school.

Chronic cannabis promotes pro-hallucinogenic signaling of 5-HT2A receptors through Akt/mTOR pathway

Long-term use of potent cannabis during adolescence increases the risk of developing schizophrenia later in life, but to date, the mechanisms involved remain unknown. Several findings suggest that the functional selectivity of serotonin 2A receptor (5-HT2AR) through inhibitory G-proteins is involved in the molecular mechanisms responsible for psychotic symptoms. Moreover, this receptor is dysregulated in the frontal cortex of schizophrenia patients. In this context, studies involving cannabis exposure and 5-HT2AR are scarce. Here, we tested in mice the effect of an early chronic Δ9-tetrahydrocannabinol (THC) exposure on cortical 5-HT2AR expression, as well as on its in vivo and in vitro functionality. Long-term exposure to THC induced a pro-hallucinogenic molecular conformation of the 5-HT2AR and exacerbated schizophrenia-like responses, such as prepulse inhibition disruption. Supersensitive coupling of 5-HT2AR toward inhibitory Gαi1-, Gαi3-, Gαo-, and Gαz-proteins after chronic THC exposure was observed, without changes in the canonical Gαq/11-protein pathway. In addition, we found that inhibition of Akt/mTOR pathway by rapamycin blocks the changes in 5-HT2AR signaling pattern and the supersensitivity to schizophrenia-like effects induced by chronic THC. The present study provides the first evidence of a mechanistic explanation for the relationship between chronic cannabis exposure in early life and increased risk of developing psychosis-like behaviors in adulthood.

The Influence of DAT1, COMT, and BDNF Genetic Polymorphisms on Total and Subregional Hippocampal Volumes in Early Onset Heavy Cannabis Users.

Introduction: Hippocampal neuroanatomy is affected by genetic variations in dopaminergic candidate genes and environmental insults, such as early onset of chronic cannabis exposure. Here, we examine how hippocampal total and subregional volumes are affected by cannabis use and functional polymorphisms of dopamine-relevant genes, including the catechol-O-methyltransferase (COMT), dopamine transporter (DAT1), and the brain-derived neurotrophic factor (BDNF) genes.Material and Methods: We manually traced total hippocampal volumes and automatically segmented hippocampal subregions using high-resolution MRI images, and performed COMT, DAT1, and BDNF genotyping in 59 male Caucasian young adults aged 18–30 years. These included 30 chronic cannabis users with early-onset (regular use at <16 years) and 29 age-, education-, and intelligence-matched controls.Results: Cannabis use and dopaminergic gene polymorphism had both distinct and interactive effects on the hippocampus. We found emerging alterations of hippocampal total and specific subregional volumes in cannabis users relative to controls (i.e., CA1, CA2/3, and CA4), and associations between cannabis use levels and total and specific subregional volumes. Furthermore, total hippocampal volume and the fissure subregion were affected by cannabis×DAT1 polymorphism (i.e., 9/9R and in 10/10R alleles), reflecting high and low levels of dopamine availability.Conclusion: These findings suggest that cannabis exposure alters the normal relationship between DAT1 polymorphism and the anatomy of total and subregional hippocampal volumes, and that specific hippocampal subregions may be particularly affected.

Neurocognitive effects of cannabis: Lessons learned from human experimental studies.

The following chapter offers an overview of results of experimental studies conducted among healthy individuals examining the effects of acute administration of Δ9-THC and other cannabinoids, alone or in combination, on brain function and behavior, also as a function of previous cannabis exposure. In light of their methodological design, these studies have advanced the understanding of the neurobiological mechanisms increasing the risk of long-lasting cognitive dysfunction as well as psychosis in regular cannabis users. Also, direct and indirect evidence supports an alteration of different neurotransmitters, such as dopamine, glutamate, and gamma-aminobutyric acid, in modulating the manifestation of neurocognitive dysfunction and psychosis in the context of both acute and chronic cannabis exposure. Future multimodal neuroimaging studies will integrate the longitudinal information to track the long-term changes in brain neurochemistry and neurophysiology as well as other potential biomarkers induced by sustained cannabis use.

Persistent and Long-Term Neuropsychiatric Implications of Cannabis Use in Adolescents

Persistent and Long-Term Neuropsychiatric Implications of Cannabis Use in Adolescents

Abstract 100: Lower Probability of Aortic Aneurysm Diagnosis Among Patients With Chronic Cannabis Exposure, An Analysis of the 2012-2014 National Inpatient Survey

Introduction: Cannabis is a commonly utilized recreational substance which contains numerous bioactive agents. As more states legalize the use of marijuana, it’s effect on various disease conditions is expected to become more pronounced. Cannabis’ anti-inflammatory effects could suppress pro-inflammatory conditions. For example, chronic inflammation with extracellular matrix degradation resulting in weakness and abnormal dilatation of the aortic wall is a hallmark of Aortic Aneurysm. We, therefore, hypothesized that cannabis users would have less prevalence of aortic aneurysms. Objective: To identify the relationship between chronic cannabis use (CU) and diagnosis of aortic aneurysms (AA) among hospitalized patients. Methods: After selecting patients who were 55 years and above from 2012 to 2014 National Inpatient Sample database, we identified those who had a diagnosis of Aortic Aneurysm and those who utilize Cannabis. We then stratified the CU into two groups: nondependent (NDU) and dependent users (DU). Using logistic regression, we estimated the Odds Ratio (AOR) after controlling for numerous factors. Results: In our total 10,461,694 sample, 99.6% (10,419,972) are non-users, 0.37% (38,514) are nondependent users and 0.03% (3,208) are dependent users. About 3.21% (336,202) of the patients had a diagnosis of AA versus 96.79% (10,125,492) without a diagnosis of AA. Compared to non-users of cannabis, the odds of AA is about 35% less among CU (AOR 0.66[0.62-0.71]), 40% less among DU (aOR 0.58[0.44-0.76]), and 33% less among NDU (AOR 0.67[0.62-0.72]). The odds of AA was lower in females (AOR 0.61[0.60-0.610]), but higher in many conditions such as: among &gt;=65 years (AOR 1.16[1.15-1.17]), tobacco users (AOR 1.18[1.17-1.19]), predisposing hereditary conditions (AOR 5.31[4.60-6.13]), and atherosclerosis (AOR 3.04[3.00-3.08]). Conclusions: Our result shows that Cannabis use is associated with less occurrence of AA. Cannabidiol, an anti-inflammatory alkaloid in Cannabis could potentially suppress the release of proteolytic inflammatory mediators which might be responsible for the gradual weakening of the vascular walls. We recommend more basic research to evaluate this effect of Cannabidiol.

Grey Matter Changes Associated with Heavy Cannabis Use: A Longitudinal sMRI Study.

Cannabis is the most frequently used illicit drug worldwide. Cross-sectional neuroimaging studies suggest that chronic cannabis exposure and the development of cannabis use disorders may affect brain morphology. However, cross-sectional studies cannot make a conclusive distinction between cause and consequence and longitudinal neuroimaging studies are lacking. In this prospective study we investigate whether continued cannabis use and higher levels of cannabis exposure in young adults are associated with grey matter reductions. Heavy cannabis users (N = 20, age baseline M = 20.5, SD = 2.1) and non-cannabis using healthy controls (N = 22, age baseline M = 21.6, SD = 2.45) underwent a comprehensive psychological assessment and a T1- structural MRI scan at baseline and 3 years follow-up. Grey matter volumes (orbitofrontal cortex, anterior cingulate cortex, insula, striatum, thalamus, amygdala, hippocampus and cerebellum) were estimated using the software package SPM (VBM-8 module). Continued cannabis use did not have an effect on GM volume change at follow-up. Cross-sectional analyses at baseline and follow-up revealed consistent negative correlations between cannabis related problems and cannabis use (in grams) and regional GM volume of the left hippocampus, amygdala and superior temporal gyrus. These results suggests that small GM volumes in the medial temporal lobe are a risk factor for heavy cannabis use or that the effect of cannabis on GM reductions is limited to adolescence with no further damage of continued use after early adulthood. Long-term prospective studies starting in early adolescence are needed to reach final conclusions.

CB1 cannabinoid receptor stimulation during adolescence impairs the maturation of GABA function in the adult rat prefrontal cortex

Converging epidemiological studies indicate that cannabis abuse during adolescence increases the risk of developing psychosis and prefrontal cortex (PFC)-dependent cognitive impairments later in life. However, the mechanisms underlying the adolescent susceptibility to chronic cannabis exposure are poorly understood. Given that the psychoactive constituent of cannabis binds to the CB1 cannabinoid receptor, the present study was designed to determine the impact of a CB1 receptor agonist (WIN) during specific windows of adolescence on the functional maturation of the rat PFC. By means of local field potential (LFP) recordings and ventral hippocampal stimulation in vivo, we found that a history of WIN exposure during early (postnatal day -P- 35-40) or mid-(P40-45) adolescence, but not in late adolescence (P50-55) or adulthood (P75-80), is sufficient to yield a state of frequency-dependent prefrontal disinhibition in adulthood comparable to that seen in the juvenile PFC. Remarkably, this prefrontal disinhibition could be normalized following a single acute local infusion of the GABA-Aα1 positive allosteric modulator Indiplon, suggesting that adolescent exposure to WIN causes a functional downregulation of GABAergic transmission in the PFC. Accordingly, in vitro recordings from adult rats exposed to WIN during adolescence demonstrate that local prefrontal GABAergic transmission onto layer V pyramidal neurons is markedly reduced to the level seen in the P30-35 PFC. Together, these results indicate that early and mid-adolescence constitute a critical period during which repeated CB1 receptor stimulation is sufficient to elicit an enduring state of PFC network disinhibition resulting from a developmental impairment of local prefrontal GABAergic transmission.

EPA-1084 - Catechol o-methyltransferase val158met genotype and neural mechanisms related to response inhibition in chronic cannabis users

Neuropsychological and neuroimaging studies of response inhibition in cannabis users have reported inconsistent results. The age of onset of cannabis use and individual genetic differences may play a critical role in the regulation of inhibition in cannabis users. We examine the influence of COMT Val158Met functional polymorphism on the response inhibition brain network in a group of early-onset chronic cannabis users compared with healthy controls. fMRI data was acquired from 27 chronic cannabis users who began use cannabis before 16 years of age, and 29 non-using control subjects matched in terms of age, educational level and intelligence quotient while undergoing the Multi-Source Interference Task (MSIT). Participants were male, Caucasians aged between 18 and 30 years. All were assessed by a structured psychiatric interview (PRISM) to exclude any lifetime Axis-I disorder (DSM-IV). COMT genotyping was performed and resonance imaging data was analysed by voxel-based morphometry (VBM). Both groups did not differ on their behavioural performance and brain responses during the MSIT task. A significant group-by-genotype interaction was observed on task-related brain activation (and on MSIT reaction times), in which met carrier load was associated with increased activation in cannabis users and val carrier load with increased activation in controls. The interaction pattern included the medial frontal cortex, ACC, inferior frontal gyrus, ventral striatum, anterior mesencephalon, inferior parietal and superior temporal cortices and the PCC. Chronic cannabis exposure interacts with the genetically driven dopamine function in the modulation of the neural mechanisms related to response inhibition. Grants:PNSD/2011/050, PNSD2006/101, SGR2009/1435.

18F]MK‐9470 PET measurement of cannabinoid CB1 receptor availability in chronic cannabis users

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.

Microglial activation underlies cerebellar deficits produced by repeated cannabis exposure

Chronic cannabis exposure can lead to cerebellar dysfunction in humans, but the neurobiological mechanisms involved remain incompletely understood. Here, we found that in mice, subchronic administration of the psychoactive component of cannabis, delta9-tetrahydrocannabinol (THC), activated cerebellar microglia and increased the expression of neuroinflammatory markers, including IL-1β. This neuroinflammatory phenotype correlated with deficits in cerebellar conditioned learning and fine motor coordination. The neuroinflammatory phenotype was readily detectable in the cerebellum of mice with global loss of the CB1 cannabinoid receptor (CB1R, Cb1(-/-) mice) and in mice lacking CB1R in the cerebellar parallel fibers, suggesting that CB1R downregulation in the cerebellar molecular layer plays a key role in THC-induced cerebellar deficits. Expression of CB2 cannabinoid receptor (CB2R) and Il1b mRNA was increased under neuroinflammatory conditions in activated CD11b-positive microglial cells. Furthermore, administration of the immunosuppressant minocycline or an inhibitor of IL-1β receptor signaling prevented the deficits in cerebellar function in Cb1(-/-) and THC-withdrawn mice. Our results suggest that cerebellar microglial activation plays a crucial role in the cerebellar deficits induced by repeated cannabis exposure.

Repetitive Vomiting and Acute Renal Failure as the Presenting Features of Cannabinoid Hyperemesis Syndrome

Cannabinoid hyperemesis syndrome (CHS) characterized by cyclic vomiting after chronic cannabis exposure has been increasingly reported but still less-appreciated with acute renal failure. An otherwise healthy 50-year-old man manifested vigorous vomiting with severe acute renal failure and metabolic alkalosis in the emergency department repetitively. Without receiving hemodialysis, all of his clinical symptoms and abnormal laboratory findings completely resolved after aggressive volume repletion, electrolyte supplementation, and control of vomiting. There was no ascertainable etiology for vomiting after serial laboratory and radiological workups. Based on his positive urine toxicology screening for tetrahydrocannabinol, an ill-concealed history of cannabis smoking, and the behavior of compulsive and prolonged hot spring baths alleviating the intractable vomiting, he was believed to have CHS. Repetitive vomiting and acute renal failure may be the presenting feature of CHS. Early recognition of CHS with prompt treatment is crucial to avoid futile examinations and inappropriate management, and to hasten cannabis cessation.

1301 – Structural and functional imaging studies in chronic cannabis users: a systematic review of adolescent and adult findings

The growing concern about cannabis use, the most used illicit drug worldwide, has led to an increase in the number of cannabis studies using neuroimaging techniques to determine its effect on brain structure and function. We conducted a systematic review to assess the evidence of the impact of chronic cannabis use on brain structure and function in adults and adolescents. Papers published until August 2012 were included from EMBASE, Medline, PubMed and LILACS databases following a comprehensive search strategy and pre-determined set of criteria for article selection. Only neuroimaging studies involving chronic cannabis users with a matched control group were considered. One hundred and forty-two studies were identified, of which 43 met the established criteria. Eight studies were in adolescent population. Neuroimaging studies provide evidence of morphological brain alterations in both population groups, particularly in the medial temporal and frontal cortices, as well as the cerebellum. These effects may be related to the amount of cannabis exposure. Functional neuroimaging studies suggest different patterns of resting global and brain activity during the performance of several cognitive tasks also in both groups, which may indicate compensatory effects in response to chronic cannabis exposure. The results pointed out methodological limitations among studies and high heterogeneity in the findings. Chronic cannabis use may alter brain structure and function in adult and adolescent population. Further studies should consider the use of convergent and multimodal methodology, prospective large samples involving adolescent to adulthood subjects, and data-sharing initiatives. Grants: PNSD/2011/050, PNSD2006/101, SGR2009/1435.

The effects of cannabinoids on serum cortisol and prolactin in humans

Cannabis is one of the most widely used illicit substances, and there is growing interest in the therapeutic applications of cannabinoids. While known to modulate neuroendocrine function, the precise acute and chronic dose-related effects of cannabinoids in humans are not well-known. Furthermore, the existing literature on the neuroendocrine effects of cannabinoids is limited by small sample sizes (n = 6-22), heterogeneous samples with regard to cannabis exposure (lumping users and nonusers), lack of controlling for chronic cannabis exposure, differing methodologies, and limited dose-response data. Delta-9-tetrahydrocannabinol (Delta-9-THC) was hypothesized to produce dose-related increases in plasma cortisol levels and decreases in plasma prolactin levels. Furthermore, relative to controls, frequent users of cannabis were hypothesized to show altered baseline levels of these hormones and blunted Delta-9-THC-induced changes of these hormones. Pooled data from a series of laboratory studies with multiple doses of intravenous Delta-9-THC in healthy control subjects (n = 36) and frequent users of cannabis (n = 40) was examined to characterize the acute, chronic, and acute on chronic effects of cannabinoids on plasma cortisol and prolactin levels. Hormone levels were measured before (baseline) and 70 min after administration of each dose of Delta-9-THC. Data were analyzed using linear mixed models with +70 min hormonal levels as the dependant variable and baseline hormonal level as the covariate. At socially relevant doses, Delta-9-THC raised plasma cortisol levels in a dose-dependent manner but frequent users showed blunted increases relative to healthy controls. Frequent users also had lower baseline plasma prolactin levels relative to healthy controls. These group differences may be related to the development of tolerance to the neuroendocrine effects of cannabinoids. Alternatively, these results may reflect inherent differences in neuroendocrine function in frequent users of cannabis and not a consequence of cannabis use.

Role of the endogenous cannabinoid system as a modulator of dopamine transmission: implications for Parkinson's disease and schizophrenia.

The endogenous cannabinoid system is a new signaling system composed by the central (CB1) and the peripheral (CB2) receptors, and several lipid transmitters including anandamide and 2-arachidonylglycerol. This system is the target of natural cannabinoids, the psychoactive constituents of Cannabis sativa preparations (marijuana, hashish). Acute and chronic cannabis exposure has been associated with subjective feelings of pleasure and relaxation, but also to the onset of psychiatric syndromes, a decrease of the efficacy of neuroleptics and alterations in the extrapyramidal system regulation of motor activity. These actions point to a tight association of the cannabinoid system with the brain dopaminergic circuits involved in addiction, the clinical manifestation of positive symptoms of schizophrenia and Parkinson's disease. The present work discusses anatomical, biochemical and pharmacological evidences supporting a role for the endogenous cannabinoid system in the modulation of dopaminergic transmission. Cannabinoid CB1 receptors are present in dopamine projecting brain areas. In primates and certain rat strains it is also located in dopamine cells of the A8, A9 and A10 mesencephalic cell groups, as well as in hypothalamic dopaminergic neurons controlling prolactin secretion. CB1 receptors co-localize with dopamine D1/D2 receptors in dopamine projecting fields. Manipulation of dopaminergic transmission is able to alter the synthesis and release of anandamide as well as the expression of CB1 receptors. Additionally, CB1 receptors can switch its transduction mechanism to oppose to the ongoing dopamine signaling. Acute blockade of CB1 receptor potentiates the facilitatory role of dopamine D2 receptor agonists on movement. CB1 stimulation results in sensitization to the motor effects of indirect dopaminergic agonists. The dynamics of these changes indicate that the cannabinoid system is an activity-dependent modulator of dopaminergic transmission, an hypothesis relevant for the design of new therapeutic strategies for dopamine-related diseases such as the psychosis and Parkinson's disease.

Canabis Dependence and Tolerance Production

The chronic abuse of many drugs produces both marked tolerance and physical dependence. Marked tolerance to cannabis has been observed in experimental animals and humans. However, reports of physical dependence, as characterized by significant withdrawal symptomatology upon cessation of chronic cannabis exposure, has not been well established or clearly defined in any species. The abuse potential of cannabis is more readily observed in humans than in experimental animal investigations. This may be due to the physiochemical characteristics of cannabis or delta 9-THC, which complicates this type of animal experimentation. It is more likely that the greatest dangers of cannabis abuse involve the pharmacological effects of the drug upon the central nervous system and other organs, rather than the development of dependence.