Brain neuroimaging in cannabis use: a review

In this study, the authors systematically reviewed structural and functional neuroimaging studies of cannabis use. Structural abnormalities generally have not been identified with chronic use. Regular users demonstrate reciprocal changes in brain activity globally and in cerebellar and frontal regions. Abstinence results in decreases, and administration results in increases correlating with subjective intoxication. Chronic use and cannabis administration result in attenuated brain activity in task-activated regions or activation of compensatory regions. Findings correlate partially with neuropsychological data, but generalization is limited by the lack of use of diagnostic criteria, appropriately paired neuropsychological testing or means to better quantify cannabis use and abstinence.     

Alteration to hippocampal shape in cannabis users with and without schizophrenia

Abnormalities in hippocampal morphology are characteristic of schizophrenia and have also been reported in chronic cannabis users. There is a paucity of research investigating potential additive effects of cannabis use on brain pathology associated with schizophrenia. In this study, we performed hippocampal shape analysis in cannabis-using and non-using patients with schizophrenia, healthy cannabis users and healthy non-using controls. Hippocampal shape changes were observed in each group relative to controls, with the greatest degree of alterations (i.e., deflations across the hippocampus, and with an anterior predisposition), in cannabis-using schizophrenia patients. These alterations were associated with cannabis use patterns and psychotic symptoms.     

Cannabis and the Lung

While most cannabis use involves inhalation of the fumes from combustion, other routes of administration are also common but the consequences of these routes of exposure are less well known than from that of smoking. It is clear that prolonged use of cannabis causes chronic bronchitis and airflow obstruction in heavy users. However, there is a need to further understand the lung biology influenced by cannabis use, the potential for lung carcinogenesis, the effects of high THC products, and the health effects of different routes of administration. This review summarizes the present state of knowledge with regard to irritation and long-term effects on the lung and bronchial tissues.     

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

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

The impact of early-onset cannabis use on functional brain correlates of working memory

Cannabis is the most commonly used illicit drug. Prevalence rates are particularly high among adolescents. Neuropsychological studies have identified cannabis-associated memory deficits, particularly linked to an early onset of use. However, it remains unclear, whether the age of onset accounts for altered cortical activation patterns usually observed in cannabis users. Functional magnetic resonance imaging was used to examine cortical activation during verbal working memory challenge in (1) early-onset (onset before the age of sixteen; n = 26) and (2) late-onset cannabis users (age at onset at least sixteen; n = 17). Early-onset users showed increased activation in the left superior parietal lobe. Correlational analyses confirmed the association between an earlier start of use and increased activity. Contrariwise neither cumulative dose, frequency nor time since last use was significantly associated with cortical activity. Our findings suggest that an early start of cannabis use is associated with increased cortical activation in adult cannabis users, possibly reflecting suboptimal cortical efficiency during cognitive challenge. The maturing brain might be more vulnerable to the harmful effects of cannabis use. However, due to a lack of a non-using control group we cannot exclude alternative interpretations.     

Adverse effects of cannabis on health: an update of the literature since 1996

Recent research has clarified a number of important questions concerning adverse effects of cannabis on health. A causal role of acute cannabis intoxication in motor vehicle and other accidents has now been shown by the presence of measurable levels of Delta(9)-tetrahydrocannabinol (THC) in the blood of injured drivers in the absence of alcohol or other drugs, by surveys of driving under the influence of cannabis, and by significantly higher accident culpability risk of drivers using cannabis. Chronic inflammatory and precancerous changes in the airways have been demonstrated in cannabis smokers, and the most recent case-control study shows an increased risk of airways cancer that is proportional to the amount of cannabis use. Several different studies indicate that the epidemiological link between cannabis use and schizophrenia probably represents a causal role of cannabis in precipitating the onset or relapse of schizophrenia. A weaker but significant link between cannabis and depression has been found in various cohort studies, but the nature of the link is not yet clear. A large body of evidence now demonstrates that cannabis dependence, both behavioral and physical, does occur in about 7-10% of regular users, and that early onset of use, and especially of weekly or daily use, is a strong predictor of future dependence. Cognitive impairments of various types are readily demonstrable during acute cannabis intoxication, but there is no suitable evidence yet available to permit a decision as to whether long-lasting or permanent functional losses can result from chronic heavy use in adults. However, a small but growing body of evidence indicates subtle but apparently permanent effects on memory, information processing, and executive functions, in the offspring of women who used cannabis during pregnancy. In total, the evidence indicates that regular heavy use of cannabis carries significant risks for the individual user and for the health care system.     

The effect of cannabis on the brain: can it cause brain anomalies that lead to increased risk for schizophrenia?

PURPOSE OF REVIEW: This review explores what is known about the association of cannabis with schizophrenia, its effects on the brain, and whether the brain changes known to be present in schizophrenia could be caused by cannabis and thus lead to a psychosis. RECENT FINDINGS: The heavy use of cannabis is known to be associated with some adverse consequences, such as the occurrence of acute psychotic episodes and the development of chronic schizophrenia in some people even after its use has terminated. Recent studies have produced controversy about whether cannabis in heavy use can cause irreversible brain damage, particularly to adolescents, and thus whether a chronic psychosis could be a result of brain changes caused by cannabis. SUMMARY: From the evidence that exists, it appears that the above view is unlikely and that cannabis may even have benign effects on brain structure, not producing deleterious damage. Its neurochemical interactions with the dopaminergic pathway, however, may, particularly in genetically vulnerable individuals, have adverse consequences.     

fMRI study of neural sensitization to hedonic stimuli in long‐term,daily cannabis users

Although there is emergent evidence illustrating neural sensitivity to cannabis cues in cannabis users, the specificity of this effect to cannabis cues as opposed to a generalized hyper‐sensitivity to hedonic stimuli has not yet been directly tested. Using fMRI, we presented 53 daily, long‐term cannabis users and 68 non‐using controls visual and tactile cues for cannabis, a natural reward, and, a sensory‐perceptual control object to evaluate brain response to hedonic stimuli in cannabis users. The results showed an interaction between group and reward type such that the users had greater response during cannabis cues relative to natural reward cues (i.e., fruit) in the orbitofrontal cortex, striatum, anterior cingulate gyrus, and ventral tegmental area compared to non‐users (cluster‐threshold z = 2.3, P < 0.05). In the users, there were positive brain‐behavior correlations between neural response to cannabis cues in fronto‐striatal‐temporal regions and subjective craving, marijuana‐related problems, withdrawal symptoms, and levels of THC metabolites (cluster‐threshold z = 2.3, P < 0.05). These findings demonstrate hyper‐responsivity, and, specificity of brain response to cannabis cues in long‐term cannabis users that are above that of response to natural reward cues. These observations are concordant with incentive sensitization models suggesting sensitization of mesocorticolimbic regions and disruption of natural reward processes following drug use. Although the cross‐sectional nature of this study does not provide information on causality, the positive correlations between neural response and indicators of cannabis use (i.e., THC levels) suggest that alterations in the reward system are, in part, related to cannabis use. Hum Brain Mapp 37:3431–3443, 2016. © 2016 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.     

Aberrant structural–functional coupling in adult cannabis users

Cellular studies indicate that endocannabinoid type‐1 retrograde signaling plays a major role in synaptic plasticity. Disruption of these processes by delta‐9‐tetrahydrocannabinol (THC) could produce alterations either in structural and functional brain connectivity or in their association in cannabis (CB) users. Graph theoretic structural and functional networks were generated with diffusion tensor imaging and resting‐state functional imaging in 37 current CB users and 31 healthy non‐users. The primary outcome measures were coupling between structural and functional connectivity, global network characteristics, association between the coupling and network properties, and measures of rich‐club organization. Structural–functional (SC–FC) coupling was globally preserved showing a positive association in current CB users. However, the users had disrupted associations between SC–FC coupling and network topological characteristics, most perturbed for shorter connections implying region‐specific disruption by CB use. Rich‐club analysis revealed impaired SC–FC coupling in the hippocampus and caudate of users. This study provides evidence of the abnormal SC–FC association in CB users. The effect was predominant in shorter connections of the brain network, suggesting that the impact of CB use or predispositional factors may be most apparent in local interconnections. Notably, the hippocampus and caudate specifically showed aberrant structural and functional coupling. These structures have high CB1 receptor density and may also be associated with changes in learning and habit formation that occur with chronic cannabis use.     

Health consequences of acute and chronic marihuana use

Chemical content, assay procedures, and pharmacokinetics of cannabis sativa are discussed briefly. Cannabinoid cellular effects relating to chromosomes and immunity including cellular metabolism and allergic reactions are presented. Gross and microscopic brain pathology due to cannabis use is reviewed involving EEG alterations, psychopathology including aggressive behaviour as well as properties of psychomotor impairment, tolerance and dependence. Cardiopulmonary effects of marihuana are recorded under pulmonary pharmacological effects including the macrophage defense system and effects of smoke constituents; under cardiovascular effects cardiac toxicity and possible mechanism of action are discussed. Alterations of reproductive hormonal production and maturation of reproductive cells by marihuana in males and females with attendant impairment of reproductive function or fertility including reproductive outcome are reported. Field studies with healthy chronic cannabis users in Jamaica, Greece and Costa Rica are related as to observed medical alterations. Potential clinical effects are summarized in point form.     

Cannabis,cannabidiol, and epilepsy — From receptors to clinical response

Recreational cannabis use in adults with epilepsy is widespread. The use of cannabis for medicinal purposes is also becoming more prevalent. For this purpose, various preparations of cannabis of varying strengths and content are being used. The recent changes in the legal environment have improved the availability of products with high cannabidiol (CBD) and low tetrahydrocannabinol (THC) concentrations. There is some anecdotal evidence of their potential efficacy, but the mechanisms of such action are not entirely clear. Some suspect an existence of synergy or “entourage effect” between CBD and THC. There is strong evidence that THC acts via the cannabinoid receptor CB₁. The mechanism of action of CBD is less clear but is likely polypharmacological. The scientific data support the role of the endocannabinoid system in seizure generation, maintenance, and control in animal models of epilepsy. There are clear data for the negative effects of cannabis on the developing and mature brain though these effects appear to be relatively mild in most cases. Further data from well-designed studies are needed regarding short- and long-term efficacy and side effects of CBD or high-CBD/low-THC products for the treatment of seizures and epilepsy in children and adults.     

Altered brain activation during visuomotor integration in chronic active cannabis users: relationship to cortisol levels

Cannabis is the most abused illegal substance in the United States. Alterations in brain function and motor behavior have been reported in chronic cannabis users, but the results have been variable. The current study aimed to determine whether chronic active cannabis use in humans may alter psychomotor function, brain activation, and hypothalamic-pituitary-axis (HPA) function in men and women. Thirty cannabis users (16 men, 14 women, 18-45 years old) and 30 nondrug user controls (16 men, 14 women, 19-44 years old) were evaluated with neuropsychological tests designed to assess motor behavior and with fMRI using a 3 Tesla scanner during a visually paced finger-sequencing task, cued by a flashing checkerboard (at 2 or 4 Hz). Salivary cortisol was measured to assess HPA function. Male, but not female, cannabis users had significantly slower performance on psychomotor speed tests. As a group, cannabis users had greater activation in BA 6 than controls, while controls had greater activation in the visual area BA 17 than cannabis users. Cannabis users also had higher salivary cortisol levels than controls (p = 0.002). Chronic active cannabis use is associated with slower and less efficient psychomotor function, especially in male users, as indicated by a shift from regions involved with automated visually guided responses to more executive or attentional control areas. The greater but altered brain activities may be mediated by the higher cortisol levels in the cannabis users, which in turn may lead to less efficient visual-motor function.     

Functional correlates of verbal memory deficits emerging during nicotine withdrawal in abstinent adolescent cannabis users.

BACKGROUND: Cannabis remains the most widely used illicit substance by adolescents and is typically consumed by this population in the context of ongoing tobacco use. Human studies have shown that both cannabis and tobacco exert effects on cognitive function; however, little is known about possible interacting effects of these drugs on brain function and cognition during adolescent development. METHODS: Verbal learning and memory were assessed in 20 adolescent users of tobacco and cannabis and 25 adolescent tobacco users with minimal history of cannabis use. Functional magnetic resonance imaging was used to examine brain function and functional connectivity while a subset of these subjects performed a verbal working memory task. RESULTS: Delayed recall of verbal stimuli deteriorated during nicotine withdrawal among cannabis users but not among comparison subjects. During high verbal working memory load, nicotine withdrawal selectively increased task-related activation of posterior cortical regions and was associated with disruption of frontoparietal connectivity in adolescent cannabis users relative to comparison subjects. CONCLUSIONS: These observations suggest that cannabis use during adolescent development may disrupt neurocircuitry supporting verbal memory formation and that deficits associated with disruption of these neurocircuits are unmasked during nicotine withdrawal.     

Delay- and dose-dependent effects of Δ?-tetrahydrocannabinol administration on spatial and object working memory tasks in adolescent rhesus monkeys

Among adolescents, the perception that cannabis can cause harm has decreased and use has increased. However, in rodents, cannabinoid administration during adolescence induces working memory (WM) deficits that are more severe than if the same exposure occurs during adulthood. As both object and spatial WM mature in a protracted manner, although apparently along different trajectories, adolescent cannabis users may be more susceptible to impairments in one type of WM. Here, we evaluate the acute effects of a range of doses (30-240 μg/kg) of intravenous Δ?-tetrahydrocannabinol (THC) administration on the performance of spatial and object WM tasks in adolescent rhesus monkeys. Accuracy on the object WM task was not significantly affected by any dose of THC. In contrast, THC administration impaired accuracy on the spatial WM task in a delay- and dose-dependent manner. Importantly, the THC-induced spatial WM deficits were not because of motor or motivational impairments. These data support the idea that immature cognitive functions are more sensitive to the acute effects of THC.     

Tolerance to the reinforcing effects of morphine in delta9-tetrahydrocannabinol treated mice

Several studies have investigated interactions between opioid and cannabinoid systems. However, the results regarding the rewarding effects of opiates in animals pre-exposed to CB1 agonists, appear inconsistent. Using the conditioned place preference, it was shown that dependence to delta9-tetrahydrocannabinol (THC) was hardly reached, while the synthetic ligand WIN55,212-2 facilitate the rewarding effects of morphine. The aim of the present study was to establish whether a chronic THC treatment (10 mg/kg, i.p., 21 days) may facilitate, in mice, the rewarding effects of morphine used at low doses (0.5 and 2 mg/kg, i.p.) or high dose (10 mg/kg, i.p.) after a long drug-free period, as it was speculated that chronic cannabinoid exposure may induce long-lasting neural changes in brain regions involved in opiate addiction. Moreover, THC was used in conditions as close as possible to those leading to cannabis drawbacks. After 15 days of abstinence, the locomotor activating properties of morphine as well as its motivational properties were not facilitated by pretreatment with THC in mice and even reduced for the higher dose of morphine used in the conditioned place preference (CPP). This lack of CPP in animals pretreated with THC was not due to discrimination impairment between different environments, as demonstrated in a two-trial recognition task. In conclusion, it appears that chronic THC treatment leads to a reduction of reinforcing effects of morphine in the CPP. This result supports the occurrence of modulatory interaction between opioid and cannabinoid systems in the reward process.     

Quantitative changes in hippocampal structure following long-term exposure to delta 9-tetrahydrocannabinol: possible mediation by glucocorticoid systems

Although cannabinoids exert strong effects on brain function, there have been no extensive analyses of the long-term effects of cannabinoids on mammalian brain structure. Consequently, we conducted quantitative light and electron microscopic studies on the brains of rats treated chronically with delta 9-tetrahydrocannabinol (THC) (5 X weekly for 8 months--approximately 30% of the life-span). In these studies, we found significant THC-induced changes in hippocampal structure: specifically, THC-treated animals exhibited decreased neuronal density and increased glial cell reactivity (i.e. an increase of cytoplasmic inclusions). In addition, we confirmed prior reports of THC-induced increases in adrenal-pituitary activity, since both adrenocorticotropic hormone (ACTH) and corticosterone were elevated substantially during an acute stress. However, the animals appeared to be only minimally affected behaviorally by the doses used (highest dose: 8 mg/kg) and no effects of THC were observed on several ultrastructural variables, including synaptic density. The observed hippocampal morphometric effects of chronic THC are similar to apparent glucocorticoid-dependent changes that previously have been found to develop in rat hippocampus during normal aging. Given that cannabinoids and steroids are similar in chemical structure in several respects, therefore, the present results seem to raise the possibility that chronic THC exposure may alter hippocampal anatomical structure by interactions with, or mimicry of, adrenal steroid activity.     

Brief report: changes in brain function during acute cannabis intoxication: preliminary findings suggest a mechanism for cannabis-induced violence

Background Recent evidence suggests that cannabis use may be associated with antisocial and violent behaviour, raising the question: What brain mechanisms mediate the disinhibiting effects of cannabis on behaviour? Aims/Hypotheses To examine whether an electrocortical measure of affective impulsivity, Go/No Go contingent negative variation, is affected by acute cannabis intoxication. Methods Slow brain potentials were recorded in a Go/No Go noise avoidance task from five habitual cannabis users before, during and after they smoked a cannabis reefer containing 11 mg D‐9‐tetrahydrocannabinol. Results Slow brain potentials developed normally in both Go and No Go conditions before and during cannabis smoking but were severely disrupted 20–40 minutes later, coincident with peak intoxication. Cannabis effects on Go/No Go brain activity resembled those reported to occur in patients with lateral prefrontal cortex lesions. Conclusion/Implications Our findings are preliminary, calling for larger‐scale studies, to confirm the present findings and to investigate whether brain responses to cannabis intoxication differentiate those who are predisposed to suffer adverse consequences of cannabis use from those who are not. Copyright © 2007 John Wiley & Sons, Ltd.     

Role of endocannabinoid system in mental diseases

In the last decade, a large number of studies using Delta9-tetrahydrocannabinol (THC), the main active principle derivative of the marijuana plant, or cannabinoid synthetic derivatives have substantially contributed to advance the understanding of the pharmacology and neurobiological mechanisms produced by cannabinoid receptor activation. Cannabis has been historically used to relieve some of the symptoms associated with central nervous system disorders. Nowadays, there are anecdotal evidences for the use of cannabis in many patients suffering from multiple sclerosis or chronic pain. Following the historical reports of the use of cannabis for medicinal purposes, recent research has highlighted the potential of cannabinoids to treat a wide variety of clinical disorders. Some of these disorders that are being investigated are pain, motor dysfunctions or psychiatric illness. On the other hand, cannabis abuse has been related to several psychiatric disorders such as dependence, anxiety, depression, cognitive impairment, and psychosis. Considering that cannabis or cannabinoid pharmaceutical preparations may no longer be exclusively recreational drugs but may also present potential therapeutic uses, it has become of great interest to analyze the neurobiological and behavioral consequences of their administration. This review attempts to link current understanding of the basic neurobiology of the endocannabinoid system to novel opportunities for therapeutic intervention and its effects on the central nervous system.     

Chronic adolescent exposure to delta-9-tetrahydrocannabinol in COMT mutant mice: impact on indices of dopaminergic, endocannabinoid and GABAergic pathways

Cannabis use confers a two-fold increase in risk for psychosis, with adolescent use conferring an even greater risk. A high-low activity polymorphism in catechol-O-methyltransferase (COMT), a gene encoding the COMT enzyme involved in dopamine clearance in the brain, may interact with adolescent cannabis exposure to increase risk for schizophrenia. The impact of such an interaction on central neurotransmitter pathways implicated in schizophrenia is unknown. Male mice with knockout of the COMT gene were treated chronically with delta-9-tetrahydrocannabinol (THC) during adolescence (postnatal day 32-52). We measured the size and density of GABAergic cells and the protein expression of cannabinoid receptor 1 (CB1R) in the prefrontal cortex (PFC) and hippocampus (HPC) in knockout mice relative to heterozygous mutants and wild-type controls. Size and density of dopaminergic neurons was also assessed in the ventral tegmental area (VTA) across the genotypes. COMT genotype × THC treatment interactions were observed for: (1) dopaminergic cell size in the VTA, (2) CB1R protein expression in the HPC, and (3) parvalbumin (PV) cell size in the PFC. No effects of adolescent THC treatment were observed for PV and dopaminergic cell density across the COMT genotypes. COMT genotype modulates the effects of chronic THC administration during adolescence on indices of neurotransmitter function in the brain. These findings illuminate how COMT deletion and adolescent cannabis use can interact to modulate the function of neurotransmitters systems implicated in schizophrenia.     

Actions of delta-9-tetrahydrocannabinol in cannabis: Relation to use,abuse, dependence

Cannabis use disorders have been recently identified as a relevant clinical issue: a subset of cannabis smokers seeks treatment for their cannabis use, yet few succeed in maintaining long-term abstinence. The rewarding and positive reinforcing effects of the primary psychoactive component of smoked cannabis, delta-9-tetrahydrocannabinol (THC) are mediated by the cannabinoid CB1 receptor. The CB1 receptor has also been shown to mediate cannabinoid dependence and expression of withdrawal upon cessation of drug administration, a phenomenon verified across species. This paper will review findings implicating the CB1 receptor in the behavioural effects of exogenous cannabinoids with a focus on cannabinoid dependence and reinforcement, factors that contribute to the maintenance of chronic cannabis smoking despite negative consequences. Opioidergic modulation of these effects is also discussed.