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Abstract

Understanding of the neurophysiological basis of cognitive, behavioural and perceptual disturbances associated with long-term cannabis use has grown dramatically. Exogenous cannabinoids alter the normative functioning of the endogenous cannabinoid system. This system is an important regulator of neurotransmission. Recent research has demonstrated abnormalities of the cannabinoid system in schizophrenia. The purpose of the present paper was to selectively review the links between cannabis use and psychosis, drawing upon recent epidemiological, clinical, cognitive, brain imaging and neurobiological research. The aim is to assist clinicians to probe more deeply into the newly unfolding world of cannabinoid physiology and to critically evaluate the potential role of cannabis in the onset and persistence of cognitive impairments and psychosis in otherwise healthy users and in schizophrenia.

Keywords

cannabinoid cannabis comorbidity dual diagnosis psychosis schizophrenia

Cannabis has the lowest initiation age of any illicit drug, with onset of use typically occurring in early adolescence [1], [2]. An Australian household survey showed that a little over one-third of persons aged 14 years and over had used cannabis at some point in their lives, and 17% reported having used it within the past 12 months [3]. Recreational users seek its induction of euphoria, depersonalization, somnolence, altered sensory perceptions and time sense, and relaxation [1], [4]. Acute intoxication can also produce less desirable perceptual, cognitive and motor impairments in healthy users [1], [4], [5] and exacerbate pre-existing disturbances in these domains in those diagnosed with schizophrenia [6], [7]. These findings suggest that cannabis use alters the functioning of brain regions responsible for control of cognition and maintenance of intact perceptual functions. Until recently, however, the physiological basis for these disturbances, the interaction between the constituents of cannabis and the endogenous cannabinoid system, were unknown. In this review we appraise the literature regarding cognitive, perceptual and neurobiological effects of cannabis in light of these recent developments, with the goal of integrating this evidence in the context of the links between cannabis and psychosis.

Cannabis and cognitive dysfunction

The acute and residual (within 12–24 h) neuropsychological effects of cannabis use include the induction of deficits in attention, executive functioning and short-term memory [8], [9]. Heavy cannabis use impairs processing speed and the ability to focus attention and ignore irrelevant information in long-term users, functions mediated by the prefrontal cortex (PFC) [10]. Solowij et al. found that these deficits last beyond the period of intoxication and worsen with increasing years of cannabis use [10]. Other studies have also shown that there are longer term effects (24 h–28 days) of cannabis on short-term memory and attention that are dose dependent [11–15]. A meta-analysis of a small number of studies of cannabis users suggested that if any deficits exist in this population beyond the acute intoxication period, they are most likely to occur in the domain of learning and forgetting or retrieval of information [15].

Brain imaging in cannabis users

Several neuroimaging studies have explored the cerebral correlates of the acute and residual effects of cannabis use. When participants are at rest (i.e. not cognitively engaged in a task), dose-related increases in global cerebral blood flow have been detected in intoxicated experienced users [16], with regionally specific changes in metabolism and cerebral blood flow in the orbitofrontal and PFC, basal ganglia [16], [17], insula, cingulate gyrus, and subcortical regions [18–20]. By contrast, recently abstinent experienced cannabis users show evidence of subnormal global cerebral blood flow [21], [22] and reduced cerebellar blood flow [18].

Tasks that are designed to engage specific cortical regions have been used in the imaging environment to assess the effects of cannabis on brain activation and function. Studies that have explored cerebral activity in acutely intoxicated participants have found increased regional cerebral blood flow (rCBF) in the anterior brain, predominantly in the paralimbic regions compared to healthy control subjects. These changes may underpin the mood-related effects of the drug [8], [23]. In contrast, decreased rCBF in the temporal lobe auditory area, visual cortex, and frontal regions was associated with impairment of attention [8], [23]. Kanayama et al. found that heavy long-term cannabis users abstinent for 6–36 h displayed greater and more widespread brain activation than non-using subjects while performing a spatial working memory task [21]. Persistent changes from expected patterns of cerebral activation have even been detected after 25 days [13] and 28 days of abstinence [22]. Researchers have proposed that additional brain regions not usually involved in the task may be called upon to support the appropriate resolution of the cognitive challenge [21], [24]. But it remains unclear whether these findings relate to cerebral adaptations to compensate for subtle residual effects of cannabis use or whether functional neuroimaging and neuropsychological testing evaluate different constructs altogether [see [25] for an in-depth review].

The changes in cerebral perfusion in cannabis users both while cognitively engaged and at rest are robust. But the evidence for structural brain change associated with cannabis use is equivocal. Positive findings include global reductions in cortical grey matter density in adolescent long-term cannabis users [26], generalized cerebral volume loss, smaller cerebellar vermi and focal temporal and frontal white matter abnormalities [27]. More convincing evidence of structural change has been demonstrated by the detection of grey and white matter density changes in heavy adult users [28] that included the same regions (e.g. parahippocampal gyrus) that showed altered activation in a decision-making task [22], and some of the density changes correlated with duration of cannabis use [28]. Most recently, a significant dose-related reduction of hippocampal and amygdala volumes has been reported in a small but well-controlled sample of very heavy long-term cannabis users [29], corroborating evidence from the animal literature. Interestingly, left hippocampal reduction was associated with subthreshold psychotic symptoms in the otherwise healthy cannabis users. More studies are required to clarify whether cannabis has direct neurotoxic effects altering brain structure. Newer enhanced anatomical data acquisition and brain structure analysis techniques [30] are likely to assist in this endeavour.

In summary, imaging studies demonstrate that cannabis use can result in regionally specific changes in the perfusion of frontal and memory-related cortical areas despite abstinence from cannabis and in the absence of detectable gross neuropsychological deficits. A compensatory cerebral mechanism, whereby additional brain regions are recruited to account for subtle cognitive deficits [13], [21] is suggested. Although there is evidence of structural brain changes associated with cannabis use, a thorough interpretation of these findings cannot yet be made.

Links between cannabis use and psychosis

An association between cannabis use and psychotic symptoms and/or schizophrenia has been evident for some time [1]. Hambrecht and Hafner conducted a cluster analysis of early psychosis patients for whom cannabis use was linked to the onset of psychotic symptoms [31]. They proposed three potential types of association. First, in the absence of a known genetic liability to schizophrenia, cannabis use was proposed to reduce the ‘schizophrenia vulnerability threshold’, thereby increasing the susceptibility to psychosis. The Andreasson et al. 1987 study was the first to report a dose–response relationship between the amount of cannabis used in adolescence and the subsequent risk of developing schizophrenia [32]. More recent analyses of these data that controlled for personality traits, amphetamines and other drugs concluded that if cannabis could be removed from the ‘schizophrenia equation’, 13% of cases of schizophrenia might be prevented [33]. Van Os et al. also showed, in a well-controlled prospective study, that the extent of lifetime exposure to cannabis constituted an independent risk factor for the emergence of psychosis in a dose–response manner in previously psychosis-free persons [34]. Among users with no genetic liability to psychosis, cannabis was linked to the development of psychosis in up to 50% of cases. In the same year, Arsenault et al. reported that after controlling for pre-existing psychotic symptoms, cannabis use increased the risk of developing schizophrenia symptoms, that this risk was specific to cannabis as opposed to the use of other drugs and that early onset cannabis use (prior to age 15) conferred the greatest risk [35]. One possible explanation for the latter finding is that the transition from the cognitive, behavioural and emotional capacities of childhood to those of adulthood entails sensitive neurodevelopmental processes, particularly of the frontal and limbic areas [36] and these maturational processes are particularly sensitive to the effects of drugs such as cannabis [37], [38].

The second type of association reported by Hambrecht and Hafner was that cannabis use was proposed to be the stress factor that precipitated the onset of psychosis in the context of a genetic predisposition to schizophrenia [31]. A number of studies provide support for this second grouping. Schizophrenia patients who use cannabis heavily have been found to be 10-fold more likely to have a family history of schizophrenia [39]. Moreover, a strong interaction between cannabis use and vulnerability to psychosis has been reported. Van Os et al. found that approximately 80% of psychosis outcome was attributable to the synergistic action of these two risk factors [34]. There may therefore be an interaction between a genetic risk for schizophrenia and cannabis acting as a biological stressor, triggering the onset of schizophrenia [40]. Recent work by Caspi et al. showed that a functional polymorphism in the catechol-O-methyltransferase (COMT) gene that results in less efficient breakdown of dopamine in the synapse by COMT, moderated the effect of adolescent cannabis use on the risk for adult psychosis [41]. Individuals homozygous for the COMT valine-158 allele, associated with increased dopamine levels in midbrain neurons that project to the ventral striatum [42], were at least fivefold more likely to develop symptoms of schizophrenia after adolescent exposure to cannabis than individuals homozygous for the methionine allele. It is biologically plausible that the cannabis users who are prone to psychosis may be unable to clear the mid-brain dopamine release known to be triggered by cannabis use [43].

The third type of proposed association was that of cannabis use as a form of self-medication to alleviate the dysphoria associated with the negative and depressive symptoms of schizophrenia. This has not, however, been borne out by the research [44]. An alternative proposition, the reverse causality model tested by Fergusson et al., asserts that the predominant direction of causality was from cannabis use to psychotic symptoms rather than the converse [45].

This suggests an explanation for the associations between cannabis use and the onset of psychosis in those who are psychosis prone. But researchers have argued that if cannabis use had an aetiological role in the development of schizophrenia, then the incidence of schizophrenia should increase in parallel with increases in cannabis use, and they argue that it has not [5]. Recent research that tracked the incidence of schizophrenia and its relationship to cannabis use in South London between 1965 and 1999 showed that the number of cases of schizophrenia has doubled in this period [46] and that there was also a large increase in the proportion of schizophrenia patients who had used cannabis in the 12 months before diagnosis [47]. Using a conservative model that regards the heavy use of cannabis as one of several risk factors for schizophrenia, with a pooled odds ratio of 2.1 [44], Hickman et al. calculated that the drug would be responsible for 10% of new schizophrenia cases [48], [49].

Cannabis use in schizophrenia

Twenty-five per cent of schizophrenia patients meet lifetime criteria for a cannabis use disorder, situating it as the most commonly used illicit drug among this patient population [50]. Cannabis-using patients experience more psychotic symptoms [51], respond poorly to neuroleptic medications [52], have poorer treatment compliance and worse clinical outcomes; experience more relapses [5] and more hospitalizations [6], [53]. These observations are biologically plausible given that psychotic disorders involve disturbances in dopamine neurotransmitter systems [54] and cannabis increases dopamine release [55]. Paradoxically, cannabis may also have symptom-relieving effects [56], helping to ameliorate negative symptoms, depression, and the side-effects of antipsychotics, as well as relieving boredom, providing stimulation and facilitating socialization with peers, with patients reporting similar reasons for using cannabis as reported in the general population [57–59]. It is possible that the beneficial and adverse effects of cannabis might be dose related. Alternatively, the conflicting conclusions of self-report and epidemiologic studies may be reconciled by the possibility that cannabis effects vary with time, so that schizophrenia patients may derive some short-term benefits from cannabis at the expense of adverse consequences in the longer term. A further explanation may be that brain regions associated with the positive, cognitive and negative symptoms of schizophrenia, which occur in various combinations from one patient to another, may respond differently to cannabis.

Endogenous cannabinoid system and changes in schizophrenia

Endocannabinoids are a family of lipid molecules involved in neuromodulation and neuroprotection [60–62]. Anandamide and 2-arachidonoyl-glycerol (2-AG) are produced on demand from membrane phospholipids [63] and once released are rapidly inactivated by membrane-bound fatty acid amide hydrolase expressed in cortical neurons [64]. Endocannabinoids are agonists at the central nervous system cannabinoid type 1 (CB1) receptor. These receptors are located presynaptically on inhibitory and excitatory neurons, where their activation causes transient neuronal suppression [65], [66]. This endocannabinoid-mediated ‘retrograde signaling’ has been reported to regulate both short- and long-term synaptic plasticity [67], [68]. Neocortical CB1 receptors are expressed mainly on γ-aminobutyric acid (GABA) interneurons, while in the amygdala, hippocampus, basal ganglia and cerebellum they are expressed on both GABAergic and pyramidal neurons [64], [69], [70]. The location and function of the endogenous cannabinoid system suggest that it is positioned to regulate the neuronal circuits involved in cognitive function, emotions, and activity in the mesolimbic reward contingency pathways [71].

Changes in the endocannabinoid system have been reported to occur in schizophrenia. First, a triple repeat polymorphism of the CB1 receptor gene, located on chromosome 6q14-15 [72], a site that includes a schizophrenia susceptibility locus 6q13-q26 [73], has been associated with the hebephrenic type of schizophrenia [74]. Second, an increased expression of the CB1 receptor has been found in the PFC in schizophrenia independent of recent exposure to cannabis [75], whereas increased CB1 density in the caudate and putamen was independent of diagnosis but correlated with recently ingested cannabis [76]. Increased CB1 densities have also been observed in the anterior and posterior cingulate in schizophrenia [77], [78]. The expression of endocannabinoids is also altered in schizophrenia [79], with a twofold elevation in the concentration of cerebrospinal fluid (CSF) anandamide levels found in a small sample of schizophrenia patients [79]. In a replication study, an 8.5-fold elevation of CSF anandamide levels was found in a larger sample of neuroleptic-naïve schizophrenia patients, but there was no elevation of anandamide levels in a medicated patient sample, nor in a ‘prodromal’ group [80]. In non-medicated acute schizophrenia, CSF anandamide was negatively correlated with psychotic symptoms, which suggests that anandamide elevation in acute schizophrenia may reflect a compensatory adaptation to the disease state [81].

Cannabinoid effects within current hypotheses of schizophrenia

In the previous sections we provided a selective overview of the effects of cannabis use in healthy individuals and in schizophrenia, the evidence for an association between cannabis use and an increased risk of schizophrenia and the changes to the endogenous cannabinoid system in schizophrenia. Next, we explore the effects of cannabinoids in the context of prevailing hypotheses of schizophrenia.

Dopamine hypothesis

The schizophrenia syndrome comprises psychotic, negative and disorganization symptoms, together with cognitive abnormalities. Dysfunction of dopamine neurotransmission in cortical and subcortical structures is central to the current understanding of schizophrenia. The dopamine hypothesis originally proposed that an excess of dopamine activity in the mesolimbic pathway between the ventral tegmental area (VTA) and limbic structures caused psychotic symptoms [82]. Although psychosis is frequently the most striking clinical feature of schizophrenia, disturbances in mesocortical dopamine function associated with negative symptoms and cognitive deficits are now regarded as core features. The latter are thought to be related to reduced dopaminergic activity in the frontal lobes, particularly that mediated by D1 receptors [83].

Behavioural, biochemical, and electrophysiological data demonstrate the involvement of endogenous cannabinoids in regulating the activity of dopaminergic neurotransmission in the VTA and in the frontal cortex. The principal VTA neurons contain dopamine and regulate motivation, reward-related behaviours, salience attribution and cognition [84], [85]. The role of endogenous cannabinoids in the VTA has not yet been fully elucidated, but it is known that prolonged depolarization of dopamine neurons within the VTA causes a transient calcium-dependent release of endocannabinoids. Anandamide and 2-AG serve as retrograde messengers [86] acting at presynaptic CB1 receptors localized on both excitatory and inhibitory neurons [87] and the release of 2-AG protects against excessive glutamate release, thereby reducing dopamine neuronal damage [88] during episodes of hypoxia or energy deprivation.

Cannabinoids such as δ−9-tetrahydrocannabinol and synthetic CB1 agonists increase the firing rate of mesolimbic dopaminergic neurons that terminate in the nucleus accumbens and PFC and enhance dopamine synthesis, release and turnover [55], [89], [90]. The mechanism that underpins cannabinoid-mediated mesolimbic dopamine agonism differs from that mediated by stimulants such as amphetamine or cocaine because cannabinoids do not act directly on mesolimbic dopamine neurons. Inhibition of GABA release from interneurons in the nucleus accumbens by exogenous cannabinoids acting at CB1 receptors (on those interneurons) and/or inhibition of glutamatergic pyramidal neurons that excite GABAergic inhibitory interneurons have been proposed as the mechanisms of dopamine agonism by cannabinoids [91], [92]. Cannabis-mediated increases in mesolimbic dopaminergic activity could provide an explanation for the reports of an increase in the relative risk of experiencing psychotic symptoms in healthy individuals who use cannabis [1], and account for the increased sensitivity of schizophrenia patients to the psychotomimetic effects of cannabis [7].

The mesocortical dopamine projection, from the A10 cell group in the VTA to the PFC, is of critical importance for some PFC functions, such as the modulation of attention and working memory [93]. The PFC has a high density of CB1 receptors, and cannabinoids have been shown to modulate the dopaminergic neuronal inputs impinging on PFC neurons [94], [95]. Lower dopamine turnover in the frontal cortex is associated with poor attention in laboratory animals [96], and stimulation of cortical dopamine levels improves their performance [97]. Acute administration of cannabinoid agonists potently increases frontal cortical dopamine metabolism and release [98]. But repeated exposure to CB1 agonists produces an adaptive change that decreases dopamine release in the PFC, but not in other dopamine-rich areas such as the nucleus accumbens or dorsolateral striatum, thus resulting in a functional lesion of the cortical dopamine system [94]. These effects of CB1 agonists in the PFC could provide a mechanism for understanding how chronic use of cannabis can induce cognitive deficits and negative symptoms, but in low doses and if used infrequently may improve cognition (as reported by patients). Thus, in schizophrenia, chronic CB1 activation could exacerbate the effects of pre-existing alterations of dopamine function [99]; that is, decrease mesocortical dopaminergic transmission and reduce D1 receptor density [100], while augmenting mesolimbic dopamine neurotransmission, thereby triggering psychotic symptoms.

GABA hypothesis

A defect in GABA neuronal functioning has been proposed to contribute to the array of disturbances in cognitive functions observed in schizophrenia [101]. Evidence cited in favour of this hypothesis includes: changes in gamma band (40 Hz) synchronization [102], which is a marker of GABA functioning; alterations in markers of cortical GABA neurotransmission in post-mortem schizophrenia studies [103]; and decreased density of GABA interneurons in the cerebral cortex of schizophrenia patients that, in turn, correlates with reduced concentrations of the enzyme responsible for GABA synthesis (GAD67) [104].

GABA interneurons are critical for complex information processing, context representation and maintenance of working memory by the regulation of gating, a process by which pyramidal cell excitation is fine-tuned for efficient information processing and signal transmission to other cortical and subcortical regions. CB1 receptors are localized presynaptically on cortical and hippocampal GABAergic interneurons [105], specifically the cholecystokinin-expressing basket cells [69], [70]. Activation of CB1 receptors reduces GABA release [106], increasing excitatory outputs from pyramidal cells, disrupting the synchronization of pyramidal cell activity [66] and inhibiting the formation of new synapses between hippocampal neurons [107].

Disruption to GABA function in the hippocampus provides a basis for understanding the effects of cannabis in interfering with memory consolidation, associative functions and normal gating mechanisms. Because basket cells form dense axon terminal plexuses on pyramidal neurons, they are critical for orchestrating pyramidal cell synchrony in the gamma frequency range [108]. Oscillations in this high-frequency range ‘bind’ perceptual stimulus features detected by the sensory cortices into coherent perceptions. The coupling of neocortical and hippocampal gamma oscillations binds representations associated with currently perceived and retrieved information [66]. Therefore, augmentation of cannabinoid receptor activation by an overactive endogenous cannabinoid system, or by the use of cannabis, could effectively ‘remove the brakes’ on signalling within and between regions critical for regulating memory and executive functions. Schizophrenia-associated GABA dysfunction may in part explain the particular sensitivity that schizophrenia patients have to cannabis [7], because the drug augments the deficits already present in this disorder.

Glutamate hypothesis

The current formulation of the glutamate hypothesis of schizophrenia proposes that hypofunctional corticolimbic and mesocortical N-methyl-d-aspartate (NMDA) glutamate receptors produce a decrease in the stimulation of inhibitory cortical GABA interneurons [109]. The evidence indicates that schizophrenia patients have altered glutamate metabolism [110] and altered NMDA subunit receptor gene expression [111]. Pharmacological, biochemical and animal model studies support this hypothesis [see [112] for review], and negative, positive and disorganization symptoms that mimic schizophrenia can all be triggered by the administration of antagonists of the NMDA subtype of glutamate receptors (e.g. phencyclidine, ketamine, MK-801) [113].

CB1 receptor activation reduces excitatory glutamatergic neurotransmission from afferent terminals in the VTA, striatum [86], substantia nigra pars reticulata, the subthalamo-nigral pathway [114], and cerebellum [115]. Although CB1 receptors are expressed on inhibitory terminals in the subcortex and cortex, expression on glutamatergic terminals is mostly limited to the subcortex. In the hippocampus, CB1 activation by exogenous cannabinoids disrupts long-term potentiation and long-term depression, and inhibits hippocampal glutamate release [7]. It has been hypothesized that some of the key symptoms of schizophrenia, such as delusions and hallucinations, could be due to altered hippocampal control of cognitive function and sensory gating [116]. Changes in hippocampal function observed in schizophrenia [see [117] for review] may therefore be augmented by the effects of cannabis on the glutamatergic system, and thus account for patients’ vulnerability to the amnesic effects of this drug [7].

Neurodevelopmental hypothesis

Kraepelin argued that some cases of schizophrenia resulted from early cerebral insults, later manifesting as a maldevelopment of the brain [118]. The modern form of the neurodevelopmental hypothesis proposes an interaction between genetic and environmental events during critical early periods in neural growth and development that negatively influence the way neurons are laid down, differentiated and then selectively culled by apoptosis [119]. Because cerebral development is highly dependent upon preceding processes, a disturbance at any one point may alter the developmental trajectory of the subsequent processes. In this way repeated subtle brain insults may accumulate over time that in later life, usually adolescence or early adulthood, may become expressed as schizophrenia.

Proponents of this hypothesis cite as evidence an increased frequency of perinatal complications in schizophrenia, the presence of minor physical anomalies, neurological, cognitive and behavioural dysfunction long before illness onset, and an absence of gliosis in post-mortem schizophrenia brains [120]. Reduced GABAergic neuron cell counts in the cortex, atypical cortical cellular architecture, reduced density of the mesocortical dopaminergic projections to the PFC and altered NMDA subunit expression, have all been cited to support this hypothesis [103], [111]. Finally, the course and outcome of schizophrenia is thought to be incompatible with a purely degenerative illness. For an in-depth review of this topic see [121].

The significance of endocannabinoid signaling for human brain development and the neurodevelopmental hypothesis is underscored by observations of cognitive, motor and social deficits that last into adulthood in the offspring of mothers who smoked marijuana during pregnancy [122], [123]. The Ottowa Prospective Perinatal study found moderate cognitive deficits in exposed children when they were 4 days old and again at 4 years. Exposure was associated with lower scores on executive function tasks affecting self-regulatory abilities such as response inhibition, and at age 13–16 years deficits in sustained attention were detected [124], [125]. At age 18–22 years functional magnetic resonance imaging was used to assess brain activation to a response inhibition task [126]. Response inhibition is a component of executive functioning, requiring the integrity of the dopaminergic systems that subserve the PFC and its connections to the rest of the brain. The authors found increased activity in the right inferior frontal gyrus and premotor cortex and left lateral orbital frontal gyrus, along with decreased activity in the left cerebellum. They concluded that prenatal cannabis exposure affects neural systems involved in response inhibition regulation at least into young adulthood. No association has been reported, however, between maternal cannabis smoking during pregnancy and schizophrenia in the offspring.

The mechanisms that underpin the effects of prenatal cannabis exposure on brain development remain unclear, but clues have emerged from the study of human fetal neural tissue. Wang et al. found that the distribution of fetal CB1 receptor mRNA was distinct from the adult pattern, with a high expression level within regions of the hippocampus and the amygdala [127]. A considerably weaker signal was found in other cortical regions, cerebellum and basal ganglia, which also contrasts with the adult distribution. A subsequent study found that in utero cannabis exposure produced alterations in D2 gene expression in distinct neuronal populations (amygdala) of the human male fetal brain [128]. Although that study was confounded by prenatal exposure to alcohol and nicotine, other recent findings show that endocannabinoid signalling regulates the proliferation, migration, specification and survival of neural progenitors [129–131], dictates the phenotypic differentiation of basket (GABAergic) cell migration and integration [132] and controls the establishment of synaptic communication and remodelling [62], [133] during cerebral development.

Although limited in their generalizability to humans, animal model cannabinoid research has shown that disturbances of endocannabinoid system homeostasis may be of particular significance for our understanding of the neurodevelopmental hypothesis of schizophrenia. Prenatal cannabis exposure in laboratory animals increases CB1 receptor numbers and alters their functioning [134]. The CB1 receptor upregulation resulted in the demasculinization of male animals, cerebral asymmetries, impaired hypothalamic–pituitary functioning [135] and nociception [136], changes in nigrostriatal dopamine system function, and impaired PFC dopaminergic activity [137]. Cannabinoids administered to animal fetuses increased levels of the dopamine synthesis enzyme tyrosine hydroxylase mRNA, the protein and its activity, and disrupted the temporal sequence of events during the development of this neurotransmitter system [138]. Prenatal treatment with cannabinoids resulted in abnormalities in motor activity [139], sociality [140], stress response [141] and cerebral reward mechanisms [142]. The effects of treatment were detected only once the animals were 40 days of age (i.e. adolescence) [134] and the onset of abnormalities was delayed in female animals and less intense than in male animals [143], in striking parallel to the gender differences seen in schizophrenia. Schneider and Koch [144] also found prepulse inhibition deficits, object recognition memory impairments, and anhedonia/avolition in laboratory animals exposed to cannabinoids during puberty, but not in adult rats. Because the prepulse inhibition deficits were reversible with the acute administration of haloperidol, a dopamine receptor antagonist, they concluded that pubertal exposure to cannabinoids could be a model for studying the development of schizophrenia.

Discussion

In the present paper we have focused attention on the significance of cannabis-mediated perturbations of brain function for schizophrenia. This is because until recently, the expansion in our knowledge and understanding of the endogenous cannabinoid system in regulating brain development and function has not been applied to further this debate. Cannabis use is highly prevalent among young people and the association between cannabis and the risk of subsequently developing schizophrenia is consistent, dose dependent and higher if cannabis is used at an early age. There is now evidence demonstrating an association between increased rates of cannabis use and new cases of schizophrenia [46], [47], [49].

The cannabinergic system regulates the development of dopamine systems, the differentiation of GABA interneurons, and the processes that regulate synaptogenesis and neural pruning, as well as the control of short- and long-term plasticity [67], [68]. Early onset cannabis use may interfere with these developmental processes, constituting a neurodevelopmental insult, and account for the association between age of onset of use and an increased risk of later developing schizophrenia. Cannabis augments mid-brain dopamine release, which is known to be associated with the induction of psychosis, and when used in higher doses cannabis suppresses PFC dopamine utilization, resulting in cognitive dysfunction. Evidence suggests that some individuals are particularly prone to these adverse effects of cannabis due to a functional polymorphism of their COMT gene, which reduces their capacity to metabolize dopamine [41].

Cannabis use is a double-edged sword for patients with established schizophrenia. Low doses may actually improve frontal lobe functioning by acutely increasing blood flow to cortices concerned with cognition, mood and perception, and by increasing the availability and utilization of dopamine. These short-term benefits may, however, come at a longer term cost, because continued use depresses cerebral flow to these areas and high doses functionally denervate the mesocortical pathway. The augmentation of mesolimbic dopamine by cannabis opposes the therapeutic effects of antipsychotic drugs, and predisposes to exacerbation of psychosis. Cannabis also enhances glutamatergic activity while suppressing GABA function. Thus the often-reported exacerbation of psychosis and frontal lobe impairment in schizophrenia patients who use cannabis may be attributable to these neurophysiological processes. The significance of the reported alterations to the endocannabinoid system in established schizophrenia remains unclear, but the production of 2-AG by striatal neurons has been found to protect dopamine neurons from excitotoxicity during periods of ischaemia and energy deprivation. This finding suggests that the endocannabinoid changes found in schizophrenia may be a neuroprotective response to an as yet unknown primary pathology.

Conclusion

The risk of psychosis is increased by approximately 40% in people who have used cannabis. There is a dose–response effect, leading to an increased risk of 50–200% in the most frequent users. If having ever used cannabis increases risk of a psychotic outcome by 1.4–2.1-fold [44], [145] (as suggested by pooled analyses), then approximately 14% of psychotic outcomes in young people would not have occurred if cannabis had not been consumed. We do have evidence that cannabis use alters the normal development of the brain dopamine systems, shifts neurotransmitter physiology towards that seen in schizophrenia and reduces frontal and temporal lobe perfusion. By sharpening our research focus on these physiological perturbations and their relationship to the onset and exacerbation of schizophrenia, our understanding of the biological basis of the disorder is likely to be enhanced.

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Cannabis,Cannabinoids and Schizophrenia: Integration of the Evidence

Abstract

Keywords

Cannabis and cognitive dysfunction

Brain imaging in cannabis users

Links between cannabis use and psychosis

Cannabis use in schizophrenia

Endogenous cannabinoid system and changes in schizophrenia

Cannabinoid effects within current hypotheses of schizophrenia

Dopamine hypothesis

GABA hypothesis

Glutamate hypothesis

Neurodevelopmental hypothesis

Discussion

Conclusion

References