Long-term cannabis use
increased risk of psychosis?
Cognitive impairments that ensue with long-term cannabis use are well documented (Solowij 1995a, Solowij 1991, Solowij 2011a, Solowij 1995b, Solowij 2002) and evidence is emerging that suggests an infl uence in the development of psychosis and schizophrenia (Di Forti 2009, Leweke 1999, omas 1996, Tien 1990, van Os 2002). ough the risks of acquiring mental illness from long term daily or near-daily cannabis use remains a debate between the proponents of its legislation and its partisans of continued prohibition (Hall 1994), there is an emerging body of evidence that researchers implore not be ignored. Studies have surfaced that clarify the understanding of the eff ects of cannabis use on the brain and that have quantifi ed the extent of the risks of long-term use (Leweke 2008, Murray 2007).
The Endocannabinoid System
Historically, explanation of reports of adverse eff ects associated with cannabis consumption, including psychotic episodes have been signifi cantly hindered by a lack of knowledge regarding their underlying neurobiological and pharmacological processes (Leweke 2004). However, the discovery of the endogenous cannabinoid system in the late 1980s has assisted in elucidating the molecular basis of cannabis, the action of cannabis and cannabinoids in the brain, and the relationship these cannabinoids have with psychotic symptoms and disorders (Leweke 2004).
The cannabinoid-1 (CB1) receptor has been discovered as the target for delta-9-tetrahydrocannabinol (Delta-9-THC) in the rat brain (Devane 1988). Delta-9-THC was the fi rst exogenous cannabinoid CB1 activator that was isolated from preparations of the cannabis sativa plant. Subsequently, two endogenous ligands for this receptor were identifi ed: anandamide and 2-arachidonylglycerol (2-AG). In recent years, many studies have investigated the CB1 receptor and the endogenous cannabinoid system (Elphick 2001, Fernandez 1997, Giuff rida 2000, Howlett 1995, Manzanares 1999, Schlicker 2001, Wilson 2002). Studies on various mammals have found that the anatomical distribution of the CB1 receptor is highly consistent among diff erent species (Herkenham 1990, Herkenham 1991, Matsuda 1993), concentrating in parts of the limbic system (particularly the hippocampus and the amygdala) and in the cerebellum (Solowij 2011b).
On a functional level, CB1 receptors are activated by endogenous cannabinoids such as anandamide and 2-AG at the presynaptic nerve terminal. Binding of these cannabinoids leads to a decrease in membrane permeability to calcium and potassium ions, as well as to a decrease in the activity of adenylate cyclase, thereby inhibiting the release of glutamate, dopamine, acetylcholine, and noradrenaline (norepinephrine) (Leweke 2004). GABA reuptake is also inhibited (Leweke 2004).
A role for the Endocannabinoid System in Psychosis and Schizophrenia
Since the discovery of the endocannabinoid system, a growing body of psychiatric research has focused on the role of this system in major psychiatric disorders (Leweke 2004). Evidence suggests that cannabinoid receptors, the pharmacological target of cannabis-derived drugs, and their accompanying system of endogenous activators may be dysfunctional in schizophrenia (Leweke 1999). Leweke et al purifi ed and quantifi ed endogenous cannabinoids from cerebrospinal fl uid (CSF) of 10 patients with schizophrenia and 11 non-schizophrenic controls. It was found that CSF concentrations of two endogenous cannabinoids (anandamide and palmitylethanolamide) were signifi cantly higher in schizophrenic patients than in non-schizophrenic controls (Leweke 1999). ese elevated endogenous cannabinoids in schizophrenic patients are thought to refl ect an imbalance in the endogenous cannabinoid signalling, which may contribute to the pathogenesis of schizophrenia (Leweke 1999).
Koethe (2009) explored the proposed homeostatic role of anandamide in schizophrenia. eir study included subjects not yet diagnosed with schizophrenia, but exhibiting signs of psychosis. CSF anandamide levels were assessed in subjects in this prodromal state of psychosis and in healthy volunteers. Results revealed that anandamide levels in subjects in the prodromal state were signifi cantly elevated and that those with lower levels of anandamide actually showed a higher risk for transiting to psychosis earlier. is anandamidergic up-regulation in the initial prodromal course may suggest a protective role of the endocannabinoid system in early schizophrenia (Koethe 2009), refl ecting a compensatory adaptation to the disease state (Giuff rida 2004). at CSF anandamide levels correlate inversely with psychotic symptoms suggests that anandamide release into the central nervous system may serve as an adaptive mechanism countering neurotransmitter abnormalities in acute psychosis (Leweke 2007).
Guiff rida and colleagues researched the infl uence that pharmaceutical treatment had on anandamide levels in patients with schizophrenia compared to anti-psychotic naïve individuals suff ering a fi rst-episode psychosis to further understand the relationship between the endocannabinoid system, neurotransmission and psychosis. ey found that individuals with schizophrenia treated with ‘typical antipsychotics’ (antagonists of the dopamine D2-like receptor) did not have the same elevations in anandamide levels, though individuals with schizophrenia treated with ‘atypical’ antipsychotics (antagonists of 5HT(2A) receptors) did (Giuff rida 2004). ese fi ndings are congruent with the hypotheses concerning the interactions between cannabis, endocannabinoids, and dopamine whereby cannabisinduced dopamine dysregulation may give rise to delusions and hallucinations (Kuepper 2010). Kuepper (2010) provide a review of possible dopamine pathways in psychosis based on animal research that suggests that delta-9-THC increases dopamine levels in several regions of the brain; however, such discussion, in its complexity, goes beyond the scope of this article.
The Relationship Between Cannabis Use, Psychosis and Schizophrenia
The consensus in the literature regarding the association between psychosis, schizophrenia, and cannabis use is one that is congruent with the vulnerability/stress model of schizophrenia developed by Nuechterlein and Dawson (Nuechterlein 1984). at is, cannabis is considered one stress factor among others that may either enhance or trigger schizophrenic symptoms (Leweke 2004). A community survey on the early course and onset of schizophrenia in Germany was able to diff erentiate three approximately equal sized groups of patients with cannabis-associated psychosis: patients who had been using cannabis for several years before the fi rst (prodromal) signs of schizophrenia emerged, patients who had experienced the onset of both cannabis use and schizophrenia within one month of each other, and patients who had started to use cannabis after the onset of symptoms of schizophrenia (Hambrecht 2000). According to Lousia Degenhardt & Wayne Hall (2002) “it is unlikely that cannabis use causes psychosis among persons who would otherwise not have developed the disorder. e evidence is more consistent with the hypotheses that cannabis use may precipitate psychosis among vulnerable individuals, increase the risk of relapse among those who have already developed the disorder, and may be more likely to lead to dependence in persons with schizophrenia”. Additionally, Degenhardt, Hall and Lyndskey (2003) state that “cannabis use does not appear to be causally related to the incidence of schizophrenia, but its use may precipitate disorders in persons who are vulnerable to developing psychosis and worsen the course of the disorder among those who have already developed it”.
Difference between delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD): Regional Brain Function and Neurophysiology
Data on the underlying composition of the herbal preparations (ie. the diff erent natural cannabinoids present) or on the plasma levels of delta-9-THC, are generally not provided in retrospective clinical studies (Leweke 2004). Generally, the term ‘cannabis’ in the literature refers to all herbal cannabis preparations with a poorly defi ned mixture of diff erent natural cannabioids. Only when a concentration is given or when a precise term is used can it be certain that the eff ects of a specifi c cannabinoid are being studied (Leweke 2004). It is important to note that delta-9-THC and cannabidiol (CBD), the two most common exogenous cannabinoids, have distinct symptomatic and behavioural eff ects (Bhattacharyya 2010). Where delta-9-THC impairs reaction on movement and response-inhibition tasks, causes acute psychotic symptoms, and destabilizes brain function, CBD does not impair performance or induce psychosis, appears to reduce anxiety, and stabilizes brain function (Fusar-Poli 2009).
Functional magnetic resonance imaging (fMRI) was used in healthy volunteers to examine whether delta-9-THC and CBD had opposite eff ects on regional brain function in healthy volunteers with minimal cannabis exposure (Bhattacharyya 2010). Subjects were scanned on three occasions following oral administration of delta-9-THC, CBD or placebo while performing a verbal memory task, a response inhibition task, a sensory processing task, and when viewing fearful faces. Results revealed that delta-9-THC and CBD have opposite eff ects on activation relative to placebo (1) in the striatum during verbal recall, (2) in the hippocampus during the response inhibition task, (3) in the amygdala when subjects viewed fearful faces, (4) in the superior temporal cortex when subjects listened to speech, and (5) in the occipital cortex during visual processing (Bhattacharyya 2010). Using an eventrelated paradigm with faces that implicitly elicited diff erent levels of anxiety, Fuser-Poli et al demonstrated distinct eff ects of delta-9-THC and CBD on neural activation with fMRI and electrodermal response during emotional processing further validating their dissimilar consequences on regional brain function (Fuser-Poli 2009). CBD attenuated the neurofunctional engagement of the amygdala and cingulated cortex and reduced the electrodermal response when subjects viewed intensely fearful stimuli, verifying its anxiolytic eff ects. Alternatively, delta-9-THC modulated activation in frontal and parietal areas and augmented the electrodermal response; eff ects validating an increase in anxiety (Fusar-Poli 2009).
These diff erences in the behavioural eff ects of delta-9-THC and CBD are paralleled by diff erences in their mechanisms of action at the molecular level (Fusar-Poli 2009). Delta-9-THC binds to neuronal CB1 receptors (Devane 1992), which are found on GABAergic and glutamatergic neurons throughout the brain (Braida 2007, Herkenham 1990, Mechoulam 2003). CBD has a very low affi nity for the cannabinoid CB1 receptor (Petitet 1998).
Brain Abnormalities and Long-term Heavy Cannabis Use
There exists confl icting evidence concerning structural consequences of long- term cannabis use on the brain. A series of preclinical investigations demonstrated induction of neurotoxic changes in the hippocampus (Chan 1998, Landfi eld 1988, Lawston 2000, Scallet 1987) leading to further investigation in human trials. Yucel et al conducted a region-of-interest-based analysis using high resolution 3 Telsa magnetic resonance imaging (3-T MRI) to assess volumetric changes in the hippocampus and the amygdala (Yucel 2008). Subjects who were non-using healthy male volunteers and those with a long history of cannabis use were carefully screened for polysubstance abuse and mental disorders as well as for subthreshold psychotic symptoms and verbal learning abilities. Findings in this study corroborate with the above cited animal research suggesting that long-term heavy cannabis use is associated with signifi cant and localized hippocampal volume reductions that relate to increasing cumulative cannabis exposure (Yucel 2008). Bilateral reduction in amygdala volume was also seen (Yucel 2008). Long-term heavy cannabis use and its association with smaller cerebellar white-matter volume similar to that observed in schizophrenia has also been shown (Solowij 2011b). Reduced volumes were more pronounced in patients with schizophrenia who use cannabis, but were apparent in healthy individuals with a cannabis use history as well (Solowij 2011b). ese fi ndings indicate that heavy cannabis use across protracted periods exert harmful effects on brain tissue, and subsequently on mental health (Yucel 2008).
Vulnerability and Genetics
Compatible with the vulnerability/stress model of schizophrenia, gene-environment interactions involving the catechol-Omethyltransferase Valine(158)Methionine polymorphism (COMT(Val158Met)) have been implicated in the causation of psychosis (van Winkel 2008). In a stress exposure study in members of the Greek army, carriers of the COMT Val158Met allele were more susceptible to the eff ects of stress on the psychosis outcome than those with the catechol-O-methyltransferase Methionine(158)Methionine genotype (Stefanis 2007). In addition, carriers of the COMT Val(158)Met allele were more likely to exhibit psychotic symptoms and to develop schizophreniform disorder if they used cannabis; whereas cannabis use had no such adverse influence on individuals with two copies of the methionine allele (COMT(Met158Met)) (Caspi 2005).
Cannabis use in adolescents is another gene-environment factor that increases the likelihood of experiencing symptoms of schizophrenia in adulthood (Arseneault 2002). After controlling for pre-existing psychotic symptoms, it was found in the Dunedin Multidisciplinary Health and Development study from New Zealand that cannabis use increased the risk of developing symptoms of schizophrenia in this cohort (Arseneault 2002). One-tenth of those in this sample who were using cannabis by the age of 15 years had developed a schizophrenia-like disorder by the age of 26 years. Onset of cannabis use prior to the age of 15 years conferred the greatest risk of subsequently developing schizophrenia. This increased risk was specific to cannabis use as opposed to the use of other drugs (Arseneault 2002). Two large studies, one out of Greece in 2004 (n=3500) (Stefanis 2004) and another out of the Netherlands in 2005 (n=2437) (Henquet 2005) found results adding credence to the hypothesis that cannabis use early in adolescents contributes to the risk of developing psychosis, particularly in those with a predisposition.
Conclusion
There is sufficient evidence that cannabinoids can induce acute transient psychotic symptoms or an acute psychosis in some individuals (Sewell 2010). It is also clear that cannabinoids can exacerbate psychosis in individuals with an established or predisposed psychotic disorder, and that these exacerbations may last beyond the period of intoxication (Sewell 2010). When these symptoms are present in a clinical setting, the practitioner should not hesitate to inquire about cannabis use, educating the patient about the possible risks involved as evidenced epidemiologically.
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