Cannabis use is common amongst individuals who are Ultra High Risk (UHR) and those who have already developed psychosis. It has also been reported that 15% of cannabis users, that do not fit into these two categories, experience acute psychotic symptoms. Therefore, the question still remains whether or not cannabis use is a factor for the development of psychosis in any persons, or if its abuse leads to psychosis in individuals already vulnerable to becoming psychotic. This paper will explore this issue and suggest possible directions of research on this subject.
Throughout the last few years, a plausible model has been proposed in which a number of factors are considered for the causes of the development of schizophrenia.[2, 3] This model emphasizes the interaction between genetic and environmental variables, and their influence on neurodevelopment. From an environmental perspective, there is growing evidence that suggests both early, and heavy cannabis use increases the risk for the development of a psychotic disorder such as schizophrenia,[5, 6] which occurs in a dose dependent manner and is especially true for adolescents. Individuals who have exhibited a first episode of psychosis (FEP) or are in the UHR population, and those who are at an increased risk for developing psychosis are more susceptible to cannabis abuse, and have more neuropsychological changes.[8, 9]
Many of the explanations for how the risk of cannabis unfolds to cause symptoms stems from neurobiological and epigenetic research, but there are some studies in the field of neurochemistry, imaging, cognition and genetics that offer possible alternative mechanisms. In spite of these explanations, it is not clear how these changes are inter-linked to produce the psychotic symptoms, and the small number of longitudinal follow-up studies available do not allow for a greater understanding of the long term neurological changes. Nevertheless, the main factors which appear to be involved in cannabis related psychosis are the cannabinoid system, the primary psychoactive component Delta-9- tetrahydrocannabinol (THC) and neuronal development. Studies from the acute effects of cannabis, cannabis users and schizophrenic subjects that abuse and do not abuse cannabis have provided exciting information. In addition to this, both human and animal studies have contributed to this body of information, lending itself to a comprehensive overview of the development of psychosis.
THC, the main metabolite of cannabis, is associated with transient exacerbation in core psychotic and cognitive deficits in patients already diagnosed with schizophrenia. Furthermore, THC might differentially affect schizophrenia patients relative to control subjects; however, it is not yet confirmed if enhanced sensitivity to the cognitive effects of THC affects neuronal cannabinoid receptors or not. THC reaches the brain easily where it stimulates CB1 receptors and their ubiquity underlies a wide variety of effects. Neurocognitive studies suggest that THC inhaled from smoking cannabis is linearly associated with a slower response time in all tasks (simple reaction time, visuo-spatial selective attention, sustained attention, divided attention and short-term memory tasks) and motor control impairment in motor control tasks. Similarly, the number of errors increases significantly with increasing doses in the short-term memory and the sustained attention tasks; however, some subjects show no impairment in motor control even at higher level of THC serum concentrations. The endocannabinoid system modulates neurotransmission at inhibitory and excitatory synapses in brain regions relevant to the regulation of pain, emotion, motivation, and cognition. As such, this system represents a critical player in the maintenance and modulation of synaptic plasticity. During frequent cannabis use, a series of poorly understood neuroplastic changes occur which can lead to the development of dependence. Early onset of cannabis use has been found to be related to increased risk of development of schizophrenia later in life, and leads to impairments in cognitive processes reliant on the circuitry of the dorsolateral prefrontal cortex (DLPFC). Animal models strongly emphasize the long-term influence of prenatal cannabinoid exposure on behavior and mental health. Prenatal, as well as developmental exposure to cannabinoids induces subtle neurofunctional alterations in the offspring.[18, 19] Approximately 4% of women in the United States abuse substances, with marijuana being by far the most common drug used during pregnancy (75%).
Recent evidence suggests that the mesocorticolimbic neuronal circuits remain vulnerable to dysfunction later in life and thus could be sensitive to developmental events and environmental stressors that can influence the onset and course of neuropsychiatric disorders. THC and cannabinoid agonists enhance striatal and mesocorticolimbic dopamine levels, and affect the maturation of the dopamine system which directly regulates motor function, cognition, motivation, and emotional processes.[22, 23] There is ample evidence that cannabis use has a heritable component, yet the genes underlying cannabis use disorders are yet to be completely identified. The evidence of high heritability comes from twin studies. Significant areas for studies are gene-gene and gene-environment interactions. Recent studies indicate the involvement of regions on chromosomes 1, 3, 4, 9, 14, 17 and 18, which harbor candidates of predicted biological relevance.[24, 25] Twin studies have also reported evidence for both genetic and environmental influences on vulnerability, but due to considerable variation in the results it is difficult to draw clear conclusions regarding the relative magnitude of these influences. Studies of systematic literature search show that vulnerability to ‘cannabis use initiation’ as well as ‘problematic use’ was influenced significantly by both shared and unshared environments.[26, 27, 28] The Val158Met polymorphism of the Catechol-O-Methyltransferase (COMT) gene which is involved in dopamine regulation and related to negative symptoms has been previously thought to interact with cannabis use in the modulation of risk of psychosis. The cannabis-COMT interaction showed a significant effect on both duration of untreated psychosis, and age of onset. There are several endophenotypes of cannabis use, for example, cannabis craving and cannabis withdrawal types which have different mechanisms underlying expression of genetic material. Some of the chromosomes involved in these endophenotypes have been identified. It is likely that cannabis suppresses the ‘delay effect’ in gene-environment interactions in vulnerable subjects, more so at an early age and specifically in early onset psychosis. A number of studies have been carried out on patients consuming cannabis with and without psychosis in order to find possible anatomical or structural changes, as well as changes occurring in physiological activity. These studies have also helped in confirming neurochemical changes occurring at receptor sites and neurotransmissions. Long-term users who started regular use in early adolescence have exhibited cerebral atrophy as well as a reduction in gray matter volume. Functional neuroimaging studies have reported increases in neural activity in regions that may be related to cannabis intoxication or mood altering effects such as the orbital and medial frontal lobes, insula cortex, and anterior cingulate cortex. There have also been observed decreases in activity of regions related with cognitive functions during acute intoxication resulting in impairments. These functional studies suggest that resting global and prefrontal blood flow is lower in cannabis users than in controls which is consistent with the observed impairments. Modulation of global and prefrontal metabolism is reduced both during the resting state and after the administration of THC or marijuana but only minimal evidence of major effects of cannabis on brain structure has been reported. Studies of acute administration of THC or marijuana report increased resting activity and activation of the frontal and anterior cingulate cortex during cognitive tasks. The anterior cingulate and amygdala play key roles in the inhibition of impulsive behavior and affective regulation, and studies using PET and fMRI have demonstrated changes within these regions in marijuana smokers.
A family history of schizophrenia may render the brain particularly sensitive to the risk-modifying effects of these substances. Furthermore, light users of cannabis have lower basal BDNF levels, which has been implicated in development of psychosis in general. As proposed by the neuroprotection theory, THC produced psychotomimetic effects, perceptual alterations, and spatial memory impairments; however, the results of several reviews regarding connection between cannabis and cognition remain inconclusive in subjects who go on to develop psychosis[36, 37]
Cognitive dysfunction associated with long-term or heavy cannabis use is similar in many respects to the cognitive endophenotypes that have been proposed as vulnerability markers of schizophrenia. The theoretical and clinical significance of further research in this field is enhancing our understanding of underlying pathophysiology and is improving the provision of treatments for substance use and mental illness. An interesting issue is that adolescent cannabis use, childhood trauma and general predictors of later psychosis are intricately related. In fact, a recent study has shown that there is a greater incidence of Childhood Sexual Abuse (CSA) in the schizophrenic population. Of particular interest is that the risk for schizophrenia increases with urban birth and/or upbringing, especially among males. The mechanism of association is unclear but may be related to biological, social/environmental factors or both, and may have considerable impact before psychotic symptoms manifest. Several psychosocial and environmental factors have synergetic effects on genetic vulnerability in light of gene-environment interactions; some of these factors are: urbanicity in developing countries, cultural
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