Abstract
Introduction - Cannabis use disorders are global emerging problem nowadays, with high prevalence and morbidity. Though cognitive impairments are one of the most replicated findings in individuals with cannabis dependence, but there are very few studies assessed cognitive functioning as a risk factor for cannabis use disorder. In this study, we assessed cognitive functioning as an endophenotype in cannabis use disorders.
Methodology- In this study comparison of cognitive functioning was done among three groups- patients with cannabis dependence syndrome, their first degree relative (FDR) and normal healthy controls (HC). Each group included 30 participants. Individuals of all three groups were assessed in domains of complex attention, executive functions, language, learning and memory and perceptual-motor.
Results- Performance of patients with cannabis dependence was impaired in attention, verbal memory, executive functions compared to both other groups. Attention, semantic verbal fluency and memory were found to be an endophenotype as both patient and FDR group performed poorly than HC group. Verbal memory was impaired in patients’ group compared to group of first-degree relatives, whose performance in-turn impaired than normal healthy controls. Performances of verbal and visual memory were correlated positively with age of onset and negatively with frequency of cannabis intake. Age of first-degree relatives was inversely correlated with verbal memory.
Conclusion - Performance of individuals with cannabis dependence was impaired than normal healthy controls in all domains of cognitive functioning. As per definition, verbal memory could be considered as an endophenotype marker in cannabis use disorders.
1. Introduction- Cannabis is a widely used psychoactive substance all over the world. According to a global epidemiological study by Degenhardt et al. (2013), point prevalence of cannabis use disorders was 0.2% and it contributed to 0.08% of total DALY loss. A recent epidemiological survey revealed 2.8% of Indian population was currently using cannabis whereas 0.25% met diagnosis of cannabis dependence syndrome (Ambekar et al., 2019).
Cannabis use modulates certain neuro-physiological changes; through activation of cannabinoid (mainly type 1, CB1) receptors. These CB1 receptors were widely distributed in central nervous system and implicated in second messenger systems, protein signaling pathways, reward pathways, regulation of some neurotransmitters like GABA and dopamine (Kinsey and Lichtman, 2019). Widespread action might be responsible for dependence or psychological effect. Among many risk factors, genetics play an important role in precipitating dependence and other psychological effect of cannabis. There are certain genetic polymorphisms which (The catechol-O-methyltransferase gene: COMT (Henquet et al., 2006; Tunbridge et al., 2015; Freyberg et al., 2010), The AKT serine/threonine kinase 1 gene: AKT1 (Niizuma et al., 2009; Ozaita et al., 2007; Sánchez et al., 2003; Bhattacharyya et al., 2014; Hess et al., 2009), The dopamine ß-hydroxylase gene: DBH (Zabetian et al., 2001; Ramaekers et al., 2016; Sharpley et al., 2014), The serotonin transporter gene: 5-HTT/SLC6A4) (Canli and Lesch, 2007; Verdejo-García et al., 2013; Dalley et al., 2004) predispose individual with cannabis use to dependence or psychosis or cognitive impairment. So, there may be chance of familial predisposition of cannabis use.
Use of psychoactive substances could impair brain circuits responsible for executive control (Dalley et al., 2004; Goldstein and Volkow, 2002), specifically response inhibition (Fillmore and Rush, 2002; Monterosso et al., 2005), mental planning (Ersche et al., 2006; Ornstein et al., 2000), working memory (Tomasi et al., 2007; Ersche et al., 2011a; Fernández-Serrano et al., 2010), and attention control (Gooding et al., 2008; Ersche et al., 2011b; London et al., 2005). There are a number of studies regarding effect of cannabis on cognitive functioning (Cami and Farré, 2003; Fletcher et al., 1996; Pope and Yurgelun-Todd, 1996; Whitlow et al., 2004; Solowij et al., 2002; Grant et al., 2003; Croft et al., 2001; Bolla et al., 2002; Bartholomew et al., 2010). Cannabis use was found to be associated with impairment in cognitive domains such as- sustained attention, response monitoring, decision making and memory. Most of the studies emphasized heavy and long term use of cannabis for such impairments (Cami and Farré, 2003; Fletcher et al., 1996; Pope and Yurgelun-Todd, 1996; Whitlow et al., 2004; Croft et al., 2001). Heavy use of cannabis and related neuro-anatomical and neuro-physiological changes (Arnone et al., 2008; Zalesky et al., 2012) were reported as predictors of cognitive impairments in some studies (Bolla et al., 2002; Arnone et al., 2008; Zalesky et al., 2012). Specially, learning and memory deficits were impaired in heavy and long term cannabis users, which was in tandem with hippocampal attrition (Grant et al., 2003; Yucel et al., 2008). Pope et al (1996) reported residual cognitive effect in patients with cannabis dependence even in abstinence, though it was negligible after 28 days of abstinence. Fontes et al (2011) reported cognitive impairments were inversely correlated with age of onset of cannabis use. In spite of advance neurobiological findings, biological underpinning of cannabis use disorders is still obscure. Emerging data suggested that biological relatives of patients with substance use have higher risk of developing drug dependence in future (Merikangas et al., 1998; Ersche et al., 2012).
So, the possibility of pre-morbid risk of drug dependence cannot be ruled out. Identification of biological vulnerability markers provides a scientific basis for development of effective preventive and therapeutic strategies for individuals at risk.
Studies are lacking in the field of preexisting vulnerability in addiction especially in cannabis use disorders.
The concept of endophenotype offers a useful strategy for evaluating the underlying factors that makes an individual vulnerable to any psychiatric disorder as well as substance use. Endophenotype have been defined as quantitative traits that are intermediate between the predisposing genes (genotype) and the clinical symptoms (phenotype) of a complex disorder. According to the criteria outlined by Gottesman and Gould, endophenotypes are quantifiable traits which 1) associated with the disorder; 2) genetically determined; 3) largely state independent (i.e., they should manifest in periods of health and during acute illness); 4) segregate with the disorder within families; and 5) overrepresented in unaffected family members relative to the general population (Gottesman and Gould, 2003; Gould and Gottesman, 2006). Based on proximity of deficit, endophenotypes are divided further into two levels- ‘level 1’- degree of deficit in FDR group is almost similar to patient probands; and ‘level 2’- degree of deficit in patient group is impaired significantly than FDR group (Tikka et al., 2015).
In our study, cognitive functions were assessed as a putative endophenotype for cannabis dependence. Relation of cognitive functioning and cannabis exposure could be bidirectional; such as, impaired cognitive functioning could be result of chronic or early cannabis exposure, or impaired cognitive functioning makes an individual vulnerable for cannabis use.
So, in this study the mentioned domains of cognition were assessed and comparison was done among three groups- patients with cannabis dependence, their un-affected first-degree relatives and normal healthy controls.
2. Methods- The study was done in a tertiary care hospital in central India. Patients were recruited from outpatient and in-patient in department of psychiatry attending in the hospital. The study was done among three groups, patients with cannabis dependence syndrome, their first-degree relatives (FDR) and normal healthy controls (HC). 30 participants were included in each group (95%CI and 65%Power). For participants of all three groups’ age range remained restricted to 18 to 45 years and 8 years of formal education. Patients were included as per ICD 10 diagnostic criteria for cannabis dependence. In our study patients with cannabis dependence were included who had positive urine screening for cannabis as well as on the basis of self-reporting. All participants in FDR and HC groups were screened by GHQ 5 to rule out any mental disorder. Moreover, any participant of all three groups was excluded to take part in the study if dependence criteria of any substance were fulfilled except tobacco and caffeine. Participants from HC groups were excluded if they had any family history of Alzheimer’s disease, mental retardation & organic brain disease, substance use disorder (except for tobacco & caffeine). Informed consent was taken from each participant (Flowchart shown in Fig 1).
Primary objective of this study was to assess and compare cognitive functioning among patients with cannabis dependence syndrome, first degree relatives & normal healthy controls. Secondary objective was to look for association and correlation between the degree of cognitive functioning in three groups (patients with cannabis dependence syndrome, first degree relatives & normal healthy controls) and their socio-demographic & clinical variables.
Attention and concentration, language, memory and executive functions were tested across three groups (Table no 1).