4.3 Correlation of socio-demographic and clinical variables with cognitive functioning-
In our study visual copy score was correlated with cannabis frequency and verbal memory deficit was correlated with frequency of cannabis. Verbal memory deficit was negatively correlated with age of onset of cannabis use (Table no 5).
4.4 Endophenotype - Patients with cannabis users have impairment in attention, verbal fluency, verbal and visual memory, executive function compared to HC group suggesting that these domains are ‘disease markers. Subsequently, we found that FDR group performed poorly than HC group in attention (digit backward), semantic verbal fluency and verbal memory; therefore, qualifying for the definition of endophenotype (Figure no 2). Among these parameters, attention and verbal fluency was found close to illness, where performance of FDR was comparable to patients with cannabis use, therefore, qualifying for being a ‘level-1’ endophenotype while verbal memorywere considered ‘level-2 endophenotype.
5. Discussion- We intended to identify candidate cognitive endophenotype for cannabis dependence.
Significant impairment was found in all domains of cognition (attention, verbal fluency, verbal and visual memory, executive function) in patients with cannabis dependence compared to normal healthy controls. Our findings were in sync with previous studies (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). In our study, group of patients with cannabis dependence included all 30 male participants. It would be better if we include female subjects too, but availability was the main limiting factor. To overcome gender as a confounding factor, we have tried not to include any female as a participant in other 2 groups. Across some studies it was found that males are better in visuo-spatial ability whereas females outperform in memory and language (Kieseppa et al., 2005). A study by Bloomfield et al. (2014) assessing cerebral glucose metabolism in cannabis users found that there were significant group differences at baseline frontal metabolism between male and female. Female group showed significant attenuation of regional brain metabolic responses to methylphenidate (dopamine enhancing agent) (Bloomfield et al., 2014). The gender differences suggested that females might be more sensitive to the adverse effects of cannabis in brain. Though in another study, sex differences in cognitive performance were not significant (Bolla et al., 2002).
Attention was assessed across a number of studies and found impaired in patients with cannabis use. Assessment tools were varied across studies, for e.g. digit symbol substitution task (DSST), immediate and delayed digit recall task (DRT) (Ramesh et al., 2013), Useful Field of View (UFOV) task, trail making task (Anderson et al., 2010). A study by Anderson et al (2010) found impaired attention in cannabis users even in frequency of 1-10times/month. In verbal fluency tests, our results replicated findings of study by Pope et al (2003); though in later study there was no significant difference between late onset users (<17 years) and control groups (Anderson et al., 2010). A study by Bolla et al (2002) revealed impaired verbal memory even after 28 days of abstinence from cannabis, compared to non-users. Themes et al (2014) reported more impairment of verbal memory in recent users compared to past users, performance of whom in turn reduced than non-users. In our study we found verbal memory deficit was negatively correlated with age of onset of cannabis use, which is in sync with results of previous studies (Solowij et al., 2011). Bolla et al (2002) found impairment using Rey complex figure—copy test, which is similar to our study and found dose related impairment in patients with cannabis use. There were studies (Thames et al., 2014; Fried et al., 2005) which replicated this finding. Thames et al (2014) used similar tools of our study (Trail making test and Stroop test) to assess executive function and found impairment in cannabis users, especially in recent users. Though assessment tools for executive functions varied like Wisconsin Card Sorting Test and Continuous Performance test (Pope et al., 2003) but the finding were consistent across studies. Besides, cognitive impairment was found more impaired in lower cognitive reserve subjects (Bolla et al., 2002), though this is not a much replicated finding across studies.
Endophenotype refers to certain phenotype (such as here cognitive functioning), which corresponds to certain genes. Here, the functional consequences of risk alleles have been assessed (cognitive functioning) rather than risk gene itself. So, susceptibility gene as well as its associated neurocognitive variables may act as predisposing factor for cannabis use disorders. Patients with cannabis use performed poorly than HC group, which makes it a disease marker; suggesting the possibility of cannabis related impairment in verbal memory. Performance of FDR group in attention, semantic verbal fluency and memory was found inferior to HC group, which fulfills definition of endophenotype. Attention and verbal fluency fulfilled the definition of level 1 endophenotype which is symptom related and may be co-segregated in families. Verbal memory of FDR group lied between patients and HC group, which defined it as a level 2 endophenotype. So, verbal memory impairment was found as symptom which has a segregated genetic pool and independent of disease (state) condition (Tikka et al., 2015).
Some studies previously found impairment of cognitive domains in unaffected biological siblings of substance use disorders. Smith DG et al (2013) assessing executive functioning in stimulant use disorders found significant impairment in siblings of patient compared to normal healthy control. This findings suggested premorbid cognitive impairment might be there to precipitate drug dependence; along with-it impairment of patient group more than siblings group suggested drug induced impairment in cognitive functions. Similar findings were reported by Ersche et al (2012) in patients with stimulant use disorder. Besides, it replicated in patients with alcohol use disorders (Tunbridge et al., 2015; Bo et al., 2019; Tarter et al., 2003). A longitudinal study (Dawes et al., 1997) found that children of patients with alcohol use disorder had poor inhibitory control, which might predict substance use in them. An original study (Euser et al., 2013) explored Error Related Negativity in offspring of individuals with cannabis use disorders and found impairment in them compared to offspring of healthy control group. This could be explanatory in view of deficits in the ability to self-monitor, ongoing behavior for errors or unsuitable actions, arguments; probably because of reduced error salience. So, our study findings were consistent with this study and explored possibility of cognitive endophenotype in cannabis use disorders.
Our study has certain limitations. Power is significantly less because of small sample size. We have included patients with cannabis dependence and assessed their cognitive functions, while other co-morbidities (both physical and psychiatric) were not ruled out in this study. It is a major limitation of this study as in psychiatric disorders, cognitive functioning may be hampered irrespective of substance use. It would be better if various forms (like edible, smoked, intravenous) of cannabis were included, as this could confound the findings. Analysis according to age of onset of cannabis use is lacking in our results because of small sample size. As it is a cross-sectional study so longitudinal relationship between cannabis use and cognitive functioning could not be explored.
As this was a pilot study, which pointed towards possible endophenotype in cannabis use disorders, it can be performed in large sample size. In case of any established cognitive endophenotype, primary prevention of cannabis use disorders may be done for defined population. Unaffected biological relatives should have cognitive screening and further rehabilitation according to their status. Further, psycho-education should be given to unaffected first-degree relatives of patients with cannabis dependence about harmful effects of cannabis and risk of precipitating cannabis use disorders; monitoring for early signs should be explained to them.