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).