Long-term effects of substance use, or cognitive functioning as

As discussed above, a major challenge in the interpretation of the observed cognitive deficits related to substance use disorders is the difficulty to distinguish between the two possibilities of cognitive deficits resulting from the neurotoxicity of substances and differences in cognition antedating the development of substance use disorders (Clark et al. 2008, Rogers and Robbins 2001, Tarter and Edwards 1986, Verdejo-Garcia et al. 2004, Yücel et al. 2007). To gain a better understanding of these two possibilities, evidence from other research paradigms besides comparisons of people with and without substance use disorders needs to be considered.

Studies on neurotoxicity of psychoactive substances

Neurobiological evidence from animal and human studies clearly supports the view that alcohol and other psychoactive substances have neurotoxic effects (Crews and Nixon 2009, Ward et al. 2009). Neuroradiological and neuropathological studies involving people with alcohol dependence have consistently revealed a reduction of the brain white matter volume, arising from changes in extracellular space, changes in the nerve fibers within the white matter or a combination of these mechanisms (Harper et al. 2005). Evidence suggests that alcohol-induced neurodegeneration occurs due to neuronal death during intoxication, related to increases in oxidative stress in the brain (Crews and Nixon 2009, Guerri and Pascual 2010), but also due to alcohol-induced reduction in neurogenesis (Taffe et al. 2010, Tateno and Saito 2008).

Animal studies have found evidence of neurodegeneration and related deficits in memory and executive functioning even after a single binge drinking episode (Nasrallah et al. 2009, Obernier et al. 2002). However, it is also well known that regeneration of brain occurs during abstinence, resulting in brain cell genesis that

can contribute to the return of brain function and reversibility of cognitive deficits during long-term abstinence (see below) (Crews and Nixon 2009, Harper et al.

2005).

Effects of abstinence on cognitive functioning

Many neuropsychological studies of people with a history of substance use disorders have reported only minor cognitive deficits after long-term abstinence (Davies et al.

2005, Davis et al. 2002, Eckardt et al. 1995, Fein et al. 2006). Some cross-sectional studies have not found a relationship between cognitive functioning and length of abstinence or chronicity of substance use disorder (Beatty et al. 2000, Medina et al. 2004), whereas there is strong evidence from longitudinal follow-up studies of people with substance use disorders that performance in many domains of cognitive functioning improves significantly during long-term abstinence (Bates et al. 2005, Manning et al. 2008, Pitel et al. 2009, Rosenbloom et al. 2007, Sullivan et al. 2000, Zinn et al. 2004). However, abstinence may have different effects on different domains of cognition, with memory functions possibly showing greater improvement than executive functioning or general cognitive ability (Bates et al. 2005, Manning et al. 2008, Rosenbloom et al. 2007), and different profiles of improvement may be related to different substances (Di Sclafani et al. 2002). Whether impairments in the functions that show least evidence of recovery have resulted from substance use, or are individual differences independent of substance use, is not clear.

Longitudinal studies on cognitive abilities predicting substance use disorders When considering the possibility that there might be cognitive differences between those who later develop substance use disorders and those who do not, evidence from prospective longitudinal studies is crucial. There has been a number of such studies, and they have in general offered support to the view that poorer cognitive abilities in childhood, adolescence or young adulthood are predictive of elevated risk for substance use and disorders later in life (Fergusson et al. 2005a, Gale et al. 2008, Gale et al. 2010, Jefferis et al. 2008, Mortensen et al. 2005, Osler et al. 2006, Windle and Blane 1989), although some studies have not found this association (Koenen et al. 2009, Whalley et al. 2005). In addition to general or verbal cognitive ability, also attention dysfunction and poor decision making strategies have been reported to increase the risk for later substance involvement (Schilt et al. 2009, Tapert et al.

2002). Further, in addition to these direct measures of cognitive functioning, also differences in childhood and adolescent school achievement—known to correlate with general cognitive ability (Deary et al. 2007)—has been found to predict differences in substance use and problems (Ensminger et al. 2002, Fothergill and Ensminger 2006, Poikolainen et al. 2001).

Studies of individuals at high risk for substance use disorders

Further evidence for cognitive deficits not resulting from substance use comes from studies of children and adolescents at elevated biological risk for substance

use disorders. These studies have typically used samples of individuals whose first-degree relatives have a history of substance use disorders, and have found that compared to control participants these high-risk individuals tend to show poorer performance in a range of cognitive functions including general and verbal cognitive ability (Aytaclar et al. 1999, Bates et al. 2002, Corral et al. 1999, Corral et al. 2003, Drejer et al. 1985, Fals-Stewart and Bates 2003, Faraone et al. 2007, Finn and Hall 2004, Gabrielli and Mednick 1983, Keenan et al. 1997, Knop et al. 2003, Poon et al.

2000, Sher et al. 1991, Shoal and Giancola 2001, Tarter et al. 1989, Tarter et al. 2003, Turner and Parsons 1988). While maternal history of substance use disorders may be more strongly predictive of cognitive deficits than paternal history, possibly in part due to prenatal exposure (Cottencin et al. 2009), many of these studies have excluded participants with early-onset maternal substance use disorders. In addition, some studies have found differences in the offspring of parents with only substance use disorders compared to offspring of parents with substance use disorders and comorbid antisocial personality disorders (Gillen and Hesselbrock 1992, Nigg et al. 2004). Besides cognitive deficits, also lower academic achievement among children of parents with substance use disorders has been reported (Knop et al.

1985, McGrath et al. 1999). Interestingly, a recent study reported that rats selectively bred for ethanol preference performed poorer in a working memory task than those bred for nonpreference, giving some additional evidence of cognitive impairments before onset of substance use in individuals at high biological risk for substance use disorders (Wenger and Hall 2010).

Cognitive functioning in comorbid conditions

Of relevance to the question of pre-existing cognitive differences are also studies on cognitive functioning related to behavioral and psychopathological traits that increase the risk for substance use disorders. Importantly, several studies have found associations between poorer neurocognitive functioning and childhood behavior problems, impulsivity, aggression and antisociality (Barker et al. 2007, de Wit et al.

2007, Finn et al. 2009, Plomin et al. 2002, Raine et al. 2005, Russo et al. 2008, Seguin et al. 2004, Seguin et al. 2009). Strikingly, significant negative correlations between language development already during the first two years of life and participating in criminal behavior in adolescence have been reported (Stattin and Klackenberg-Larsson 1993). In addition, the overlap between externalizing problems and academic underachievement in childhood and adolescence is well documented, with general cognitive ability and language deficits as possible antecedent variables (Hinshaw 1992). A further comorbidity-related finding is that also cigarette smoking is associated with a variety of cognitive functions and general intelligence (Caspers et al. 2010, Friend et al. 2005, Greenstein and Kassel 2009, Weiser et al. 2010), and a recent twin study found no evidence of a causal relationship between smoking and IQ (Wennerstad et al. 2010). Smoking has been found to be one factor associated with and possibly explaining some of the cognitive deficits in alcohol use disorders (Ceballos 2006, Durazzo et al. 2007, Glass et al. 2006, Glass et al. 2009).

In summary, a bulk of research suggests that alcohol and other substance use disorders are associated with deficits in several cognitive functions, possibly reflecting more general cognitive abilities. There is neurobiological evidence that these differences in cognition may reflect neurotoxic effects of heavy alcohol and other substance use, but strong evidence also exists from various research paradigms for pre-existing differences in general cognitive abilities. However, neuropsychological studies on substance use disorders have often used clinical samples combined with selected groups of control participants, and there is a lack of representative population-based studies. In the present thesis, the associations of alcohol and other substance use disorders with verbal cognitive ability and other cognitive functions were investigated in a population-based sample of Finnish young adults (Study II).

The contribution of underlying genetic and environmental factors to the association between alcohol dependence and cognitive functioning was further investigated in an independent sample of young adult twins (Study III).

2.4 Twin studies of substance use disorders and