Abstract

Introduction

Alcoholism is a common psychiatric disorder that has devastating consequences for afflicted individuals, their families and for society in general. The lifetime prevalence of alcoholism (alcohol dependence and abuse) is 30% (Hasin et al. 2007). It is well established that the heritability (the genetic component of the variance) of alcoholism is around 50%; similarly, the heritability of cocaine and opiate addiction is around 60 – 70% (Goldman et al. 2005). Therefore genetic and environmental influences on the development of addictive disorders are equally important although the proportions of risk may vary according to societal groups. For example, in populations exposed to severe current and historical trauma such as some Native American tribes and Australian aboriginal groups, environmental stressors can swamp genetic influences.

An important risk factor for alcoholism or drug dependence is having a parent with the disorder. A prospective New Zealand birth cohort of nearly 1000 individuals has shown that family history is a strong predictor of alcohol and drug dependence and is associated with a more recurrent course, worse impairment but not younger age of onset (Milne et al. 2009). It is a well established fact that stressors experienced in childhood, particularly childhood maltreatment, are also predictors of adult psychopathology, including addiction to alcohol and drugs. Although the genetic risk for externalizing disorders, including alcohol and drug dependence, transmitted from parents to child influences both the likelihood that the child will be exposed to early life stress and will develop the disorder, nevertheless numerous studies, some of which are described below, have shown that stressors in childhood have an independent effect on the risk for adult alcohol and drug dependence (Anda et al. 2002; Eaves et al. 2010; Verona and Sachs-Ericsson 2005).

This review will look at exposure to early life stress as a specific predictor for adolescent and adult alcohol and drug dependence and will focus on studies in humans, non-human primates and rodents that have shown that early life stress is associated with neurohormonal and hypothalamic-pituitary-adrenal (HPA) axis changes, morphological changes in the brain and gene expression changes in the mesolimbic dopamine (DA) reward pathway, all of which are implicated in the development of addiction. A large proportion of children who are exposed to early life stress do not go on to develop psychopathology therefore this review will discuss risk-resilience factors, including gene-environment interactions. Other pertinent questions will be addressed in this review: are there factors that maximize the effects on addiction vulnerability such as the nature of the stressor (childhood maltreatment, stressful life events), specificity of stressors for addiction, acute or chronic exposure, severity, timing (critical time period for influence on brain development?) and sex differences in effects of stressors?

Alcoholism and Drug Dependence; Definition and Prevalence

Addiction to alcohol and drugs has been described as a perpetual cycling of preoccupation and anticipation, binge/intoxication and withdrawal/negative affect (Koob 2003). The essential features of addiction are loss of control over consumption, obsessive thoughts about the drug and continuation of use despite knowledge of negative health and social consequences (American Psychiatric Association 1994). Both positive (euphoric) and negative (anxiolytic) reinforcement are features of addiction. Negative reinforcement tends to become the driving force as the disease progresses.

Results from a nationally representative sample of U.S. adults (NESARC, N = 43,093) have shown that the prevalence of lifetime DSM-IV alcohol dependence (AD) and alcohol abuse (a less severe from of addiction) is 12.5% and 17.8% respectively (Hasin et al. 2007). Lifetime alcohol use disorders (abuse + dependence, AUD) are twice as common in men (42%) as women (19.5%) (Hasin et al. 2007). The same survey looked at the prevalence of dependence and abuse across classes of drugs including cocaine, cannabis, heroin and other opiates, tranquilizers, sedatives, stimulants, hallucinogens and inhalents/solvents. The prevalence of lifetime DSM-IV drug dependence was 2.6% and drug abuse was 7.7%. Unlike AD, the prevalence of drug dependence was similar in men (3.3%) and women (2.0%) (Compton et al. 2007). Since AUD is a much more widespread problem in society, this addiction will be the predominant focus of this review.

Early Life Stress; Definition and Prevalence

For the purposes of research, early life stress can be compartmented into childhood maltreatment and stressful life events (SLE) although in reality there is considerable overlap between the two (see below). The degree of risk for adult psychopathology tends to be correlated with the severity of childhood maltreatment (see below) and the number of childhood SLE (Afifi et al. 2008; Enoch et al. 2010a; Jaffee et al. 2007; Pilowsky et al. 2009). Cumulative SLE experienced in adulthood have also been shown to have pathological effects (Blomeyer et al. 2008; Caspi et al. 2003; Covault et al. 2007; Schmid et al. 2009). Children tend to experience SLE alongside family members and friends. In contrast, childhood maltreatment: physical abuse and neglect, emotional abuse and neglect and sexual abuse (CSA), is directed at children and can be experienced in isolation and over an extended period of time (Goldman et al. 2003; Goodman-Brown et al. 2003).

Exposure to SLE is common in the general population; for example, a nationally representative U.S. sample of 9282 adults, The National Comorbidity Survey Replication (NCS-R), reported that 53% of adults had experienced some kind of stressor before the age of 18 (Green et al. 2010), the most common being parental divorce (17.5%), family violence (14%), economic adversity (11%), parental death (10%) and mental illness (10%). Childhood maltreatment is also common although reported prevalence varies depending on several factors including definition (Caspi et al. 2010), population sampled (Simpson and Miller 2002), survey methods (Arnow 2004) and whether data is obtained longitudinally or retrospectively. Most studies on early life stressors have been performed retroactively, therefore recall bias can be an issue. It has been shown that individuals, particularly over the age of 65, often under-report when questioned retroactively about exposure to childhood abuse (Fergusson et al. 2000; Green et al. 2010). Bearing this in mind, data from the NCS-R reveals the following prevalences: physical abuse 8.4%, CSA 6%, and parental neglect 5.6% (Green et al. 2010). Higher prevalences have been reported in other studies. A general population survey showed that 31% of men and 21% of women reported a history of childhood physical abuse while 4% of men and 13% of women had been exposed to CSA (Holmes and Slap 1998; Macmillan et al. 1997). A random U.S. sample of 935 individuals revealed that 22% of men and 20% of women reported childhood physical abuse and 14% of men and 32% of women reported CSA whereas 21% had experienced both types of abuse (Briere and Elliott 2003). In a retrospective cohort study on 17,337 adult U.S. HMO members, contact CSA was reported by 16% of men and 25% of women (Dube et al. 2005). In a U.S. nationally representative sample of approximately 1000 women aged 21 and older, prevalence rates for CSA (Russell criteria) experienced below the age of 18 ranged from 15% to 26% (Vogeltanz et al. 1999). Some populations experience even higher rates of childhood maltreatment. A study across six Native American tribes with high rates of lifetime AD reported that 35–70% of men and 40–56% of women had experienced physical abuse in childhood; 17–40% of men and 24–53% of women had been exposed to CSA and 13–40% of men and 30–49% of women had experienced childhood emotional abuse (Koss et al. 2003). Similarly, in a Southwestern American Indian tribe, clinical interviews elicited the fact that 14% of men and 49% of women had experienced contact CSA, more than half before the age of 10 and more than half with intercourse (Robin et al. 1997).

Children who are subjected to early life stress are often exposed to multiple stressors (Dong et al. 2004; Ney et al. 1994) Childhood maltreatment often emerges from disturbed and disrupted family backgrounds (Mullen et al. 1996). The NCS-R revealed that 95% to 88% of individuals who had experienced parental neglect and physical abuse respectively, and 72% exposed to sexual abuse had been subjected to multiple early life stressors (Green et al. 2010). Older studies have generally reported on only one or two forms of childhood maltreatment, notably CSA and physical abuse, but more recent studies have used newly developed measures including the Childhood Trauma Questionnaire (Bernstein et al. 2003) and the Early Trauma Inventory (Bremner et al. 2007) to assess various maltreatment types and their cumulative effect.

Early Life Stress as a Predictor of Psychopathology

Numerous studies have shown that childhood maltreatment and SLE predict a wide range of adverse physical and emotional health outcomes, psychopathology including alcoholism and drug dependence, socioeconomic disadvantage and an increased risk for physical assault and rape in adulthood (Arias 2004; Arnow 2004; Bulik et al. 2001; Caspi et al. 2002; De Bellis 2002; Dube et al. 2005; Hyman and Sinha 2009; Kendler et al. 2000; Poulton et al. 2002; Simpson and Miller 2002; Sinha 2001; Walker et al. 1999; Yuan et al. 2006). The NCS-R study identified three meaningful factors: (a) maladaptive family functioning, including parental substance abuse, criminality, domestic violence, childhood abuse and neglect; (b) parental death and other loss and (c) parental divorce, both with associated economic adversity. The maladaptive family functioning stressors were the strongest correlates of onset of psychopathology (Green et al. 2010). Little specificity has been found for the association of particular types of childhood maltreatment and SLE with particular psychiatric disorders (Green et al. 2010; Kendler et al. 2000). Also, a study in 17,337 U.S. HMO members has shown that the long-term impact of CSA on multiple health and social problems is similar for both men and women (Dube et al. 2005).

Predictably, the severity of childhood maltreatment is positively correlated with poorer outcomes in adulthood (Arnow 2004; Bulik et al. 2001; Caspi et al. 2002; Ducci et al. 2009; Kendler et al. 2000; Robin et al. 1997). For example, in a population based sample of 1411 female adult twins, 30% reported CSA of whom 8% reported severe CSA (intercourse before age 16) and this group of women experienced a greater risk for psychopathology: the adjusted odds ratios for non-genital – penetration, respectively were: AD, OR = 3.2 – 6.5; drug dependence, OR = 3.6 – 6.6; development of ≥ 2 disorders, OR = 1.4 – 4.8 (Kendler et al. 2000). In Southwestern American Indians, men and women exposed to severe CSA were more likely to be diagnosed with more than three psychiatric disorders (Robin et al. 1997) and in African American substance dependent, treatment-seeking men, greater severity of childhood maltreatment was associated with a greater likelihood of polysubstance abuse (Ducci et al. 2009). Chronic childhood maltreatment can have more deleterious effects than ‘one-off’ episodes as illustrated by a longitudinal study of 113 African American women with documented CSA that found that multiple incidents of CSA, more than the characteristics of such abuse, were predictors of heavy alcohol use and binge drinking in adulthood, even after controlling for parental drinking behavior (Jasinski et al. 2000).

Relationship between Early Life Stress and Alcohol/Drug Dependence

Numerous studies have demonstrated a link between retrospectively documented childhood stressors and alcohol and drug dependence (Arnow 2004; De Bellis 2002; Dodge et al. 1990; Ducci et al. 2009; Heffernan et al. 2000; Hyman et al. 2006; Nelson et al. 2006; Nelson et al. 2010; Pilowsky et al. 2009; Verona and Sachs-Ericsson 2005). Data from the general population NESARC study showed that experiencing two or more childhood SLE compared with none, significantly increased the risk for AD after controlling for socieodemographic and other variables (adjusted OR = 1.4 [95% CI, 1.1–1.8]) (Pilowsky et al. 2009). In treatment seeking African American men with substance dependence, the odds ratios for risk of developing alcohol, cocaine or heroin dependence after exposure to childhood maltreatment ranged from 3.2 to 4.2 (Ducci et al. 2009). In a Southwestern American Indian tribe with a high prevalence of AD, CSA in women significantly increased the risk for lifetime AD (OR = 2.1 [95% CI, 1.2–3.6]) and drug dependence (OR = 4.2 [95% CI, 2.2–7.8]) (Robin et al. 1997). A study in of 1362 individuals from six American Indian tribes with a high lifetime prevalence of AD found that, in men, childhood exposure to physical and sexual abuse was associated with an increased risk of AD: OR = 1.6 [95% CI 1.1–2.3] whereas for women, all forms of abuse and neglect increased the risk of AD [OR = 1.6 – 2.4] (Koss et al. 2003). In this study, 29% of men had experienced 4 or 5 maltreatment categories and these individuals had a 3 fold greater risk of AD; 35% of women had experienced 4 or 5 maltreatment categories of maltreatment and had a 7 fold greater risk of AD (Koss et al. 2003).

The Association between Early Life Stress and Early Onset Problem Drinking

The effect of early life stress on adult AD may result from the earlier effect on adolescent problem drinking. Several studies have demonstrated the influence of childhood stressors on early age of onset of drinking and on binge drinking (≥ 5 drinks/occasion in any two week period). A survey of a probability sample of 3592 U.S. current or former drinkers reported that childhood stressors including physical abuse and sexual abuse were predictors of early onset (≤ 14 yrs) drinking, controlling for parental and peer alcohol use and parental attitudes toward drinking (Rothman et al. 2008). A study of 8417 adult HMO members, including 4 successive birth cohorts dating back to 1900, who completed a survey about adverse childhood experiences showed that early life stressors, including abuse and neglect, were strongly associated in with early onset of alcohol use in a ‘dose response’ relationship in all 4 cohorts demonstrating that this association has been stable over a long period of time (Dube et al. 2006). An earlier age of first alcohol use has been associated with childhood emotional abuse in both sexes and additionally sexual abuse and overall maltreatment in women (Hyman and Sinha. 2006). Retrospective questionnaire data from the U.S. National Longitudinal Study of Adolescent Health (AddHealth) (N = 12,748), showed that the co-occurrence all types of childhood maltreatment (< 11years) increased the risk for adolescent (ages 12 – 18 years) binge drinking, controlling for age, sex, ethnicity, parental alcoholism and monitoring (Shin et al. 2009). Another study showed that individuals exposed to childhood abuse were substantially more likely to report that they drank to cope during the first year of alcohol use (Rothman et al. 2008), a predictor of the development of alcohol problems (Grayson and Nolen-Hoeksema. 2005).

Early age of onset (< 15 years) of alcohol use predicts adult AD (Englund et al. 2008; Grant et al. 2001). A large (N = 11,261) U.K. longitudinal study has shown that adolescent binge drinking at age 16 predicts numerous adverse outcomes in adulthood (age 30) including AD (OR = 1.6 [1.3–2.0]) and illicit drug use (OR = 1.4 [1.1–1.8]) (Viner and Taylor 2007). Another UK longitudinal study (N = 2000) showed that, after adjustment for other teenage predictors, frequent drinking at age 14–15 years (OR = 3.1 [1.2–7.7]) and antisocial behavior (OR = 2.4 [1.2–5.1]) predicted AD at age 20–21 years (Bonomo et al. 2004). A total of 5% of boys and girls aged 12 – 17 years have a diagnosis of AUD. The peak prevalence is at age 18 – 23 years when 20% of men and 10% of women have a current diagnosis of AUD (Harford et al. 2005; Bonomo et al 2004). By the ages of 23 years, 50% of all alcoholics have developed their symptoms (Kessler et al. 2005). Therefore adolescence and young adulthood is a risk period for problem drinking and the subsequent development of AUD, particularly for children who have experienced maltreatment.

Effects of Early Life Stress on Stress Circuitry and the Mesolimbic Dopamine Reward Pathway

Stress induces secretion of the glucocorticoid hormones cortisol in human and non-human primates and corticosterone in rodents. The activation of the HPA axis, central corticotrophin releasing hormone (CRH) and peripheral catecholamine systems in response to acute stress are essential for survival, however chronic activation of these stress response systems results in increased risk for numerous physiological problems as well as vulnerability to psychopathology such as anxiety, depression and addiction to alcohol and drugs (Sapolsky et al. 2000).

The Effects of Early Life Stress on Brain Morphometry

Childhood maltreatment has been associated with abnormalities in brain development, including a reduction in size of the corpus callosum (CC), the brain’s most extensive white matter tract (Andersen et al. 2008; Teicher et al. 2004), together with other white tract abnormalities (Choi et al. 2009). Emotionally deprived rhesus macaque monkeys showed a diminution in CC volume in one study (Sanchez et al. 1998) but not another (Spinelli et al. 2009). The latter study showed that early life stress (peer rearing vs maternal rearing) was associated with enlargements of stress sensitive brain regions (vermis, dorsomedial prefrontal cortex, dorsal anterior cingulate cortex) without any apparent differences in the CC and hippocampus (Spinelli et al. 2009). Childhood maltreatment has been associated with attenuated development of the left neocortex, amygdala and hippocampus (Teicher et al. 2003) and smaller hippocampal volumes in adolescents (Rao et al. 2010) and adults but not in children (Woon et al. 2008). Dissociative symptom severity of CSA has been negatively correlated with hippocampal volume in women (Stein et al. 1997). Although smaller hippocampal volumes have been reported in alcoholics, this may be proportional to the overall reduction in brain volume (Agartz et al. 1999).

AUD in adults is associated with white matter volume loss and demyelination, particularly in the CC (Chanraud et al. 2007; Schulte et al. 2005) and this has implications for efficiency in interhemispheric processing. Heavy drinking during adolescence can impair brain development (Guerri and Pascual. 2010; Monti et al. 2005; Witt 2010). Disrupted CC microstructure is found in adolescent binge drinkers (McQueeny et al. 2009) and adolescent onset AUD (De Bellis et al. 2008). Hippocampal volume is reduced in adolescent onset AUD and correlates negatively with duration of drinking (De Bellis et al. 2000). Since childhood maltreatment is a predictor of adolescent binge drinking it would be very interesting to know whether disrupted CC microstructure and changes in the hippocampus results from both childhood maltreatment and the effects of alcohol on the developing adolescent brain and if so, whether there are additive effects of these two environmental stressors. Moreover, since alcoholics able to abstain from drinking for 8 months show extensive brain volume recovery, including of the CC (Cardenas et al. 2007), it would be interesting to see whether abstainers who had experienced childhood maltreatment show the same rate of recovery (or any recovery) of brain volume.

Resilience to the Damaging Effects of Early Life Stress

Not all children who have been exposed to maltreatment go on to develop psychopathology, indicating that resilience and mediating factors play a role (Enoch 2006). In a prospective study using court documented and therefore presumably severe cases of childhood maltreatment (physical abuse, sexual abuse and neglect experienced from 0 – 11 years), 33.5% of adolescents (up to age 18) and 56% of young adults (18 or older) who had experienced childhood maltreatment met criteria for alcohol or drug abuse or dependence. Likewise, 46% of adolescents and 47% of young adults met criteria for anxiety disorders, depression, PTSD or antisocial personality disorder (ASPD) (DuMont et al. 2007). A community survey, the NCS-R, showed that retrospectively reported childhood stressors (SLE plus maltreatment) predicted 26% of substance use disorders with onset at ages 13–29 years (Green et al. 2010) but did not predict persistence of the disorders (McLaughlin et al. 2010). Likewise, at ages 13 – 19 years and 20 – 29 years childhood stressors respectively predicted 31% and 25% of mood disorders and 29% and 31% of anxiety disorders (Green et al. 2010). Another large retrospective study showed that exposure to CSA accounted for approximately 13% of adult psychopathology, including substance dependence, but, once controlled for family factors, childhood physical abuse had only weak effects (Fergusson et al. 2008).

Conclusion

Exposure to early life stress, even to more severe forms such as physical and sexual abuse and emotional neglect, is common in the general population. The degree of risk for adult psychopathology tends to be correlated with the severity of childhood maltreatment and the number of childhood SLE. An important causal pathway that links early life stress to the onset of psychiatric disorders is the altered homeostasis in the HPA axis and the altered stress response circuitry that underlies many disorders including anxiety, depression, PTSD and addiction. There appears to be a direct pathway from chronic stress exposure in pre-pubertal children via adolescent problem drinking to alcohol and drug dependence in early adulthood that is independent of family history. Of course this can only occur in individuals exposed to the availability of alcohol or drugs. Early life stress may increase vulnerability to addiction through permanent effects on the expression of genes within the mesolimbic dopamine reward pathway. Early onset of problem drinking in stress-exposed children may exacerbate the deleterious effects on the developing brain. Since a large proportion of stress-exposed children do not go on to develop addiction, clearly resilience factors, including gene-environment interactions, are important. This review of the literature indicates that prevention should focus on early intervention in problem families to forestall maltreatment. Adolescence is a critically vulnerable time for the development of risky drinking habits and this is an area where prevention, through the development of positive family, peer and neighborhood mediating factors, is vital. A holistic approach to the treatment of alcohol and drug dependence is essential since treatment is unlikely to be effective unless underlying impediments such as early life stress are recognized and addressed.

Acknowledgments

References