Chapter 3 – Stress psychobiology in the context of addiction medicine: from drugs of abuse to behavioral addictions (2016)

Volume 223, 2016, Pages 43–62

Neuroscience for Addiction Medicine: From Prevention to Rehabilitation – Constructs and Drugs


In this chapter, we briefly review the basic biology of psychological stress and the stress response. We propose that psychological stress and the neurobiology of the stress response play in substance use initiation, maintenance, and relapse. The proposed mechanisms for this include, on the one hand, the complex interactions between biological mediators of the stress response and the dopaminergic reward system and, on the other hand, mediators of the stress response and other systems crucial in moderating key addiction-related behaviors such as endogenous opioids, the sympathetic-adrenal-medullary system, and endocannabinoids. Exciting new avenues of study including genomics, sex as a moderator of the stress response, and behavioral addictions (gambling, hypersexuality, dysfunctional internet use, and food as an addictive substance) are also briefly presented within the context of stress as a moderator of the addictive process.

Keywords Stress; Stress response pathways; Relapse; Emotions; Addictive behaviors; Hypothalamic-pituitary-adrenocortical axis; Sympathetic-adrenal-medullary response; Addictive behaviors; Cortisol



Stress psychobiology in the context of addiction medicine from drugs of abuse to behavioral addictions

While a variety of stressors external to the addiction process may facilitate initial experimentation, chronic use, or relapse, the withdrawal and negative affect that accompanies withdrawal are in themselves an aversive and stressful experience (Kassel et al., 2007).Use in response to negative affect will result in negative reinforcement (removal of an aversive stimulus) which, in turn, increases the probability of subsequent use and, if repeated, chronic use. Positive reinforcement stems from the high or the pleasure experienced in response to use of an addictive substance

The current DSM 5 (American Psychiatric Association, 2014) has redefined the definition of addiction to include both substance abuse and dependence that occur along a natural continuum from mild to severe. Qualifying for a diagnosis under this new system the words “addiction” and “dependence” are avoided in favor of the more broad substance use disorders

Many of these attempts to cope with or eliminate the stressor during the resistance phase are either unsuccessful, or in the case of substance use in humans, harmful.


There is evidence that, in many ways, the dynamic neurophysiology of the stress response mirrors that of the neurophysiology evident in humans and animals who have been chronically exposed to drugs of abuse. For example, both stress and addiction share similar changes in behavior, similar neurophysiological changes in the HPA, LC–NE, autonomic, and eCB systems, and similar risk profiles (sex, psychopathology, etc.). Chronic social stress in animals and humans leads to increases in anxiety, negative affect, and changes in sleep and eating (Adam and Epel, 2007; Akerstedt, 2006; Chida and Hamer, 2008), all of which are common in persistent substance abuse. The same is true for disruptions in attention, concentration, memory, and decision making (Het et al., 2005). From a neurophysiological perspective, there are also many common pathways. As indicated above, both chronic social stress and chronic exposure to drugs of abuse such as morphine leads to changes in LC–NE functioning that appears to be dependent upon endogenous opioid functions (Chaijale et al., 2013; Curtis et al., 2012). In general, though there is some variability based on the chemistry of the abused substance, acute drug use also leads to increased HPA and SNS functioning in much the same way as stress (al’Absi et al., 2008; Fox et al., 2006; Hamidovic et al., 2010; Mick et al., 2013).

One common pathway that has received the most intense research attention is the role of dopaminergic reward pathways in the brain. As stated above, drugs of abuse heighten the activity of the HPA, SNS, and endogenous opioid systems in much the same way as chronic stress. The behavioral effects are, in turn, moderated by multiple neurobiological systems including the catecholamines: dopamine, NE, and serotonin (Salamone and Correa, 2013). The HPA and dopaminergic systems are interdependent (Boyson et al., 2014). Dopamine in particular has been linked to the reward properties of drug use. For example, pharmacological studies have shown that stress increases dopamine production via glucocorticoid receptor activation (Boyson et al., 2014). In particular, increased central CRF activity potentiates N-methyl-D-aspartate receptor activity which, in turn, results in increased dopaminergic transmission (Marinelli, 2007). Support for the role of HPA activation in increasing dopaminergic activity has been evident in studies using a variety of methodologies (Barrot et al., 2000; Graf et al., 2013). Through this research, critical CNS reward pathways and structures have identified including the ventral tegmental area, nucleus accumbens, and prefrontal cortex (Baik, 2013; Kringelbach et al., 2012; Lawrence and Brooks, 2014).

In addition to the dopaminergic reward pathway, both stress and drugs of abuse negatively impact the serotonergic pathway consisting of the raphe nucleus, striatum, nucleus accumbens, and the entire neocortex. The effects of altered serotonergic functioning are expressed as changes in mood, memory, sleep, and cognition; all of which are evident in chronic stress states and drug abuse (Kirby et al., 2011; Meerlo et al., 2008; Meneses, 2013)

Various physiological markers of stress predict relapse. For example, smokers who demonstrate an attenuated sympathetic and HPA stress response during the first 24 h of relapse have an increased risk of relapse status at 4 weeks postquit (al’Absi, 2006; al’Absi et al., 2004, 2005; Ceballos and al’Absi, 2006) as does heightened negative affect

Likewise, craving or distress-induced relapse is a powerful negative reinforcement for persistent smoking (Ahmed and Koob, 2005). Although this experience is psychologically stressful, the seemingly counterintuitive attenuated response of those who relapse appears to be related, at least in part, to CRF (Erb, 2007).

In addition to the HPA axis, catecholamines and glutamate within the nucleus accumbens and prefrontal cortex are induced by drug cues, drug use, and/or stress

Although we began this section using nicotine addiction as an example, it is important to point out that stress and abnormal cortisol responses have also been linked to relapse with other substances cessation attempts including cocaine, opiates, alcohol, amphetamines, and marijuana (Fox et al., 2013; Hamidovic et al., 2010; Higley et al., 2011; Sinha, 2011). With some abuse substances such as heroin, however, the cortisol response is elevated rather than attenuated, especially in response to drug paraphernalia cues (Fatseas et al., 2011). Regardless of the direction of the HPA changes, there is abundant evidence that drug use is related to dysregulation of the HPA axis, perhaps in concert with dysregulation in the emotional regulation, central reward, and executive function systems


For the first time, gambling disorder was added to the DSM 5 in 2013 due to its clear addictive behavior patterns (Hasin et al., 2013). If, as we have argued above, psychological stress is a key factor in the initiation, maintenance, and relapse for all addictions, then it would stand to reason that there should be evidence of such a stress and addiction relationship among all behavioral, emotional, cognitive, and physiological parameters of stress specific to gambling. This is, indeed, the case for many of these parameters. For example, reported psychosocial stresses such as divorce, marital strife, and a history of childhood abuse are more prevalent in samples of pathological gamblers (PGs) (Black et al., 2012). Higher life stress at the time of treatment is one of the strongest predicts PG relapse at 4 months posttreatment (Gomes and Pascual- Leone, 2014). Although baseline cortisol may not be elevated with gambling

disorder, there are negative correlations with the length of pathological gambling and cortisol, total gambling dysfunction, and distress over gambling behavior (Geisel et al., 2015). Further, gambling-related behaviors increase with experimental induction of a stress state, though not with all types of stressors (Steinberg et al., 2011). Early research indicates that stress physiology, as measured by the HPA, sympathetic, serotonergic, dopaminergic, and endogenous opioid systems, has been linked to gambling behaviors, maintenance, and relapse (Blanchard et al., 2000; Campbell-Meiklejohn et al., 2011; van den Bos et al., 2009). For PGs, basal circulating NE, EPI, and dopamine are elevated and the act of gambling is an arousal state (Meyer et al., 2004). In contrast to basal levels or gambling behaviors, the cortisol response to gambling cues may be absent for PGs but not recreational gamblers

(Paris et al., 2010a,b). Finally, neuroimaging studies indicate that, like alcohol addiction, pathological gambling is associated with abnormalities in the anterior cingulate, ventral striatum, and prefrontal cortices (Koehler et al., 2013). Other behaviors with addictive qualities (persistent and dysfunctional use or behavior leading to clinically significant impairment or distress) include hypersexuality, internet use disorder, and noneating disordered excessive eating (AKA “food addiction”). While each of these have not yet risen to the level of inclusion in the DSM 5 as a substance use disorder, there is some recognition that each of these have in common an escalating pattern of use leading to dysfunction. Further, early evidence exists of a link between these potential behavioral addictions (purported sex addiction and internet use disorder) and dopamine, self-reported stress, or the HPA axis dysregulation (Farre et al., 2015; Hou et al., 2012). Finally, there is currently a large debate on whether or not there is a “food addiction” or “eating addiction” that is distinct from the traditional eating disorders of anorexia or bulimia exists (Rogers and Smit, 2000). Although still quite controversial, those who support the notion of a food addiction point to its vulnerability to stress and the dopaminergic reward system as supporting evidence of its distinction from other eating disorders (Adam and Epel, 2007; Volkow et al., 2013).