Childhood Maltreatment and later Alcoholism/Addiction

One old timer I know often says two things that I often take issue with – 1. there are as many alcoholisms as alcoholics and that 2. we all come to AA in different boats but end up in the same dock.

Thanks to having a wife in Al Anon I have had the benefit of her insight and from other al-anons who state how remarkably similar we alcoholics are in our behaviour, particularly in dealing/coping with distress and stress, our emotional reactivity and at times immaturity (or so-called defects of character), I disagree that we are so different in our addictive behaviours.

All addictive behaviours from alcoholism, substance addiction, eating disorders to hypersexual disorder seem to be based on an inherent problem with emotion and stress dysregulation.

I believe I have a distress based condition. It results in what appear to be distress based reactions such as perfectionism, distress intolerance and frustration intolerance, normally exemplified in my shouting at my PC when it doesn’t work quickly enough or crashes!

I also believe I have distress based impulsivity, I want that thing, whatever it is, NOW. That anything!

In fact I have noticed when I want something, anything, I end up pathological wanting it in no time at all! It seems then like I NEED it. I too think this is based on distress and heighten stress reactivity.

In fact it is through this pathological wanting that my so-called defects of character that my examples  of emotional dysregulation appear.

If I can’t get what I want, all range of negative emotions spill forth such as intolerance, impatience, arrogance, pride, shame, selfishness etc .  They only appear when I want something and you are getting in the way of me having it!!

So there is a link between my motivation (which is dysregulated due to the effects of chronic stress which turns simple wanting into something more akin to “needing”) and my subsequent emotional dysregulation.

So where does this distress come from? Is it purely the effects of chronic stress dysregulation caused by years of neuro toxic brain damage or does it go back further, into childhood?

I do not think we all have separate alcoholisms, I feel we have remarkably similar reactions to life and these centre on an inherent difficulty regulating stress and emotion.

I also believe we have come to recovery in similar boats. In fact the majority of us have come to recovery in a remarkable similar boat so much so that it would resemble a gigantic ship rather than a boat. That boat is the ship of childhood maltreatment.

Child maltreatment has been frequently identified in the life histories of adolescents and adults in treatment for substance use disorders, as well as in epidemiological studies of risk factors for substance use and abuse.

 Child Maltreatment

One study (1) suggests there is ample evidence exists for higher rates of substance abuse and dependence among maltreated individuals.

In clinical samples undergoing treatment for substance use disorders, between one third and two thirds evince child abuse and neglect histories (Dembo, Dertke, Borders, Washburn, & Schmeidler, 1988Edwall, Hoffman, & Harrison, 1989Pribor & DiWiddie, 1992Schaefer, Sobieragi, & Hollyfield, 1988).

In the US a survey of over 100,000 youth in 6th though 12th grade, Harrison, Fulkerson, and Beebe (1997) Harrison, Fulkerson, and Beebe (1997) found that those reporting either physical or sexual abuse in childhood were from 2 to 4 times more likely to be using drugs than those not reporting abuse; the rates were even higher for youth reporting multiple forms of child maltreatment. Similar findings have been reported by Rodgers et al. (2004) and Moran, Vuchinich, and Hall (2004).

Among youth with Child Protective Services documented maltreatment, Kelly, Thornberry, and Smith (1999) reported one-third higher risk for drug use among those with an abuse history. In a large epidemiological study, Fergusson, Boden, and Horwood (2008) have shown physical abuse and particularly sexual abuse to be related to illicit drug use, as well as abuse and dependence.

Another Study (2) study would suggest the figures are much higher –   data were collected on 178 patients–101 in the United States and 77 in Australia–in treatment for drug/alcohol addiction. The purpose of the study was to determine the degree to which a correlation exists between child abuse/neglect and the later onset of drug/alcohol addiction patterns in the abuse victims. The questionnaire explored such issues as family intactness, parental violence/abuse/neglect, parental drug abuse, sibling relationships and personal physical/sexual abuse histories, including incest and rape. The study determined that 84% of the sample reported a history of child abuse/neglect.

A third study (1) stated that, using the Childhood Trauma Questionnaire-Short Form (CTQ-SF; Bernstein & Fink, 1998; Bernstein et al., 2003) to assess childhood maltreatment in a community sample of active drug users, Medrano, Hatch, Zule, and Desmond (2002) found that 53% of women and 23% of men were sexually abused, 53% of women and 43% of men were physically abused, 58% of women and 39% of men were emotionally abused, 52% of women and 50% of men were physically neglected, and 65% of women and 52% of men were emotionally neglected.

Substance abusers, in addition to having higher rates of childhood maltreatment than members of the general population, have been found to have levels of psychological distress that increase with increasing severity of all types of childhood maltreatment (Medrano et al., 2002). This association is important considering that stress increases an individual’s vulnerability to addiction and addiction relapse (Goeders, 2003; Sinha, 2001;Wills & Hirky, 1996).

There is also evidence that the way in which people cope with stress is related to substance use. For example, researchers have found that greater use of avoidance stress-coping strategies (i.e., disengaging from investing effort to cope with a problem) is related to a greater likelihood of drug use initiation, higher levels of ongoing drug use, and a greater probability of relapse, whereas greater use of active stress-coping strategies (i.e., taking steps to deal with a problem) most consistently functions to protect individuals from substance use initiation and relapse (Wagner, Myers, & McIninch, 1999; Wills & Hirky, 1996).

Childhood maltreatment may influence substance use behavior through its effect on stress and coping. There is emerging evidence that childhood maltreatment may negatively affect the maturation of self-regulatory systems that enable an individual to modulate and tolerate aversive emotional states (Cicchetti & Toth, 2005; Hein, Cohen, & Campbell, 2005). Childhood maltreatment may disrupt neurobiological development and elevate subjective stress by biologically altering the brain’s response to stress (Bugental, 2004;DeBellis, 2002; Heim & Nemeroff, 2001; Heim et al., 2000; Sinha, 2005; Wills & Hirky, 1996). Childhood maltreatment may also affect an individual’s characteristic style of coping with stress so that he or she may be more likely to rely upon maladaptive strategies, such as avoidance of problems, wishful thinking, and social withdrawal, rather than active strategies, such as seeking information and advice from others (Bal, Crombez, Van Oost, & Debourdeaudhuij, 2003; Futa, Nash, Hansen, & Garbin, 2003; Krause, Mendelson, & Lynch, 2003; Leitenberg, Gibson, & Novy, 2004; Thabet, Tischler, & Vostanis, 2004).

Elevated stress and maladaptive coping related to childhood maltreatment may translate to greater substance use behavior by making the coping motives of substance use appear more attractive (Wills & Hirky, 1996). Indeed, substance users commonly report using psychoactive substances such as alcohol, cannabis, and cocaine to cope with stress and regulate affect (Boys, Marsden, & Strang, 2001)

Most cocaine dependent inpatients reported multiple types of childhood maltreatment, and only 15% reported no maltreatment at all, (similar figures to study 2).

“Our findings suggest that the severity of overall childhood maltreatment experienced by recently abstinent cocaine dependent adults has a significant relationship with perceived stress and avoidance coping in adulthood.

Our findings suggest that having a more severe childhood maltreatment history may result in a greater sensitivity to stress…basic coping skills training may not be adequate in decreasing distress and avoidant coping in order to decrease substance use and relapse. Additional interventions that focus on stress tolerance, altering appraisals of stress, stress desensitization, and affect and emotion regulation skills may be of particular benefit to patients with childhood maltreatment histories.

The fact that childhood maltreatment is a preventable phenomenon that occurs early in life and affects psychological functioning well into adulthood makes our findings relevant to clinical practice with children as well. Early identification and treatment of maltreated children may help prevent stress sensitivity or the development of a less adaptive style of coping. Assessment of coping ability and the implementation of coping skills and stress tolerance training may also be indicated for maltreated children in an effort to increase their coping efficacy and decrease their vulnerability to stress later in life.”

I may have been in recovery for a number of years now but coping with stress/distress is still central to my recovery. Dealing with the effects of childhood maltreatment not only via negative self esteem and self schema but in the real sense of coping with every day stress/distress, mainly prompted in my interpersonal relationships (other people!) and with my PC!

 

References

1. Rogosch, F. A., Oshri, A., & Cicchetti, D. (2010). From child maltreatment to adolescent cannabis abuse and dependence: A developmental cascade model.Development and psychopathology, 22(04), 883-897.

2. Cohen, F. S., & Densen-Gerber, J. (1982). A study of the relationship between child abuse and drug addiction in 178 patients: Preliminary results. Child Abuse & Neglect, 6(4), 383-387.

3.  Hyman, S. M., Paliwal, P., & Sinha, R. (2007). Childhood maltreatment, perceived stress, and stress-related coping in recently abstinent cocaine dependent adults. Psychology of Addictive Behaviors, 21(2), 233.

What is craving – do neurobiological accounts explain relapse in recovering alcoholics? Pt 2

If you want to drink, you will. It you do not, and depending on your regulation of emotions and stress, you may still relapse, even if one never intended to drink again.

In our previous blog we looked at automatic physiological response to cues that alcoholics appear to experience. These habitual responses are well explained by reinforcement, conditioning or neurobiological models of addiction.

However, do these neurobiological models predict relapse in abstinent alcoholics and addicts? In other words, do recovering alcoholics act and react to cues and have the same attentional bias, i.e. are they lured siren-like to alcohol or drug cues like lemmings to a drink or a drug or are there more  cognitive-affective processes at work in the craving than these models suggest!?

Does the mind play a role in transmuting these physiological urges into “craving”.

When I have seen a new comer to recovery craving they do not seem to walk around like a robot, salivating and rubbing their sweaty hands together. I have seen that when I was in active drinking and was like that innumerable times myself while under the spell of this “fleshy hunger” called having a pathological urge for a drink.

I am not downplaying this urge state, it is quite horrendous, it is like craving a glass of water after days in the desert. It feels like your very life depends on it, in other words. It can be a life or death feeling.

 

PowerPoint Presentation

In recovery, this urge state becomes more complicated and various other brain regions may become involved in this “craving” and there may be a interplay between regions rather than regions simply acting in concert – we will explore this more in series 3 of this theme of “craving”.

For now we examine how well do neurobiological accounts (i.e. accounts which focus primarily on impairments in neurotransmitter and stress systems and brain function in areas which create a cascade of ‘knock on’ impairment and dysfunction in areas of the prefrontal cortex which deals with cognitive control of behaviour with resultant dysfunction in areas which deal with reward, motivation stress and emotional response and more motoric, habitualized action) predict behaviour in abstinent, treatment seeking individuals?

Here we simply consider how well aspects of these theories, such as the ideas relating to craving (urge) via cue reactivity (an attentional bias towards alcohol and drug associated cues in the environment)  and positive memory associations for previous alcohol or drug use, relate to, or are relevent to the experiential reality of everyday recovering alcoholics and addicts.

In simple terms, it is the duty of science to attempt to predict behaviour, so how well do these models, especially the positive reinforcement model, predict the behaviour of treatment seeking abstinent alcoholics and addicts. 

Factors in relapse

Cues, external especially, which is a central part of positive reinforcement models, seem to be only one of various factors in relapse. They are present in a relatively small minority of studies or interact with other variables such as stress and negative affect (NA). So how well does this then validate this theory of addiction, when it is only present in a minor way in relapse and usually alongside stress and NA. Does this mean it plays a role when interacting with these variables of stress/NA. Does it play a role on it’s own?

I forward this question because the looking at an alcohol cue by an alcoholic even in recovery/abstinence invokes stress reactions such as anxiety or negative emotions such as anger, sadness ( ). Can we say there is a non-stress influenced cue-reactivity? Is there a purely dopaminergic cue reactivity? It doesn’t appear so.

In fact moving on from noting this intrinsic stress response in cue reactivity, various studies show that the highest high-risk relapse situations are negative emotions, testing personal control, social pressure, and urge and temptations  (1), that 62 –73% of relapse episodes were due to negative emotion and social pressure. Heroin addicts relapse primarily because of NE and lack of social supports. Mood state, along with social isolation and family factors, was more likely to be related to relapse incidences with a positive correlation between NE and alcohol-seeking behaviour. Thus the most commonly cited reason for relapse was negative mood states, consistent with previous studies of relapse factors (2).  Also reasons for relapse did not differ in relation to the primary drug of dependence (alcohol, methamphetamine, heroin), reflecting the commonality of relapse processes across diverse types of substances.

Marlatt (3,4) , views relapse as an unfolding process in which resumption of substance use is the last event in a long sequence of maladaptive responses to internal or extemal stressors such as negative emotional states, interpersonal conflicts, and social pressures. In fact negative emotional states ….coping, self-efficacy and stressful life events appeared to be of greater import in determining relapse than ‘cues’.

It would appear that cue associated stimuli plays a minor role in relapse, with stress and NA appearing to be a more important determinant of relapse. So conditioning models do not appear to give a comprehensive account of relapse and this may be particularly the case in abstinent, treatment seeking alcoholics.

How does conditioning methodology adequately explain this group?

Attentional Bias

Do treatment seeking alcoholic have the same attentional bias as non treatment seeking active alcoholics?

In fact, studies seem to show a negative attentional bias in alcohol-dependent patients that may be interpreted as an avoidance of alcohol-related stimuli.

Townshend and Duka (2007) propose that treatment seeking individuals have established active avoiding strategies and  are able to disengage their attention from alcohol cues (5). In fact is suggested that a positive attentional bias towards alcohol cues occurs when stimuli were presented shortly (50 ms), followed by a disengagement from alcohol cues in the 500 ms interval of cue presentation. This corresponds with a cognitive model of craving of Tiffany (6) where the 50ms may represent automatic approach before this automatic bias is interfered with by cognitive control, perhaps resulting in ‘craving’.

Does this visual approach–disengagement pattern reflect an  attentional bias which is appetitive or threat based? If there is avoidance are cues similar as  seen as in those with trait anxiety who have attentional bias for threat-related cues (7). A large body of evidence indicates that aversive emotional states are associated with biases in cognitive processing and, specifically, with increased attentional processing of threat-related cues.Is this also how treatment seeking addicted individuals are responding to substance-related cues? It may that stress heightens the salience of attractiveness of the cues so that abstinent individual relapse because of stress based response which makes relapse via internal and external cues a solution to their chronic stress/emotional distress?

Or it may be that relapse is based on difficulties coping with the manifestation of chronic stress, emotional distress and that  relapse  is a more complicated process than simply being lured, siren-like, to relapse via cues.

In most of the relapses we have encountered it has been a ongoing build up to relapse. There has been a period of emotional dyregulation whereby individuals get more and more distressed, often in inter-personal relationships, and have a “to hell with it!” relapse to relieve escalating emotional distress and the distorted thinking that goes with it. It is not due to automatic or motoric proceses, it is mediated via affective-cognitive mechanisms and this is why the information processing model, with some modifications, appears to explain craving and relapse more satisfactorily.

If you want to drink, you will, it you do not, and depending on your regulation of emotions and stress, you may still relapse, even if one never intended to drink again, due to the torturous intrusive thoughts which accompany this cognitive and emotionally based “craving”, more akin to the “mental obsession ” of AA’s Big Book than purely physiological urges.

References

1. El, S., Salah El, G., & Bashir, T. Z. (2004). High-risk relapse situations and self-efficacy: Comparison between alcoholics and heroin addicts. Addictive behaviors29(4), 753-758.

2.  Hammerbacher, M., & Lyvers, M. (2006). Factors associated with relapse among clients in Australian substance disorder treatment facilities. Journal of substance use11(6), 387-394.

3. Marlatt, G.A. (1978) Craving for alcohol, loss of control and relapse: Cognitive behavioural analysis. In: Nathan, P.E., Marlatt, G.A., and Loberg, T. eds. Alcoholism: new directions in behavioural research and treatment. Plenum Press, New York, 271-314.

4. Marlatt, G.A., and Gordon, J.R. (1985). Relapse prevention: maintenance strategies in the treatment of addictive behaviors. Guilford  Press, New York.

5. Townshend JMDuka Attentional bias associated with alcohol cues: differences between heavy and occasional social drinkersPsychopharmacology (Berl)2001;157:6774.

6. Tiffany, S. T. (1990). A cognitive model of drug urges and drug-use behavior: role of automatic and nonautomatic processes. Psychological review97(2), 147.

7.  Bar-Haim, Y., Lamy, D., Pergamin, L., Bakermans-Kranenburg, M. J., & van IJzendoorn, M. H. (2007). Threat-related attentional bias in anxious and nonanxious individuals: a meta-analytic study. Psychological bulletin133(1), 1.

8.  McCusker CG  Cognitive biases and addiction: an evolution in theory and methodAddiction 2001;96:4756.

What is craving?

When I first came into recovery I used to get frightened by other abstinent  alcoholics proclaim that they were so glad they did not get the “wet tongue” when they saw alcohol or people drinking alcohol.  I used to feel ashamed as I did have an instantaneous “wet tongue” and still do  years later when I see people drinking alcohol. Is this a “craving” for alcohol, do I still want to drink? Do I still have an “alcoholic mind?“.

It used to churn me up, these so-called alcoholics who had no a  physiological response to alcohol-related “cues”.

What I have discovered is that I have an “alcoholic brain” and not a “alcoholic mind” and there is a huge difference. So if there are people out there relatively new to recovery, listen up. For chronic alcoholics there is an automatic physiological response when we see cues such as other people drinking. Automatic, habitual, it happens to us rather than us wanting or willing it to happen. It happens unconsciously without our say so!

Some researchers in science call this a craving. I disagree. I call this an physiological urge, distinct from craving. I think a craving is more akin to a “mental obsession” about alcohol.

It is hugely important for recovering persons that we distinguish between urges and craving, in a clear manner that science seems to have been unable to do! Lives can depend on this. We are so vulnerable in early recover that we need so sound direction on what is happening to us automatically and what we are encouraging to happen, consciously.

An urge for me is a physiological response to cues, external and internal (e.g. stress). A craving is different but interlinked.

If I have an urge and it becomes accompanied by automatic intrusive thoughts such as a drink would be nice, and maybe a suggestion on where to get this drink, this does not mean I want a drink. It is simply automatically prompted intrusive thoughts, the type of thought I used to get all the time and so became habitual, became stored away in an automatized addiction schema or addiction action plan.

If I realize this and simply  these thoughts go, i.e. do not react to them, then they lessen and dissipate altogether.

This is not a craving. I have not consciously and emotionally engaged with these intrusive thoughts.

So what I am saying is that there is no simple urge state that automatically leads to drink. We have to cognitively and emotionally react to it.

In my time in recovery, I have rarely heard of or witnessed  someone lured siren-like by a cue to a drink and when I have it is because he wanted to drink really, were testing their alcoholism, or that he was in huge emotional distress and went to “hell with it!”. As we will see below, stress and cues certainly do not mix but again there is still a cognitive-emotional reaction which mediates between an urge and a relapse!

In the first of a four part series of blogs we discuss “what is craving?” and consider whether the emotional dysregulation we consider to be at the heart of alcoholism and addiction also plays a role in both craving and relapse.

We start this series by considering the neurobiological accounts of craving and will then consider how well these accounts explain craving and relapse in abstinent, treatment seeking, or recovering alcoholics and addicts.

Part 1

What is craving?

Craving persists years into abstinence (1).

Precise definitions of craving have remained elusive (2-5). Two general categories are based on conditioning and cognitive mechanisms (6) but are not mutually exclusive.

A Neuroadaptive Model of Craving – Scientists believe that a gradual and, perhaps, permanent adaptation of brain function (i.e., neuroadaptation) to the presence of alcohol is a central feature in the development of alcohol dependence (7,8).

Conditioning Models – The “conditioning” models posit that cues elicit the same physiological and psychological response as drug consumption itself  with these ‘respondent’ conditioning theories predicting that responses to drug-related cues either reflect aversive abstinence symptoms or mimic drug effects  have dominated explanatory models in cue reactivity studies (9).

The definition of addiction by the American Society of Addiction Medicine (ASAM) includes the terms craving and persistent risk, and emphasises risk of relapse after periods of abstinence triggered by exposure to substance-related cues and emotional stressors (10).

This conceptualisation points to the role of substance-related cues, e.g., environmental stimuli that are strongly associated with the effects of the administration of substances and acquire incentive salience through Pavlovian conditioning, as well as stress (an internal cue), as major determinants of relapse.

The Incentive Sensitisation (IS) Model (11), addiction is the result of neural sensitisation of reward circuits (centred in the ventral striatum (VS)) by the neurotransmitter dopamine. Positive reinforcement mechanisms lead to a non-associative learning process, referred to as sensitization, in which repeated confrontation with a substance-related cue (which acts as a reinforcer) results in the progressive amplification of a response (substance seeking).

This ‘sensitisation’ or hypersensitivity may be independent of negative withdrawal symptoms or an individual’s general negative emotional state and leads to compulsive substance-seeking and substance-taking. These mechanisms of positive reinforcement leave addicts vulnerable to relapse when confronted with substance-related cues that trigger a pathological “wanting”. In short, IS produces a bias of attentional processing towards substance-associated stimuli and a pathological wanting of alcohol or substances. Sensitisation and attentional bias have been demonstrated in various studies (12,13).

Negative reinforcement model of addiction Basic negative reinforcement models pose that addictive behaviour is the consequence of persistent negative affect (NA). This NA is associated with maladaptive changes in the brain’s stress and reward circuits, which leave addicts vulnerable to cue-associated stimuli prompting a desire to relieve their negative emotional states (14).

One prominent stress-based negative reinforcement model, the Hedonic Dysregulation (HD) Model, mainly associated with Koob and le Moal (14), In sum, the HD model posits that, in substance dependent individuals,  an overactive stress  axis creates a progressive allostasis in the brain reward systems which underlies transition from substance use to addiction and creates a persistent state of NA (altered and excessive stress) and emotional reaction to “cues”. These changes continue to persist even when an addicted individual experiences a state of protracted abstinence.

Persistent NA increases their incentive salience and desire to use substances in an attempt to relieve this NA.

Evidence for the involvement of both the reward and the stress system of the brain  comes from imaging studies of addicted individuals during withdrawal or protracted abstinence, which have shown decreases in dopamine D2 receptor density (hypothesized to reflect hypodopaminergic function) (15) as well as alteration in brain stress systems, such as increase in CRF and glucocorticoids (16).

These models to me appear to be describing urges based on cues and the effect of cues with stress/emotional distress. This last one can impact on recovery and relapse mentioned in another blog.

The question remains however whether these neurobiological models predict relapse in abstinent alcoholics and addicts?

 

References 

1.  Anton, R. F. (1999). What is craving. Alcohol Research and Health23(3), 165-173.

2. LUDWIG, A.M., AND STARK, L.H. Alcohol craving: Subjective and situational aspects. Quarterly Journal of Studies on Alcohol 35:899–905, 1974.

3. KOZLOWSKI, L.T., AND WILKINSON, D.A. Use and misuse of the concept of craving by alcohol, tobacco, and drug researchers. British Journal of Medicine 82:31–45, 1987.

4.  KOZLOWSKI, L.T.; MANN, R.E.; WILKINSON, D.A.; AND POULOS, C.X. “Cravings” are ambiguous: Ask about urges and desires. Addictive Behaviors 14:443–445, 1989

5.  SITHARTHAN, T.; MCGRATH, D.; SITHARTHAN, G.; AND SAUNDERS, J.B. Meaning of craving in research on addiction. Psychological Reports 71:823–826, 1992.

6. SINGLETON, E.G., AND GORELICK, D.A. Mechanisms of alcohol craving and their clinical implications. In: Galanter, M., ed. Recent Developments in Alcoholism: Volume 14. The Consequences of Alcoholism. New
York: Plenum Press, 1998. pp. 177–195.

7. Robinson, T.E., & Berridge, K.C. (1993). The neural basis of drug craving: An incentive-sensitization theory of addiction. Brain Research, 18, 247-291

8. Koob GF, Le Moal M. Drug abuse: hedonic homeostatic dysregulation. Science. 1997;278:52–58

9.  Ingjaldsson, J. T., Laberg, J. C., & Thayer, J. F. (2003). Reduced heart rate variability in chronic alcohol abuse: relationship with negative mood, chronic thought suppression, and compulsive drinking. Biological Psychiatry54(12), 1427-1436.

10.  Morse RM, Flavin DK (1992). “The definition of alcoholism. The Joint Committee of the National Council on Alcoholism and Drug Dependence and the American Society of Addiction Medicine to Study the Definition and Criteria for the Diagnosis of Alcoholism“. JAMA 268 (8): 1012–4

11. Robinson, T. E., & Berridge, K. C. (2008). The incentive sensitization theory of addiction: some current issues. Philosophical Transactions of the Royal Society B: Biological Sciences, 363(1507), 3137-3146

12. Leyton M. Conditioned and sensitized responses to stimulant drugs in humans. Prog. Neuropsychopharmacol. Biol. Psychiatry. 2007;31:1601–1613.

13. Franken, I. H. (2003). Drug craving and addiction: integrating psychological and neuropsychopharmacological approaches. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 27(4), 563-579

14. Koob, G. F., & LeMoal, M. (2001). Drug addiction, dysregulation of reward, and allostasis. Neuropsychopharmacology, 24, 97–129.

15. Volkow ND, Wang GJ, Fowler JS, et al. Decreased striatal dopaminergic responsiveness in detoxified cocaine-dependent subjects. Nature. 1997;386:830–3.

16.. Koob GF, Le Moal M. Addiction and the brain antireward system. Annu Rev Psychol. 2008;59:29–53