Current Addiction Reports (2020) 7:252–259

https://doi.org/10.1007/s40429-020-00324-w

ALCOHOL (A HEINZ AND N ROMANCZUK-SEIFERTH, SECTION EDITORS)

(Neuro)therapeutic Approaches in the Field of Alcohol Use Disorders

A Beck 1 & A Rosenthal 1 & M Auriacombe 2,3,4 & N Romanczuk-Seiferth 1

Published online: 27 June 2020

# The Author(s) 2020

Abstract
Purpose of Review Alcohol use disorder (AUD) is a burdening chronic condition that is characterized by high relapse rates
despite severe negative consequences. There has been a recent emergence of interest in (neuro)therapeutic intervention strategies
that largely involve the detrimental change in mechanisms linked to addiction disorders. Most prominently, the latter include
habitual decision-making, cue-induced behavioral tendencies, as well as the amplifying effects of stressful events on drinking
behavior. This article discusses these learning mechanisms and modification thereof as possible targets of (neuro)therapeutic
interventions for AUD.
Recent Findings Psychological therapies that target dysregulated neurocognitive processes underlying addictive behavior may
hold promise as effective treatments for AUD.
Summary Despite the progression in psychological and neuroscience research in the field of AUD, many behavioral interven-
tions fail to systematically integrate and apply such findings into treatment development. Future research should focus on the
targeted modification of the aforementioned processes.

Keywords Alcohol use disorder . Treatment . Addiction . Habitual decision-making . Stress . Cue . EMA . Intervention

Introduction and financial costs and its treatment is problematic [1, 3].
Currently, the psychological treatment of post-acute AUD
Substance use disorders (SUD) are defined as problematic mainly comprises of motivational enhancement therapy, cog-
patterns of use associated with clinical impairment and persis- nitive behavioral therapy, contingency management, as well
tent relapse overtime [1, 2]. Alcohol use disorder (AUD) is as supervised patient group therapy [4].
remarkable because it causes immense global health burden However, effectiveness of current therapeutic approaches
would benefit from better taking into account improved un-
A Beck and A Rosenthal contributed equally to this work. derstanding of AUD underlying processes and their modifica-
This article is part of the Topical Collection on Alcohol tion. Overall, addiction disorders in which substance intake is
dysregulated [2] can be referred to as “pronounced preference
* A Rosenthal disorders.” Regardless of the addiction condition, substance
[email protected] intake is somewhat similar to other automatic actions based on
preferences and reinforcing everyday experiences, but due to
1
Charité – Universitätsmedizin Berlin, corporate member of Freie the pharmacological effect of the substance, the stimulus is
Universität Berlin, Humboldt-Universität zu Berlin, and Berlin particularly pronounced [5] and as such may contribute to
Institute of Health, Department of Psychiatry and Psychotherapy, the dysregulation of substance intake.
Charité Campus Mitte, Charitéplatz 1, 10117, Berlin, Germany AUD and other addiction disorders are characterized by a
2
University of Bordeaux, Phenomenology and Determinants of gradual shift from initial goal-directed drug use mediated by
Appetitive Behaviors (Addiction Team), Sleep, Addiction and the reinforcing and hedonic effects of the drug (regulated sub-
Neuropsychiatry Laboratory (SANPSY), USR CNRS 3413, 146 Bis
Rue Léo Saignat, 33076 Bordeaux, France stance intake) to an increasing loss of control over drug intake
3 (dysregulation), which thus becomes habitual, that is, auto-
Pôle Addictologie, CH Ch. Perrens and CHU de Bordeaux, 121 Rue
De La Béchade, 33076 Bordeaux, France mated and disconnected from its consequence, one behavioral
4 outcome of which is compulsive use. One unique characteris-
Center for Studies of Addiction, Department of Psychiatry, Perelman
School of Medicine, University of Pennsylvania, 3535 Market St, tic of addictive disorders is persistent relapse rates over time
Suite 4000, Philadelphia, PA 19104, USA despite awareness of severe negative consequences [6]. Even
Curr Addict Rep (2020) 7:252–259 253

in the face of severely aversive consequences, it can be nearly repetition of previously rewarded action without taking into
impossible to stop drug intake in spite of conscious decisions account that the outcome value might have changed [19]. In
to reduce consumption or to remain abstinent [7, 8]. context of this, preclinical research and human neuroimaging
Despite that habitual and compulsive drug intake are to be studies have related goal-directed and habitual action control
differentiated, they can be triggered by drug-associated cues, to two separable neuronal systems [20, 21]. Habitual control
acute stress events, or a priming dose of the drug [9]. In mainly relies on the putamen, while the goal-directed system
chronic problem drug users, conditioned drug cues gain in- has been suggested to involve the ventromedial prefrontal
centive salience, whereas alternative reinforcers become less cortex as well as the ventral striatum [22–24]; however, see
important [10–13]. Finally, drug addiction also involves neg- Deserno and colleagues [25] for indication of ventral striatal
ative reinforcement during withdrawal distress and early and activation in habitual control.
long-term abstinence, which is defined as drug-taking that The shift from goal-directed to habitual behavior that is
alleviates a distress-associated aversive emotional state [14], seen with disease progression might render individuals with
which may be a characteristic of craving as a diagnostic crite- AUD to be insensitive to aversive outcomes associated with
rion [15]. alcohol use [26]. Furthermore, subjects with AUD might also
However, some AUD patients are able to regain control be more insensitive to aversive events in general, as, e.g.,
over their alcohol intake, suggesting that the above-named could be shown in terms of a reduced loss aversion in com-
mechanisms can be partly reversed or compensated [16••]. parison with healthy subjects [27]. In addition to this, craving
There has been a recent emergence of interest in and acquired (learned) habitual patterns of alcohol intake
(neuro)therapeutic intervention strategies that largely involve could aggravate the phases of early abstinence [28].
the detrimental change in learning mechanisms linked to ad- Regarding a controlled selection of goals in contrast to habit-
diction disorders [17]. This report aims at reviewing potential ual drug intake, it was recently observed that an increased
therapeutic targets that have been highlighted in recent AUD general tendency for habitual responding predicted poor treat-
research. Most prominently, they include habitual decision- ment outcome only in the presence of high alcohol expectan-
making, cue-induced behavioral tendencies, as well as the cies [24••]. Such biases can be modified by, e.g., systemati-
amplifying effects of stressful events on drinking behavior cally training habitual rejection of alcohol-related stimuli (e.g.,
(see Fig. 1). We will also review intervention strategies that pictures) [29]. Following training, a good treatment outcome
are designed to target the aforementioned processes. was associated with reduced limbic activation elicited by
alcohol-related pictures [30••].
Habitual Decision-Making In addition to lack of goal-directed reward choices, avoid-
ance behavior is proposed to be impaired as well. Ersche and
According to dual-process theories of addiction, alcohol con- colleagues showed that patients with cocaine use disorder
sumption in addiction can be driven by an attentional bias as (CUD) show similarly increased habitual responding as
well as by a habitual approach toward drug cues in expense of AUD cohorts and furthermore failed to avoid aversive out-
initially goal-directed control [18]. Goal-directed action con- comes in a punitive learning task [26]. In terms of therapeutic
trol supports flexible planning to promote desirable choices implications, the authors state that impaired avoidance behav-
when facing potential actions and probabilistic consequences. ior, as well as habitual drug intake should be targeted and
On the other hand, habitual control encompasses the mere replaced by healthy habits. This approach is extended by
Stock in a perspective article [31] arguing for the establish-
ment of habit reversal therapy (HRT) in AUD. HRT embodies
multiple components that aim at altering dysfunctional habits
and has been proven to be efficacious in repetitive behavioral
disorders [32]. Briefly, HRT encompasses an awareness train-
ing phase in which automatic behavioral tendencies are iden-
tified to then be replaced by competing (healthy) habits in the
therapy phase. These factors are accompanied by generaliza-
tion to relevant contexts and motivational techniques such as
social support training or the review of inconvenience caused
by the habit [33]. The establishment of adequate motivational
support, as well as concrete long-term perspectives, has been
shown to be essential in any treatment strategy that addresses
automatisms in AUD [34].
Fig. 1 Processes underlying the development and maintenance of alcohol In light of this, it was also observed that goal-directed de-
use disorders cision-making is affected by increased life stressors [35],
254 Curr Addict Rep (2020) 7:252–259

underlining the strong potential of interventions aimed at al- One hypothesis is that such contextual stimuli directly
tering stress-related effects on AUD. Overall, there is a prom- stimulate the motivation to drink via Pavlovian-to-
inent lack of therapeutic interventions that target the overreli- Instrumental Transfer (PIT): a behavioral phenomenon de-
ance on habitual control in AUD directly. However, habitual scribing how Pavlovian-conditioned cues enhance instrumen-
alcohol use largely depends on instrumental conditioning with tal behavior for rewarding outcomes (e.g., alcohol seeking and
learned stimulus-response associations. This indicates that intake) [54, 55]. In a current study in alcohol-dependent pa-
alcohol-associated environmental stimuli act as powerful mo- tients, it was shown that there is an enhanced PIT effect on
tivators for recurrent alcohol intake [36]. instrumental behavior using Pavlovian cues that have been
passively associated with monetary reward and loss [56].
Furthermore, enhanced PIT was negatively related to goal-
Cue Reactivity directed control, suggesting a strong common basis of
Pavlovian inference and habitual control that might affect
As an individual diagnostic criterion, craving is the most se- the course and maintenance of AUD [57].
lective and specific across addictive disorders [15], but it is Using alcohol-related stimuli in a PIT task, Schad and col-
also an individual experience that varies over time and is elic- leagues [58] showed that alcohol-related background stimuli
ited by exposure to different drug-related cues and autonomic inhibited the approach behavior in prospective abstinent
responses, which can manifest as higher heart rate as well as alcohol-dependent patients, but not in healthy controls or pro-
higher skin conductance [37, 38] but predominantly trigger spective relapsing patients. This observation could indicate
aversive responses such as tension, restlessness, and trembling that subsequent abstainers acquired a successful way to deal
[39]. In line with that, higher heart rate variability (HRV) with alcohol cues and that such behavior inhibition may be
during exposure to stress-primed alcohol cues was linked to specifically trained in therapeutic interventions.
relapse rates [40], while HRV might reflect increased active Despite these promising findings, the mechanism underly-
suppression of appetitive motivational responses in highly ing approach avoidance behavior related to different
cue-reactive individuals [41, 42]. Others argue that physiolog- Pavlovian stimuli is not known to date. However, it is known
ical responses to alcohol cues are mainly unconsciously proc- that in patients with AUD there is a bias toward action ten-
essed, as they were not correlated to self-ratings of arousal, dencies to approach alcohol and alcohol-related stimuli [59].
valence, and craving [43]. The same study also linked shorter One method to assess such an approach bias, i.e., automated
abstinence duration in AUD patients to an attenuated startle instrumental behavior in reaction to Pavlovian stimuli, is the
response toward alcohol cues [43]. Studies furthermore re- so-called Approach-Avoidance Task (AAT, see 60). Here,
ported a positive link between display of alcohol cues and patients are explicitly or implicitly asked to initiate approach
subsequent craving as well as alcohol consumption in heavy or avoidance movements (pulling/pushing a joystick) in re-
social drinkers [44, 45]. A promising approach to assess crav- sponse to alcohol-related pictures. Wiers and colleagues [61]
ing in a valid manner without biases associated with retrospec- observed that heavy drinkers indeed showed strong automatic
tive reporting is the so-called Ecological Momentary approach tendencies for alcohol (approach bias). Here, the so-
Assessment (EMA, e.g., see 46 for review). This method of- called Approach Bias Modification (ABM), which uses a
fers the opportunity to examine both craving and substance training version of the AAT, has been shown to be effective
use with strong ecological validity by collecting real-time data in the treatment of AUD: By using AAT training, patients’
in daily life and to identify relevant moderators of craving initial approach bias could be changed into an avoidance bias
[47•]. for alcohol-related stimuli [62]. This effect even generalized to
On a neural level, relapse in AUD patients was also directly untrained pictures, and patients showed better treatment out-
linked to cue-induced functional activation in the striatum, comes in terms of reduced relapse rates 1 year later [60].
anterior cingulate cortex, as well as medial prefrontal cortex However, the underlying mechanisms of ABM are not fully
[48, 49]. Furthermore, examining functional correlation be- understood (see 29).
tween brain regions active during a cue-reactivity task, Another psychological treatment approach that aims at
Stroche and colleagues [50] found that prefrontal-striatal con- diminishing the impact of cues (both contextual and specific)
nectivity during cue reactivity was negatively related to crav- on drug intake and relapse is based on animal extinction re-
ing and alcohol consumption, indicating a potential top-down search [17, 63]. The so-called cue exposure therapy (CET)
control effect that limits craving. operationalizes the prediction that conditioned responses to
It has been argued that alcohol cues affect subsequent drug cues can be extinguished by prolonged non-reinforced
drinking via a direct stimulus-response association [51–53]. drug cue exposure [64, 65]. One meta-analysis examined the
In extension of this, neutral environmental stimuli can become effect of CET on abstinence or drug-use reduction across sev-
associated with drinking and also reinforce alcohol intake eral studies and concluded the intervention to be ineffective
[36]. for other substance use disorders [66], but significant effect
Curr Addict Rep (2020) 7:252–259 255

sizes indicated clinical efficacy in AUD [67–69]. In line with adolescence. Thus, the experience of stress may act as an
this, a more recent meta-analytic review indicated that AUD internal cue for drug-seeking behavior in addictions, compa-
patients do benefit from CET, specifically on secondary out- rable with effects of drug-associated external cues. Further,
comes such as drinking score, latency to relapse, and alcohol- stress exposure has a strong moderating influence on cogni-
induced cravings [70]. tive abilities, reward learning, risk-taking, reward
In neuroimaging studies, it was shown that CET reduced responsivity, and decision-making [35, 87–90]. In particular,
neural cue reactivity in the ventral and dorsal striatum [71, a recent study assessed the influence of stress exposure on
72]. In extension to traditional CET, the so-called memory behavior (i.e., button presses to earn junk food) induced by
retrieval-extinction has been proposed as an augmentation. Pavlovian stimuli in a group of healthy controls [91]. Here, it
Based on fear extinction research in animals, it was shown was found that high levels of stress were associated with ele-
that memories can be diminished if non-reinforced exposure vated responding in the presence of a cue associated with a
takes place during memory consolidation [73, 74]. In a study non-rewarding outcome, whereas low levels of stress were
combining human and rodent research, Xue and colleagues associated with appropriate suppression of responding
[75] showed that retrieval of drug-associated memories before (inhibition) during presentation of this cue. Noteworthy, gen-
the extinction phase led to decreased cue-induced craving as der and age effects were not found so far in previous studies
well as increased abstinence rates. Recently, research into [56, 58, 92].
CET has been extended by technological advances to improve Moreover, stress has a high propensity to shift goal-
the effects and accessibility of CET for AUD [76]. A gamified directed behavior to more habitual behavior (e.g., 93). This
version of CET in combination with virtual reality (VR) was phenomenon plays a key role in addictive behaviors:
well received in a cohort of AUD patients [77], and another Although initially drugs are consumed to, for example, avoid
study could show that VR CET reduced craving [78]. A discomfort or to relax (i.e., to achieve a certain goal), drug-
video-enabled live action CET showed a promising treatment taking behavior can become habitual without considering the
outcome as well [79]. One study assessed if cognitive behav- outcome when intake is regularly repeated. Habitual behavior
ioral therapy was more effective when combined with CET is then performed automated and largely independent of its
and training of urge-specific coping skills or with aftercare as consequences by simply repeating actions associated with past
usual [80]. In addition, the deliverance of CET between group reward, while goal-directed actions are performed because
sessions and via a smartphone app was tested, and no differ- they are expected to produce a certain (desirable) outcome
ence in efficacy was found; however, also no additional ben- [19]. Regarding the impact of stress, Schwabe and Wolf [93]
efit to cognitive behavioral therapy was indicated [80]. observed that stress modulates the control of instrumental ac-
An additional line of research aims to enhance the efficacy tion in a manner that favors habitual over goal-directed action.
of CET using pharmacological adjuncts like D-cycloserine, a In line with this finding, Friedel and colleagues [90•] observed
partial N-methyl-D-aspartate (NMDA) receptor agonist that high chronic life stress reduced goal-directed and in-
shown to facilitate extinction learning in animal models of creased habitual decision-making in healthy subjects moder-
drug addiction [81]. While translating these findings to cue ated by low cognitive capacity.
exposure in addiction revealed very heterogeneous results Although generally adaptive, these changes in the control
[82], at least some preliminary evidence indicate that DCS- of instrumental action under stress may promote dysfunctional
augmented cue exposure reduced cue-induced BOLD activa- behaviors and the development of mental disorders such as
tion in the ventral striatum [71] and subjective craving [83] in addiction.
subjects with AUD. Although there is evidence on the prominent role of stress
Overall, there is ample information on the effects of drug- in the course of addiction, surprisingly, only a few studies are
related cues on various addiction-related processes, and dif- focusing on stress reduction in this field of research. Based on
ferent interventional approaches such as ABM and cue expo- mindfulness-based stress reduction, mindfulness-based inter-
sure therapy have been developed based on this evidence. ventions (MBIs) such as mindfulness-based relapse preven-
However, to date it remains unclear whether these approaches tion (MBRP) [94, 95] or mindfulness-oriented recovery en-
enhance treatment effects beyond standard interventions such hancement (MORE) [96], among others, target several patho-
as CBT. logical mechanisms in SUDs. Notably, there is support for the
effectiveness of MBIs in reducing stress in the context of
Stress addiction: Measures of heart rate variability (HRV) are often
used as an index of stress regulatory ability [97], while higher
Besides contextual (Pavlovian drug-associated) cues, stress HRV in response to drug cues might indicate the need for
has also been shown to induce drug-seeking behavior [84, higher regulatory effort [40]. In samples with SUDs, MBRP
85]. Moreover, in a study by Seo et al. [86], stressful life was associated with increased HRV in response to stress
events were associated with heavy drinking in early [98–100]. In AUD patients, participation in MORE compared
256 Curr Addict Rep (2020) 7:252–259

with a control intervention led to increased HRV recovery indicated mixed results. These discrepant results may be due
from stress-primed alcohol cues in AUD patients [101]. to unidentified modifying variables, which may well be
Other studies observed that 2 weeks of meditation training targeted using ambulatory assessment with EMA [16, 46,
(integrative body-mind training) produced a significant reduc- 47]. In light of these digital technologies and opportunities,
tion in smoking among a group of smokers while progressive mechanism-based interventions with the aim of (1) the pro-
muscle relaxation as an active control condition did not [102, motion of goal-directed control, (2) modification of Pavlovian
103]. effects on instrumental behavior, and (3) reduction of stress to
Furthermore, in smokers, decreased hair cortisol was asso- enhance cognitive control over drug urges can be tested within
ciated with mindfulness training, indicating a decrease in intense longitudinal datasets that also reflect differences in
chronic stress [104]. Brewer and colleagues [105] assessed gender, age, social status, and cultural diversity within an es-
mindfulness training (MT) compared with cognitive behavior- sential future field of research [16••].
al therapy (CBT) in individuals with alcohol and or cocaine
use disorder showing reduced psychological and physiologi- Funding Information Open Access funding provided by Projekt DEAL.
This work was supported by the German Research Foundation (DFG,
cal indices of stress during stress provocation in MT compared
Project-ID 402170461 – TRR 265).
with CBT. A.B. was moreover in part supported by the German Ministry for
Likewise, Back and colleagues [106] observed significant- Education and Research (BMBF 01ZX1311E/1611E) and the German
ly less stress-induced craving and stress-related responses Ministry of Health (BMG, ZMVI1-2516DSM223).
(during stress provocation) and greater ability to resist urges
to consume in subjects with SUD receiving a cognitive- Compliance with Ethics Guidelines
behavioral stress management intervention in contrast to the
comparison group. In pathological gamblers, a stress manage- Conflict of Interest The authors declare no conflicts of interest in the
production of this work.
ment program including relaxation breathing revealed a sig-
nificant reduction of stress, depression, and anxiety symptoms Human and Animal Rights and Informed Consent This article does not
as well as an increase of life satisfaction and a better daily contain any studies with human or animal subjects performed by any of
routine compared with a waiting list control group [107]. A the authors.
neuroimaging study associated mindfulness training in
Open Access This article is licensed under a Creative Commons
smokers with decreased neural activity within insula and Attribution 4.0 International License, which permits use, sharing, adap-
amygdala during exposure to stress, which was in turn asso- tation, distribution and reproduction in any medium or format, as long as
ciated with the amount of cigarettes smoked at follow-up you give appropriate credit to the original author(s) and the source, pro-
vide a link to the Creative Commons licence, and indicate if changes were
[108].
made. The images or other third party material in this article are included
Another interesting instrumental learning approach for pa- in the article's Creative Commons licence, unless indicated otherwise in a
tients with AUD—which might also be used in stress credit line to the material. If material is not included in the article's
regulation—is real-time fMRI neurofeedback (rtfMRI NF). Creative Commons licence and your intended use is not permitted by
statutory regulation or exceeds the permitted use, you will need to obtain
By feeding back the neural activity in circumscribed brain
permission directly from the copyright holder. To view a copy of this
regions to the patient while presenting alcohol cues, its goal licence, visit http://creativecommons.org/licenses/by/4.0/.
is to enhance control over brain activation and related cogni-
tive processes [109]. First study results indeed indicate a re-
duction of neuronal activity and craving in patients with AUD
[109] and of striatal cue-reactivity in heavy drinkers by rtfMRI References
NF [110].

Papers of particular interest, published recently, have been

Conclusion highlighted as:
• Of importance
Several key mechanisms that control the course of AUD have •• Of major importance
been identified by a large body of research that has been con-
1. AmericanPsychiatricAssociation. Diagnostic and Statistical
tinuously expanded over the last decade. Integration of this Manual of Mental Disorders (DSM-5). Washington D.C. and
literature on habitual decision-making [20, 57], cue-induced London: American Psychiatric Publishing; 2013.
behavioral tendencies [56, 92], as well as the amplifying ef- 2. Auriacombe M, Serre F, Denis C, Fatseas M. Diagnosis of addic-
fects of stressful events [86, 90] can provide a framework to tions. The Routledge Handbook of the Philosophy and Science of
Addiction. H. Pickard and S. Ahmed. London and New York,
identify and disentangle the relative contributions of these Routledge; 2018. pp. 132–144.
mechanisms to AUD. However, while there have been at- 3. World Health Organization. Global status report on alcohol and
tempts to target these mechanisms to treat AUD, studies health 2018; Geneva, World Health Organization; 2019.
Curr Addict Rep (2020) 7:252–259 257

4. Mann K, Batra A, Fauth-Bühler M, Hoch E. German guidelines 23. Tanaka SC, Balleine BW, O'Doherty JP. Calculating conse-
on screening, diagnosis and treatment of alcohol use disorders. quences: brain systems that encode the causal effects of actions.
Eur Addict Res. 2017;23(1):45–60. J Neurosci. 2008;28(26):6750–5.
5. Garbusow M, Sebold M, Beck A, Heinz A. Too difficult to stop: 24.•• Sebold M, Nebe S, Garbusow M, Guggenmos M, Schad DJ, Beck
mechanisms facilitating relapse in alcohol dependence. A, et al. When habits are dangerous: alcohol expectancies and
Neuropsychobiology. 2014;70(2):103–10. habitual decision making predict relapse in alcohol dependence.
6. Koob GF, Volkow ND. Neurobiology of addiction: a Biol psychiatry. 2017;82(11):847–56 This important study indi-
neurocircuitry analysis. Lancet Psychiatry. 2016;3(8):760–73. cates poor treatment outcome specifically resulting from an
7. Everitt BJ, Robbins TW. From the ventral to the dorsal striatum: interaction between high drug expectancies and low model-
devolving views of their roles in drug addiction. Neuroscience and based decision making.
biobehavioral reviews. 2013;37(9 Pt A):1946–54. 25. Deserno L, Huys QJM, Boehme R, Buchert R, Heinze H-J, Grace
8. Volkow ND, Morales M. The brain on drugs: from reward to AA, et al. Ventral striatal dopamine reflects behavioral and neural
addiction. Cell. 2015;162(4):712–25. signatures of model-based control during sequential decision mak-
ing. Proc Natl Acad Sci. 2015;112(5):1595–600.
9. Bossert JM, Marchant NJ, Calu DJ, Shaham Y. The reinstatement
26. Ersche KD, Gillan CM, Jones PS, Williams GB, Ward LH,
model of drug relapse: recent neurobiological findings, emerging
Luijten M, et al. Carrots and sticks fail to change behavior in
research topics, and translational research. Psychopharmacology.
cocaine addiction. Science. 2016;352(6292):1468–71.
2013;229(3):453–76.
27. Genauck A, Quester S, Wüstenberg T, Mörsen C, Heinz A,
10. Berridge KC, Robinson TE. Liking, wanting, and the incentive- Romanczuk-Seiferth N. Reduced loss aversion in pathological
sensitization theory of addiction. Am Psychol. 2016;71(8):670–9. gambling and alcohol dependence is associated with differential
11. Beck A, Schlagenhauf F, Wustenberg T, Hein J, Kienast T, Kahnt alterations in amygdala and prefrontal functioning. Sci Rep.
T, et al. Ventral striatal activation during reward anticipation cor- 2017;7(1):16306.
relates with impulsivity in alcoholics. Biol Psychiatry. 2009;66(8): 28. Tiffany ST, Conklin CA. A cognitive processing model of alcohol
734–42. craving and compulsive alcohol use. Addiction. 2000;95(8s2):
12. Romanczuk-Seiferth N, Koehler S, Dreesen C, Wustenberg T, 145–53.
Heinz A. Pathological gambling and alcohol dependence: neural 29. Eberl C, Wiers RW, Pawelczack S, Rinck M, Becker ES,
disturbances in reward and loss avoidance processing. Addict Lindenmeyer J. Approach bias modification in alcohol depen-
Biol. 2015;20(3):557–69. dence: do clinical effects replicate and for whom does it work
13. Heinz A. Dopaminergic dysfunction in alcoholism and best? Dev Cogn Neurosci. 2013;4:38–51.
schizophrenia–psychopathological and behavioral correlates. 30.•• Wiers CE, Stelzel C, Gladwin TE, Park SQ, Pawelczack S,
Eur Psychiatry. 2002;17(1):9–16. Gawron CK, et al. Effects of cognitive bias modification training
14. Koob GF. Negative reinforcement in drug addiction: the darkness on neural alcohol cue reactivity in alcohol dependence. The
within. Curr Opin Neurobiol. 2013;23(4):559–63. American journal of psychiatry. 2015;172(4):335–43
15. Kervran C, Shmulewitz D, Serre F, Stohl M, Denis C, Hasin D, Remarkably, the authors show that Approach Avoidance
et al. Item response theory analyses of DSM-5 substance use dis- Training is effective in reduction of craving as well as decreas-
order criteria in French outpatient addiction clinic participants. ing cue-induced mesolimbic brain activity in patients with
How much is craving special? Drug and alcohol dependence. AUD.
2020:108036. 31. Stock A-K. Barking up the wrong tree: why and how we may need
16.•• Heinz A, Kiefer F, Smolka MN, Endrass T, Beste C, Beck A, et al. to revise alcohol addiction therapy. Front Psychol. 2017;8(884).
Addiction research consortium: losing and regaining control over https://doi.org/10.3389/fpsyg.2017.00884.
drug intake (ReCoDe)—from trajectories to mechanisms and in- 32. Bate KS, Malouff JM, Thorsteinsson ET, Bhullar N. The efficacy
terventions. Addiction biology. 2020;25(2):e12866 The domains of habit reversal therapy for tics, habit disorders, and stuttering: a
of this described collaborative research center aim at identifi- meta-analytic review. Clin Psychol Rev. 2011;31(5):865–71.
cation of key addiction mechanisms as well as interventions to 33. Yang C, Hao Z, Zhu C, Guo Q, Mu D, Zhang L. Interventions for
specifically target these mechanisms in order to regain control tic disorders: an overview of systematic reviews and meta analy-
over drug intake. ses. Neurosci Biobehav Rev. 2016;63:239–55.
17. Everitt BJ, Robbins TW. Drug addiction: updating actions to 34. Gladwin TE, Wiers CE, Wiers RW. Interventions aimed at auto-
habits to compulsions ten years on. Annu Rev Psychol. 2016;67: matic processes in addiction: considering necessary conditions for
23–50. efficacy. Curr Opin Behav Sci. 2017;13:19–24.
18. Gladwin TE, Wiers CE, Wiers RW. Cognitive neuroscience of 35. Friedel E, Schlagenhauf F, Beck A, Dolan RJ, Huys QJ, Rapp
cognitive retraining for addiction medicine: from mediating mech- MA, et al. The effects of life stress and neural learning signals
anisms to questions of efficacy. Prog Brain Res. 2016;224:323– on fluid intelligence. Eur Arch Psychiatry Clin Neurosci.
44. 2015;265(1):35–43.
36. Berridge KC. From prediction error to incentive salience:
19. Dolan RJ, Dayan P. Goals and habits in the brain. Neuron.
mesolimbic computation of reward motivation. Eur J Neurosci.
2013;80(2):312–25.
2012;35(7):1124–43.
20. Balleine BW, O'Doherty JP. Human and rodent homologies in
37. Carter BL, Tiffany ST. Meta-analysis of cue-reactivity in addic-
action control: corticostriatal determinants of goal-directed and
tion research. Addiction. 1999;94(3):327–40.
habitual action. Neuropsychopharmacology. 2010;35(1):48–69.
38. Sinha R, Talih M, Malison R, Cooney N, Anderson GM, Kreek
21. Smittenaar P, FitzGerald TH, Romei V, Wright ND, Dolan RJ. MJ. Hypothalamic-pituitary-adrenal axis and sympatho-adreno-
Disruption of dorsolateral prefrontal cortex decreases model- medullary responses during stress-induced and drug cue-induced
based in favor of model-free control in humans. Neuron. cocaine craving states. Psychopharmacology. 2003;170(1):62–72.
2013;80(4):914–9. 39. Bergquist KL, Fox HC, Sinha R. Self-reports of interoceptive
22. Valentin VV, Dickinson A, O'Doherty JP. Determining the neural responses during stress and drug cue-related experiences in
substrates of goal-directed learning in the human brain. J cocaine-and alcohol-dependent individuals. Exp Clin
Neurosci. 2007;27(15):4019–26. Psychopharmacol. 2010;18(3):229–37.
258 Curr Addict Rep (2020) 7:252–259

40. Garland EL, Franken IH, Howard MO. Cue-elicited heart rate 57. Sebold M, Schad DJ, Nebe S, Garbusow M, Jünger E, Kroemer
variability and attentional bias predict alcohol relapse following NB, et al. Don’t think, just feel the music: individuals with strong
treatment. Psychopharmacology. 2012;222(1):17–26. Pavlovian-to-instrumental transfer effects rely less on model-based
41. Ingjaldsson JT, Laberg JC, Thayer JF. Reduced heart rate variabil- reinforcement learning. J Cogn Neurosci. 2016;28(7):985–95.
ity in chronic alcohol abuse: relationship with negative mood, 58. Schad DJ, Garbusow M, Friedel E, Sommer C, Sebold M, Hägele
chronic thought suppression, and compulsive drinking. Biol C, et al. Neural correlates of instrumental responding in the con-
Psychiatry. 2003;54(12):1427–36. text of alcohol-related cues index disorder severity and relapse
42. Segerstrom SC, Nes LS. Heart rate variability reflects self- risk. Eur Arch Psychiatry Clin Neurosci. 2019;269(3):295–308.
regulatory strength, effort, and fatigue. Psychol Sci. 2007;18(3): 59. Palfai TP, Ostafin BD. Alcohol-related motivational tendencies in
275–81. hazardous drinkers: assessing implicit response tendencies using
43. Leménager T, Hill H, Reinhard I, Hoffmann S, Zimmermann US, the modified-IAT. Behav Res Ther. 2003;41(10):1149–62.
Hermann D, et al. Association between alcohol-cue modulated 60. Wiers RW, Eberl C, Rinck M, Becker ES, Lindenmeyer J.
startle reactions and drinking behaviour in alcohol dependent Retraining automatic action tendencies changes alcoholic pa-
patients—results of the PREDICT study. Int J Psychophysiol. tients’ approach bias for alcohol and improves treatment outcome.
2014;94(3):263–71. Psychol Sci. 2011;22(4):490–7.
44. Baines L, Field M, Christiansen P, Jones A. The effect of alcohol 61. Wiers RW, Rinck M, Dictus M, van den Wildenberg E. Relatively
cue exposure and acute intoxication on inhibitory control process- strong automatic appetitive action-tendencies in male carriers of
es and ad libitum alcohol consumption. Psychopharmacology. the OPRM1 G-allele. Genes Brain Behav. 2009;8(1):101–6.
2019;236(7):2187–99. 62. Wiers RW, Rinck M, Kordts R, Houben K, Strack F. Retraining
45. Van Dyke N, Fillmore MT. Operant responding for alcohol fol- automatic action-tendencies to approach alcohol in hazardous
lowing alcohol cue exposure in social drinkers. Addict Behav. drinkers. Addiction. 2010;105(2):279–87.
2015;47:11–6. 63. Berridge KC, Kringelbach ML. Affective neuroscience of plea-
46. Serre F, Fatseas M, Swendsen J, Auriacombe M. Ecological mo- sure: reward in humans and animals. Psychopharmacology.
mentary assessment in the investigation of craving and substance 2008;199(3):457–80.
use in daily life: a systematic review. Drug Alcohol Depend. 64. Boening JAL. Neurobiology of an addiction memory. J Neural
2015;148:1–20. Transm. 2001;108(6):755–65.
65. Drummond DC, Cooper T, Glautier SP. Conditioned learning in
47.• Fatseas M, Serre F, Swendsen J, Auriacombe M. Effects of anx-
alcohol dependence: implications for cue exposure treatment. Br J
iety and mood disorders on craving and substance use among
Addict. 1990;85(6):725–43.
patients with substance use disorder: an ecological momentary
66. Conklin CA, Tiffany ST. Applying extinction research and theory to
assessment study. Drug and alcohol dependence. 2018;187:242–
cue-exposure addiction treatments. Addiction. 2002;97(2):155–67.
8 Notably, by monitoring of AUD patients with ecological mo-
67. Monti PM, Rohsenow DJ, Rubonis AV, Niaura RS, Sirota AD,
mentary assessment, the authors found that substance use was
Colby SM, et al. Cue exposure with coping skills treatment for
predicted by craving intensity, while higher craving intensity
male alcoholics: a preliminary investigation. J Consult Clin
was associated with comorbid mood or anxiety disorders.
Psychol. 1993;61(6):1011–9.
48. Beck A, Wüstenberg T, Genauck A, Wrase J, Schlagenhauf F,
68. Rohsenow DJ, Monti PM, Rubonis AV, Gulliver SB, Colby SM,
Smolka MN, et al. Effect of brain structure, brain function, and
Binkoff JA, et al. Cue exposure with coping skills training and
brain connectivity on relapse in alcohol-dependent patients. Arch
communication skills training for alcohol dependence: 6-and 12-
Gen Psychiatry. 2012;69(8):842–52.
month outcomes. Addiction. 2001;96(8):1161–74.
49. Grüsser SM, Wrase J, Klein S, Hermann D, Smolka MN, Ruf M,
69. Sitharthan T, Sitharthan G, Hough MJ, Kavanagh DJ. Cue expo-
et al. Cue-induced activation of the striatum and medial prefrontal
sure in moderation drinking: a comparison with cognitive–
cortex predicts relapse in abstinent alcoholics.
behavior therapy. J Consult Clin Psychol. 1997;65(5):878–82.
Psychopharmacology. 2004;175(3):296–302.
70. Mellentin AI, Skøt L, Nielsen B, Schippers GM, Nielsen AS,
50. Strosche A, Zhang X, Kirsch M, Hermann D, Ende G, Kiefer F, Stenager E, et al. Cue exposure therapy for the treatment of alco-
et al. Investigation of brain functional connectivity to assess cog- hol use disorders: a meta-analytic review. Clin Psychol Rev.
nitive control over cue-processing in alcohol use disorder. Addict 2017;57:195–207.
Biol. 2020:e12863. 71. Kiefer F, Kirsch M, Bach P, Hoffmann S, Reinhard I, Jorde A,
51. Belin D, Jonkman S, Dickinson A, Robbins TW, Everitt BJ. et al. Effects of D-cycloserine on extinction of mesolimbic cue
Parallel and interactive learning processes within the basal gan- reactivity in alcoholism: a randomized placebo-controlled trial.
glia: relevance for the understanding of addiction. Behav Brain Psychopharmacology. 2015;232(13):2353–62.
Res. 2009;199(1):89–102. 72. Vollstädt-Klein S, Loeber S, Kirsch M, Bach P, Richter A, Buhler
52. Hogarth L, Dickinson A, Duka T. The associative basis of cue- M, et al. Effects of cue-exposure treatment on neural cue reactivity
elicited drug taking in humans. Psychopharmacology. in alcohol dependence: a randomized trial. Biol Psychiatry.
2010;208(3):337–51. 2011;69(11):1060–6.
53. Everitt BJ, Dickinson A, Robbins TW. The neuropsychological 73. Schiller D, Monfils M-H, Raio CM, Johnson DC, LeDoux JE,
basis of addictive behaviour. Brain Res Brain Res Rev. Phelps EA. Preventing the return of fear in humans using
2001;36(2–3):129–38. reconsolidation update mechanisms. Nature. 2010;463(7277):
54. Talmi D, Seymour B, Dayan P, Dolan RJ. Human pavlovian- 49–53.
instrumental transfer. J Neurosci. 2008;28(2):360–8. 74. Monfils M-H, Cowansage KK, Klann E, LeDoux JE. Extinction-
55. Cartoni E, Balleine B, Baldassarre G. Appetitive Pavlovian- reconsolidation boundaries: key to persistent attenuation of fear
instrumental transfer: a review. Neurosci Biobehav Rev. memories. Science. 2009;324(5929):951–5.
2016;71:829–48. 75. Xue Y-X, Luo Y-X, Wu P, Shi H-S, Xue L-F, Chen C, et al. A
56. Garbusow M, Schad DJ, Sebold M, Friedel E, Bernhardt N, Koch memory retrieval-extinction procedure to prevent drug craving
SP, et al. Pavlovian-to-instrumental transfer effects in the nucleus and relapse. Science. 2012;336(6078):241–5.
accumbens relate to relapse in alcohol dependence. Addict Biol. 76. Byrne SP, Haber P, Baillie A, Giannopolous V, Morley K. Cue
2016;21(3):719–31. exposure therapy for alcohol use disorders: what can be learned
Curr Addict Rep (2020) 7:252–259 259

from exposure therapy for anxiety disorders? Substance Use & editor. Mindfulness-Based Treatment Approaches (Second
Misuse. 2019;54(12):2053–63. Edition). San Diego: Academic Press; 2014. p. 141–57.
77. Vollstädt-Klein S, Mildner P, Bumb JM, Karl D, Ueberle C, 95. Witkiewitz K, Marlatt GA, Walker D. Mindfulness-based relapse
Shevchenko Y, et al. The training game SALIENCE for the therapy prevention for alcohol and substance use disorders. J Cogn
of alcohol use disorder. Health Informatics Journal. 2020;26(1): Psychother. 2005;19(3):211–28.
499–512. 96. Froeliger B, Mathew AR, McConnell P, Eichberg C, Saladin M,
78. Lee SH, Han DH, Oh S, Lyoo IK, Lee YS, Renshaw PF, et al. Carpenter M, et al. Restructuring reward mechanisms in nicotine
Quantitative electroencephalographic (qEEG) correlates of crav- addiction: a pilot fMRI study of mindfulness-oriented recovery
ing during virtual reality therapy in alcohol-dependent patients. enhancement for cigarette smokers. Evid Based Complement
Pharmacol Biochem Behav. 2009;91(3):393–7. Alternat Med. 2017;2017:1–10.
79. Nattala P, Murthy P, Leung KS, Rentala S, Ramakrishna J. Video- 97. Castaldo R, Melillo P, Bracale U, Caserta M, Triassi M, Pecchia
enabled cue-exposure-based intervention improves postdischarge L. Acute mental stress assessment via short term HRV analysis in
drinking outcomes among alcohol-dependent men: a prospective healthy adults: a systematic review with meta-analysis.
study at a government addiction treatment setting in India. J Ethn Biomedical Signal Processing and Control. 2015;18:370–7.
Subst Abus. 2018;17(4):532–47. 98. Brewer JA, Sinha R, Chen JA, Michalsen RN, Babuscio TA, Nich
80. Mellentin AI, Nielsen B, Nielsen AS, Yu F, Mejldal A, Nielsen C, et al. Mindfulness training and stress reactivity in substance
DG, et al. A Mobile phone app featuring cue exposure therapy as abuse: results from a randomized, controlled stage I pilot study.
aftercare for alcohol use disorders: an investigator-blinded ran- Subst Abus. 2009;30(4):306–17.
domized controlled trial. JMIR Mhealth Uhealth. 2019;7(8): 99. Carroll H, Lustyk MKB. Mindfulness-based relapse prevention
e13793. for substance use disorders: effects on cardiac vagal control and
81. Dhonnchadha BAN, Kantak KM. Cognitive enhancers for facili- craving under stress. Mindfulness. 2018;9(2):488–99.
tating drug cue extinction: insights from animal models. 100. Paz R, Zvielli A, Goldstein P, Bernstein A. Brief mindfulness
Pharmacol Biochem Behav. 2011;99(2):229–44. training de-couples the anxiogenic effects of distress intolerance
82. Otto MW, Kredlow MA, Smits JA, Hofmann SG, Tolin DF, de on reactivity to and recovery from stress among deprived smokers.
Kleine RA, et al. Enhancement of psychosocial treatment with d- Behav Res Ther. 2017;95:117–27.
cycloserine: models, moderators, and future directions. Biol 101. Garland EL, Gaylord SA, Boettiger CA, Howard MO.
Psychiatry. 2016;80(4):274–83. Mindfulness training modifies cognitive, affective, and physio-
83. MacKillop J, Few L, Stojek M, Murphy C, Malutinok S, Johnson logical mechanisms implicated in alcohol dependence: results of
F, et al. D-cycloserine to enhance extinction of cue-elicited crav- a randomized controlled pilot trial. J Psychoactive Drugs.
ing for alcohol: a translational approach. Translational psychiatry. 2010;42(2):177–92.
2015;5(4):e544-e. 102. Tang YY, Tang R, Posner MI. Mindfulness meditation improves
84. Shalev U, Grimm JW, Shaham Y. Neurobiology of relapse to heroin emotion regulation and reduces drug abuse. Drug Alcohol
and cocaine seeking: a review. Pharmacol Rev. 2002;54(1):1–42. Depend. 2016;163(Suppl 1):S13–8.
85. Sinha R. How does stress lead to risk of alcohol relapse? Alcohol 103. Tang YY, Tang R, Posner MI. Brief meditation training induces
Res. 2012;34(4):432–40. smoking reduction. Proc Natl Acad Sci U S A. 2013;110(34):
86. Seo S, Beck A, Matthis C, Genauck A, Banaschewski T, Bokde 13971–5.
ALW, et al. Risk profiles for heavy drinking in adolescence: dif- 104. Goldberg SB, Manley AR, Smith SS, Greeson JM, Russell E, Van
ferential effects of gender. Addict Biol. 2019;24(4):787–801. Uum S, et al. Hair cortisol as a biomarker of stress in mindfulness
87. Petzold A, Plessow F, Goschke T, Kirschbaum C. Stress reduces training for smokers. J Altern Complement Med. 2014;20(8):630–
use of negative feedback in a feedback-based learning task. Behav 4.
Neurosci. 2010;124(2):248–55. 105. Brewer JA, Sinha R, Chen JA, Michalsen RN, Babuscio TA, Nich
88. Cavanagh JF, Frank MJ, Allen JJ. Social stress reactivity alters C, et al. Mindfulness training and stress reactivity in substance
reward and punishment learning. Soc Cogn Affect Neurosci. abuse: results from a randomized, controlled stage I pilot study.
2011;6(3):311–20. Subst Abus. 2009;30(4):306–17.
89. Otto AR, Raio CM, Chiang A, Phelps EA, Daw ND. Working- 106. Back SE, Gentilin S, Brady KT. Cognitive-behavioral stress man-
memory capacity protects model-based learning from stress. Proc agement for individuals with substance use disorders: a pilot
Natl Acad Sci U S A. 2013;110(52):20941–6. study. J Nerv Ment Dis. 2007;195(8):662–8.
90.• Friedel E, Sebold M, Kuitunen-Paul S, Nebe S, Veer IM, 107. Linardatou C, Parios A, Varvogli L, Chrousos G, Darviri C. An 8-
Zimmermann US, et al. How accumulated real life stress experience week stress management program in pathological gamblers: a pilot
and cognitive speed interact on decision-making processes. Frontiers randomized controlled trial. J Psychiatr Res. 2014;56:137–43.
in human neuroscience. 2017;11:302 Although done in healthy 108. Kober H, Brewer JA, Height KL, Sinha R. Neural stress reactivity
subjects, this important study highlights the effect of stressful relates to smoking outcomes and differentiates between mindful-
events on decision making, as stress significantly decreases ness and cognitive-behavioral treatments. NeuroImage. 2017;151:
model-based control in subjects with slow cognitive speed. 4–13.
91. Quail SL, Morris RW, Balleine BW. Stress associated changes in 109. Karch S, Keeser D, Hümmer S, Paolini M, Kirsch V, Karali T,
Pavlovian-instrumental transfer in humans. Q J Exp Psychol et al. Modulation of craving related brain responses using real-
(Hove). 2017;70(4):675–85. time fMRI in patients with alcohol use disorder. PLoS One.
92. Sommer C, Garbusow M, Junger E, Pooseh S, Bernhardt N, 2015;10(7):e0133034-e.
Birkenstock J, et al. Strong seduction: impulsivity and the impact 110. Kirsch M, Gruber I, Ruf M, Kiefer F, Kirsch P. Real-time func-
of contextual cues on instrumental behavior in alcohol depen- tional magnetic resonance imaging neurofeedback can reduce
dence. Transl Psychiatry. 2017;7(8):e1183. striatal cue-reactivity to alcohol stimuli. Addict Biol. 2016;21(4):
93. Schwabe L, Wolf OT. Stress prompts habit behavior in humans. J 982–92.
Neurosci. 2009;29(22):7191–8.
94. Bowen S, Chawla N, Witkiewitz K. Chapter 7 - Mindfulness- Publisher’s Note Springer Nature remains neutral with regard to jurisdic-
based relapse prevention for addictive behaviors. In: Baer RA, tional claims in published maps and institutional affiliations.