Behavioral dysregulations by chronic alcohol abuse. Motivational enhancement therapy and cognitive behavioral therapy outcomes

Flavio Maria Ceci1, Silvia Francati1, Giampiero Ferraguti1, Giovanna Coriale2, Rosaria Ciccarelli2, Antonio Minni3, Antonio Greco3, Angela Musacchio3, Simone De Persis4, Mario Vitali5, Luigi Tarani6, Mauro Ceccanti7, Marisa Patrizia Messina8, elena fico9, pamela rosso9, marco fiore9

1Department of Experimental Medicine, Medical Faculty, Sapienza University of Rome, Italy; 2Centro Riferimento Alcologico Regione Lazio (CRARL), ASL 1 Roma, Italy; 3Department of Sense Organs, Medical Faculty, Sapienza University of Rome, Italy; 4ASL Rieti, Italy; 5Azienda Sanitaria Unica Regionale (ASUR) Marche, AV4, Ancona, Italy; 6Department of Pediatrics, Medical Faculty, “Sapienza” University of Rome, Italy; 7Società Italiana per il Trattamento dell’Alcolismo e le sue Complicanze (SITAC), Rome, Italy; 8Department of Gynecology, Obstetrics and Urology, Sapienza University of Rome, Italy; 9Institute of Biochemistry and Cell Biology (IBBC-CNR), Rome, Italy.

Summary. Patients with alcohol use disorder (AUD) do not manifest homogeneous clinical symptoms. Various studies described both cognitive impairments and psychiatric disorders among people with AUD. This disorder is one of the most frequent mental disorders in developed countries, due to excessive alcohol consumption. Alcohol is toxic as it increases the production of reactive oxygen species (ROS) and can cause dependence. This causes negative effects on brain development and cognitive functions that affect the individual’s work, health, and social life. Current pharmacology treatment for alcohol addiction is based on direct action against the neurotransmitters involved in alcohol dependence. AUD patients without comorbid psychiatric disorders or severe cognitive deficits are defined as “pure alcoholics”. To date, poor is known about effective treatments for this typology of AUD patients. Psychotherapy is largely used in resolving many psychiatric disorders, including substance use disorders. Motivational enhancement therapy (MET) and cognitive-behavioral therapy (CBT) are two psychotherapies used to achieve and maintain abstinence in patients affected by substance use disorders. This short review aims to describe two CBT and MET and to present the advantages and disadvantages of these two psychotherapies in the treatment of AUD.

Key words. Alcohol use disorders, cognitive-behavioral therapy, motivational enhancement therapy, reactive oxygen species.

Disregolazioni comportamentali da abuso cronico di alcol. Terapia di potenziamento motivazionale e risultati della terapia cognitivo comportamentale.

Riassunto. I pazienti con disturbo da uso di alcol (AUD) non manifestano sintomi clinici omogenei. Vari studi hanno descritto sia i disturbi cognitivi che i disturbi psichiatrici tra le persone con AUD. Questo è uno dei disturbi mentali più frequenti nei paesi sviluppati, a causa del consumo eccessivo di alcol. L’alcol è tossico in quanto aumenta la produzione di specie reattive dell’ossigeno (ROS) e può causare dipendenza. Ciò provoca effetti negativi sullo sviluppo del cervello e sulle funzioni cognitive che influenzano il lavoro, la salute e la vita sociale dell’individuo. L’attuale trattamento farmacologico per la dipendenza da alcol si basa sull’azione diretta contro neurotrasmettitori coinvolti nella dipendenza da alcol. I pazienti AUD senza disturbi psichiatrici in comorbilità o deficit cognitivi gravi sono definiti “alcolisti puri”. A oggi, si conosce poco sui trattamenti efficaci per questa tipologia di pazienti con AUD. La psicoterapia è ampiamente utilizzata per risolvere molti disturbi psichiatrici, compresi i disturbi da uso di sostanze. La terapia di potenziamento motivazionale (MET) e la terapia cognitivo-comportamentale (CBT) sono due psicoterapie utilizzate per raggiungere e mantenere l’astinenza nei pazienti affetti da disturbi da uso di sostanze. Questa breve rassegna si propone di descrivere due CBT e MET e di presentare i vantaggi e gli svantaggi di queste due psicoterapie nel trattamento dell’AUD.

Parole chiave. Disturbi da uso di alcol, specie reattive dell’ossigeno, terapia cognitivo-comportamentale, terapia di potenziamento motivazionale.

Alcohol use disorders

Alcohol use disorder (AUD) is the most common and untreated mental disorder worldwide, especially in more developed countries. Approximately 2 billion people consume alcohol in the world with 76.3 million who met the criteria for the AUD diagnosis1. According to the National Institute on Alcohol Abuse and Alcoholism, AUD is defined as a medical condition characterized by an impaired ability to stop or control alcohol abuse despite its negative effects2-5. AUD is a heterogeneous disorder for its medical, behavioral, cognitive, and social implications6,7. Chronic alcohol consumption is correlated with different diseases, although positive effects are gained when a moderate quantity of alcohol is used. Moderate alcohol consumption may increase the cardioprotective effect by upregulating the capacity of removing cholesterol, esterification of cholesterol, and the transfer of cholesteryl ester from high-density lipoprotein to the liver8-11. On the contrary, binge and chronic alcohol consumption cause injury, cirrhosis, stroke, cancer, and gastrointestinal diseases12-15.

Stressors and psychiatric illnesses, such as depression, anxiety, and bipolar disorder, can contribute to the development of AUD, as people believe they can solve their problems by drinking alcohol16-19. Indeed, different types of stressful factors like exposure to early life stress, acute stress, chronic stress, and posttraumatic stress disorders are responsible for the development of alcohol dependence20. In addition to psychological factors, alcohol addiction is caused by environmental factors, social factors, and biological factors, such as genetic predisposition21. Indeed, different studies have identified the presence of genetic variants involved in alcohol metabolism, and the pathogenesis and treatment of AUD22.

According to the Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-5), the diagnosis of AUD is done by using interview tests and psychometric tools for collecting signs and symptoms. One of the most used tests in the world is the AUD Identification Test. This test was developed by the World Health Organization as a ten-item questionnaire to identify risky and harmful alcohol consumption, and it helps and helps drinkers to reduce or quit alcohol consumption23. Measuring alcohol consumption through laboratory tests is also crucial for monitoring and managing dependence in abusers. Biomarkers of alcohol consumption are divided into direct biomarkers of ethanol metabolism, or indirect biomarkers, i.e., markers of cell and tissue damage induced by ethanol24. Among direct biomarkers, we find ethyl glucuronide (EtG): a metabolite of ethanol detectable in blood, urine, and hair25. In the urine, EtG is used as a marker of acute intoxication as it remains detectable in the urine for 2/3 days. Instead, in the hair, EtG is used as a marker of chronic consumption as it remains detectable for months26. Amongst indirect biomarkers, we find the carbohydrate-deficient transferrin (CDT): a robust marker of chronic alcohol consumption in men and non-pregnant women24. Unfortunately, it is not appropriate for pregnant women for the possible false positives due to the week of pregnancy.

Oxidative stress

Oxidative stress is the result of an imbalance between the production of reactive oxygen species and the ability to promptly eliminate reactive species and repair the resulting damage27. The loss of these defense mechanisms increases the production of reactive oxygen species (ROS) which damage cellular structures, such as proteins, lipids, and DNA28. Oxidative stress can cause severe DNA mutations up to the rupture of both strands29. Oxidative stress is involved in various acute and chronic disruptions, such as cardiovascular diseases, acute and chronic kidney diseases, neurodegenerative diseases, biliary diseases, liver diseases, and cancer30,31.

Alcohol is toxic as ethanol metabolism is directly involved in the production of ROS32. ROS are highly reactive oxygen-containing molecules that can react and damage complex cellular molecules. Furthermore, alcohol can alter the levels of some metals in the body, thus inducing the production of ROS. Finally, alcohol lowers the levels of antioxidants such as superoxide dismutase which can eliminate ROS33. In recent years it has been shown that resveratrol, a nonflavonoid phenol, and hydroxytyrosol may reduce the formation of oxygen radical species in the serum caused by chronic alcohol consumption34-39.

Effect alcohol on the human organism

The effects of alcohol on the human organism are heterogeneous, varying with the type of beverage, dose, sex, and age40. Women are found to be more susceptible to the effects of alcohol than men when considering the same amount ingested. Genetics also plays a crucial role as ethanol metabolism, reward neurological circuits, and therapeutic outcomes depend on specific inherited genetic variations41. Alcohol abuse is associated with numerous diseases. In particular, alcohol intoxication is correlated with cardiovascular diseases, liver diseases, cancer, and neurodegenerative diseases14,15.

In the last decades, numerous studies highlighted a strong relationship between alcohol abuse and cardiovascular diseases such as coronary heart diseases, stroke, hypertension, and peripheral arterial diseases. Acute alcohol intoxication and chronic consumption increases both systolic blood pressure and diastolic blood pressure and is associated with a higher risk of developing hypertension. In the study by Zhang and colleagues, results show how alcohol consumption from 0 to 20 g/day was associated with a reduced risk of stroke. Instead, alcohol consumption greater than 30 g/day was associated with a higher risk of stroke. Regarding coronary heart disease, a strong association was found between alcohol consumption and reduced risk of developing coronary heart disease in various countries of the world except in South Asian ethnicity. In 2016, the World Health Organization (WHO) found that 19% of all alcohol-attributable deaths in 2016 were from cardiovascular diseases42.

Excessive use of alcohol also promotes neurodegenerative diseases. Peng et al. highlighted a correlation between excessive alcohol consumption and the development of Alzheimer’s disease and Parkinson’s disease, but this link has not been confirmed in the onset of amyotrophic lateral sclerosis43. Furthermore, in Alzheimer’s disease patients a reduced cognitive decline was observed when the patient stopped drinking alcohol44.

Alcohol is the second main cause of chronic liver diseases and is one of the main triggers for the development and progression of liver cirrhosis. Chronic alcohol exposure induces a low expression of the cytokine interferon-γ which is an inhibitor of hepatic fibrosis45. Moreover, ROS can trigger the production of profibrotic cytokines and collagen in liver cells33. In a study conducted in the north of Italy, 13.5% of the sample developed alcoholic liver diseases after the exposition to high alcohol intake46. In addition, alcohol plays a synergy role with other risk factors of liver damage like hepatitis virus B or C, human immunodeficiency, and nonalcoholic fatty liver diseases47.

Cancer represents one of the leading causes of mortality in the world. In 2020, nearly 4% of cancers worldwide are caused by alcohol abuse48. Chronic alcohol abuse increases the risk of several types of cancer, including upper aerodigestive tract cancers, liver, colorectal, and breast. The mechanism that associates alcohol consumption with carcinogenesis is due to the production of acetaldehyde, a carcinogenic molecule, increased ROS production, increased inflammation, and reduced immune function45.

Drinking alcohol during pregnancy can also alter fetal development causing negative fetal events known as Fetal Alcohol Spectrum Disorders (FASD)49-52. FASD collects different conditions appearing in children, including microcephaly, dimorphism, psychomotor retardation, behavioral disorders, attention and concentration problems as shown in human and animal models6,53,54. Actually, due to the non-existence of a safe threshold of alcohol consumption, the only possible solution recommended by medical authorities is to avoid any form of alcohol drinking during pregnancy and lactation55-57.

Cognitive damage induced by alcohol abuse

Alcohol abuse has negative psychiatric and psychological consequences also throughout the disruptions of neurotrophins, polypeptides known to regulate the growth, survival and development of nerve cells58-62. Prolonged and excessive use of alcohol is a risk factor for the development of schizophrenia, dementia, bipolar disorder, depression, insomnia, and other disorders63. Bolton et al. found in their study that 24.1% of people with mood disorders used alcohol and drugs64. Stressful events during childhood and other chronic stressors have a great effect on health leading to the development of mental disorders (figure 1).

Alcohol consumption reduces stress, but at the same time its prolonged use alters the activity of the hypothalamus-pituitary-adrenal cortex causing neuroadaptive changes20,65. Sometimes even abstinence can lead to anxiety and dysphoria which stimulate a high use of substances19.

Schizophrenia is a cognitive disorder whose symptoms are hallucinations, disorganized speech, trouble with thinking, and lack of motivation66. The correlation between AUD and schizophrenia appears to be established67. In one study it was found that 18.9% of those with a diagnosis of substance-induced psychosis had alcohol as their most-used substance68.

Dementia is a neurodegenerative disease characterized by a progressive deterioration of cognitive abilities over time63. Chronic alcohol abuse has been shown to cause dementia and cognitive decline. This disorder is defined as alcohol-related dementia69. It was highlighted that people defined as heavy drinkers have a higher risk of developing dementia than abstains and light-moderate drinkers70. On the contrary, Solfrizzi et al. we’re not able to show a relationship between the quantity of alcohol consumed and the incidence of cognitive impairment71.

Bipolar disorder is a mental illness that causes an uncommon shift in mood, activity levels, energy, and concentration72. Previous works have shown a correlation between bipolar disorder and substance use disorders, particularly for AUD73. The bipolar condition is often worsened by the use of substances such as alcohol and drugs74.

Insomnia is related to alcohol dependence as the percentage of insomniacs who also use alcohol increases with increasing exposure to alcohol75. Previous studies have shown that patients who suffered from insomnia, intermittent sleep, and difficulty falling asleep, are exposed to a higher risk of developing alcohol dependence76.

Many studies have also shown that people with anxiety disorders are more predisposed to abuse alcohol77. It has also been seen that withdrawal is associated with various anxiety symptoms including panic attacks78.

Treatment of alcoholism

Alcohol addiction involves several neurotransmitters and their respective receptors in the brain, including dopamine, serotonin, opioid peptides, glutamate, and GABA79. Current drug treatment for alcohol addiction targets mainly the neurotransmitter systems80. One of the most common methods is based on the administration of benzodiazepine or diazepam81. In addition, disulfiram, acamprosate, and naltrexone, all approved by the FDA, can also be used to prevent further alcohol consumption82. These drugs are administered either during hospitalization in a health care institution or sometimes to people who remain in the community under close observation. Disulfiram is an aldehyde dehydrogenase inhibitor. It causes an increase in the acetaldehyde in the circulation and causes hangover symptoms. When patients taking disulfiram start drinking, they will experience unpleasant hangover symptoms. Acamprosate acts on GABA and the glutamate system by reducing the intensity of alcohol withdrawal, thus reducing the risk of relapse83. Naltrexone is an opioid antagonist, used for the treatment of alcohol and opioid dependence. The µ opioid receptor and endorphin induce a feeling of euphoria among individuals with AUD and different studies support that blocking the sensation of euphoria may reduce the risk of relapse and excessive alcohol consumption83.

Psychotherapy in the treatment
of alcoholism

Psychotherapy was defined by Brent et al. as «a modality of treatment in which the therapist and patient(s) work together to ameliorate psychopathologic conditions and functional impairment through a focus on the therapeutic relationship, the patient’s attitudes, thoughts, affect, and behavior; and social context and development»84. In recent years, many studies have shown that this psychological approach to therapy was highly effective in resolving many psychiatric conditions, including substance use disorders85,86. The implementation of psychotherapy must follow international guidelines and its aim is always to reduce symptoms, prevent relapses, improve cognitive, social, and emotional functioning, improve the quality of life and self-awareness87.

AUD is mainly dealt with through psychological interventions. In a study, the importance of psychotherapy is emphasized for adolescents suffering from alcohol abuse disorders88. According to some testimonies from members of anonymous alcoholics, the Hamburg review states that the purpose of psychotherapy must be lifelong abstinence to avoid loss of control caused by small doses of alcohol. It was seen that twelve-step facilitation therapy (TSF), motivational enhancement therapy (MET), and cognitive-behavioral therapy (CBT) are the psychotherapies most used to achieve and maintain abstinence89. TSF is based on a program that facilitates the active involvement of alcoholics and emphasizes in patients twelve spiritual principles. Among them, the first five are based on acceptance, surrender, and moral inventories90.

MET is a therapy that leads the patient through a motivational interview, of a directive and non-authoritarian nature, to behavioral change91. CBT aims to identify, in about 12 sessions, those situations of “high risk” for patients, that is, those conditions that increase the use of alcohol, making the subjects more responsible and with greater self-control. Despite the efficacy demonstrated in recent years of these treatments, there is great individual variability in the response. For example, a motivational interview is appropriate for a moderate AUD, while more protracted intervention will be required for an individual with a more severe disorder. For this reason, the “personalized medicine” approach is becoming increasingly popular in the resolution of this disorder92. The effectiveness of the therapy also depends on the fidelity of the treatment93. The Institute of Medicine in the United States, analyzing the literature, stated that there is no one best approach for all individuals, that patients may respond differently to different therapeutic approaches, and that treatment programs should be built with the various approaches that have proven effective. This problem of patient heterogeneity and its effects on therapy can be limited through the subdivision of patients into subgroups92. National Institute on Alcohol Abuse and Alcoholism funded The Project MATCH, which consisted of dividing more than 1,700 patients into the three main types of psychotherapy CBT, MET, and TSF. It was shown a significant improvement in most patients94. The United Kingdom Alcoholism Treatment Trial UKATT research team compared in terms of costs, health outcomes, and consequences for public sector resource the social network behavior therapy, a more intensive, socially based treatment, and MET, a more intensive, socially based treatment95.

Motivational Enhancement Therapy (MET)

MET is based on Motivational Interviewing (MI) and is typically very short as it needs 3-sessions of client-centered intervention96. It centers on improving patient motivation for variation in addictive behavior and solving ambivalence by growing intrinsic motivation97. In particular, MET aims to help these people to reach a reason for the change. It can be called a “motivational conversation”98. The therapist must bring about a behavioral change in the patient and strengthen the commitment to maintain this change. It examines the pros and cons of change by focusing on motivational factors99. It can be added to other therapies or used on its own. In the first case, MET has been found to reduce the abandonment of other treatments100. The COMBINE study investigated an intervention for alcoholics that combined MI-based therapy with alcohol medications101. The MI technique is having a wide diffusion in recent years with 212 ongoing projects that are analyzing effectiveness102. Despite this, negative results were shown in some clinical studies103. Amrhein et al. focused attention on the patient’s language during his therapy, creating a scale of the different preparatory language that goes from positive affirmations, of subjects in favor of a change, to negative affirmations of less favorable subjects. Those patients with favorable preparatory language had the best results99. The importance of patient commitment and determination was confirmed a few years later by Hodgins and his collaborators104.

Cognitive-behavioral therapy (CBT)

CBT is certainly the most used treatment for alcohol and other substance use disorders. Its purpose is to identify potential situations in which patients are at risk of relapse and to teach them methods to overcome them, both behaviorally and cognitively105. CBT is based on Marlatt and Gordon’s model of relapse prevention providing training to the patient that allows him to face moments at risk of relapse. It has been standardized in the MATCH project as approximately 12 sessions of 7-8 hours, which are videotaped. The breath test in which sobriety is measured precedes them. Therapy must be completed in 90 days. The meetings can be individual or group106.

The purpose of the sessions is to lead patients to master the skill of maintaining alcohol or drug abstinence. The points on which CBT is based are: (1) identification of the intrapersonal and interpersonal triggers that can cause a relapse, (2) training on reaction skills, (3) training on substance rejection skills, (4) analyzing functionally the use of those substances and (5) stimulation of activities not related to use. It includes self-control, identifying situations of alcohol use, setting goals, learning and practicing skills, and the rewards for achieving goals107. This technique requires active participation on the part of the patient108. Over the years it was shown to improve effectiveness on the heterogeneous population of alcohol users. The same positive result was obtained from the use of CBT for substance use disorders109. Behavioral Self-Control Training is a variant of CBT developed by Miller110. This variant aims at self-monitoring, therefore the management of alcohol consumption by the patient111.

CBT is used for many mental disorders, not just those due to alcohol, but also anxiety, schizophrenia, chronic migraine, obesity, bipolar disorder, depression, personality disorder, or other substance use disorders109. Carroll in his work underlines the importance of defining CBT as a dynamic model that evolves to improve his technique and have greater success in addictions112. Cognitive-behavioral therapy is also chosen because it has a longer duration of effects than other techniques and is very effective when used in combination with pharmacotherapy113. In the field of alcoholism, the combination of pharmacological and psychosocial treatments has aroused more interest but the effectiveness of the combination in preventing relapses must be further ascertained114. CBT has also been combined with other valid treatments such as Motivational Interviewing and this combination brought more valid results than the results obtained from the techniques used individually. The Cannabis Youth Treatment is a manualized treatment that uses a combination of both techniques115. Gonzalez and Dulin conducted a 6-week study of 52 people with alcohol disorders, the treatments were provided by a MET/CBT smartphone app and at the end of the six months, there was a strong reduction in alcohol consumption116. The combined use of CBT and MI requires particular attention to the conflicts that exist between the two techniques. CBT aims at absolute abstinence while Motivational Interviewing supports the autonomy of the client who can independently choose the goal to be achieved117. To date, CBT has been shown to give positive results compared to a lack of treatment, but studying the duration of effect and effectiveness compared to other treatments has led to conflicting and non-homogeneous results109. Butler et al. analyzed a meta-analysis on CBT and some psychiatric disorders concluding that a specific meta-analysis is needed for CBT used for substance use disorders118. Therefore, CBT is an effective therapy for alcohol or other substance disorders but is most effective when used in combination with drug therapy and psychosocial treatment.

MET versus CBT: efficacy of the treatment on abstinence

It is essential to validate and standardize approaches for the psychological treatment of AUD that increase the probability of success and are increasingly affordable. Many psychosocial treatments, including MI, have been shown to achieve good results at low cost. The United Kingdom Alcohol Treatment Trial in their study chose to use MET therapy being as effective as CBT and TSF but less expensive119.

The comparison between CBT and MET is based on some considerations: i) CBT and MET are validated AUD treatments; ii) that MET is more expensive than CBT; iii) CBT exists in a short form. CBT treatment appears to have stronger power to keep patients on treatment especially during the first three months and in these initial months, dropout occurs more often. Coriale et al. investigated and compared the efficacy of short form of CBT and MET in a cohort of men and women with AUD without comorbid or severe psychiatric disorders or cognitive impairment («pure alcoholics»)120. It was found that after one year of treatment of pure alcoholics with CBT and MET, in patients following MET there was a higher percentage of people who did not complete therapy. This abandonment was linked to the relapse especially during the first three months. What did not vary between the two therapies was the consumption of alcohol per day and the percentage of days of abstinence. In the same year, in a study conducted on college students who consumed alcohol, it was shown that MI administered in a short group is as effective as CBT121. In a previous study conducted with AUD patients admitted to Sapienza University of Rome, it was found that after one year of treatment with CBT, 47% of patients persisted in attending. In contrast, with MET-based treatment, only 17% had standard care. Khan et al. found that combining CBT and MET for two years resulted in a significant increase in abstinence122.


The studies cited in this review lead to the conclusion that cognitive and motivational therapies are important for improving AUD symptoms. Being a heterogeneous disorder, AUD needs further studies to be able to say with certainty which among MET or CBT are the best therapy. According to previous studies, we do hypothesize that these two therapies if added to drug treatment may provide better results. Finally, from the data we have to date, it emerges that the less expensive and intensive MET treatment gives significantly the same results of CBT.

Funding: this research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Conflict of interests: the authors have no conflict of interest to declare.

Acknowledgements: authors do thank Sapienza University of Rome, Italy, IBBC-CNR and SITAC, Società Italiana per il Trattamento dell’Alcolismo e le sue Complicanze, Rome, Italy, for the logistic support.


1. World Health Organisation. Global status report on alcohol and health. vol. 122. Geneva: World Health Organization, 2011.

2. Ceccanti M, Hamilton D, Coriale G, et al. Spatial learning in men undergoing alcohol detoxification. Physiol Behav 2015; 149: 324-30.

3. Ceccanti M, Coriale G, Hamilton DA, et al. Virtual Morris task responses in individuals in an abstinence phase from alcohol. Can J Physiol Pharmacol 2018; 96: 128-36.

4. Ceccanti M, Iannitelli A, Fiore M. Italian Guidelines for the treatment of alcohol dependence. Riv Psichiatr 2018; 53: 105-6.

5. National Institute on Alcohol Abuse N. Understanding Alcohol Use Disorder Fact Sheet 2021.

6. Ceci FM, Ferraguti G, Petrella C, et al. Nerve Growth Factor in Alcohol Use Disorders. Curr Neuropharmacol 2021; 19: 45-60.

7. Ciafrè S, Carito V, Ferraguti G, et al. How alcohol drinking affects our genes: an epigenetic point of view. Biochem Cell Biol 2019; 97: bcb-2018-0248.

8. Chianese R, Coccurello R, Viggiano A, et al. Impact of dietary fats on brain functions. Curr Neuropharmacol 2017; 16: 1059-85.

9. Ceci FM, Ceccanti M, Petrella C, et al. Alcohol drinking, apolipoprotein polymorphisms and the risk of cardiovascular diseases. Curr Neurovasc Res 2021; 18: 150-61.

10. Brinton EA. Effects of ethanol intake on lipoproteins. Curr Atheroscler Rep 2012; 14: 108-14.

11. Brien SE, Ronksley PE, Turner BJ, Mukamal KJ, Ghali WA. Effect of alcohol consumption on biological markers associated with risk of coronary heart disease: systematic review and meta-analysis of interventional studies. BMJ 2011; 342: d636.

12. Ferraguti G, Terracina S, Petrella C, et al. Alcohol and head and neck cancer: updates on the role of oxidative stress, genetic, epigenetics, oral microbiota, antioxidants, and alkylating agents. Antioxidants 2022; 11: 145.

13. Petrella C, Farioli-Vecchioli S, Cisale GY, et al. A healthy gut for a healthy brain: preclinical, clinical and regulatory aspects. Curr Neuropharmacol 2020; 19: 610-28.

14. Pohl K, Moodley P, Dhanda AD. Alcohol’s impact on the gut and liver. Nutrients 2021; 13: 3170.

15. Rumgay H, Murphy N, Ferrari P, Soerjomataram I. Alcohol and cancer: epidemiology and biological mechanisms. Nutrients 2021; 13: 3173.

16. Ciafrè S, Ferraguti G, Greco A, et al. Alcohol as an early life stressor: epigenetics, metabolic, neuroendocrine and neurobehavioral implications. Neurosci Biobehav Rev 2020; 118: 654-68.

17. Coriale G, Gencarelli S, Battagliese G, et al. Physiological responses to induced stress in individuals affected by alcohol use disorder with dual diagnosis and alexithymia. Clin Ter 2020; 171: e120-9.

18. Ledda R, Battagliese G, Attilia F, et al. Drop-out, relapse and abstinence in a cohort of alcoholic people under detoxification. Physiol Behav 2019; 198: 67-75.

19. Becker HC. Influence of stress associated with chronic alcohol exposure on drinking. Neuropharmacology 2017; 122: 115-26.

20. Sinha R. The role of stress in addiction relapse. Curr Psychiatry Rep 2007; 9: 388-95.

21. Carvalho AF, Heilig M, Perez A, Probst C, Rehm J. Alcohol use disorders. Lancet 2019; 394: 781-92.

22. Chen YC, Peng GS, Wang MF, Tsao TP, Yin SJ. Polymorphism of ethanol-metabolism genes and alcoholism: correlation of allelic variations with the pharmacokinetic and pharmacodynamic consequences. Chem Biol Interact 2009; 178: 2-7.

23. Bush K, Kivlahan DR, McDonell MB, Fihn SD, Bradley KA. The AUDIT alcohol consumption questions (AUDIT-C): an effective brief screening test for problem drinking. Arch Intern Med 1998; 158: 1789-95.

24. Cabezas J, Lucey MR, Bataller R. Biomarkers for monitoring alcohol use. Clin Liver Dis 2016; 8: 59-63.

25. Ferraguti G, Ciolli P, Carito V, et al. Ethylglucuronide in the urine as a marker of alcohol consumption during pregnancy: comparison with four alcohol screening questionnaires. Toxicol Lett 2017; 275: 49-56.

26. Biondi A, Freni F, Carelli C, Moretti M, Morini L. Ethyl glucuronide hair testing: a review. Forensic Sci Int 2019; 300: 106-19.

27. Sies H. Oxidative stress: concept and some practical aspects. Antioxidants 2020; 9: 1-6.

28. Liguori I, Russo G, Curcio F, et al. Oxidative stress, aging, and diseases. Clin Interv Aging 2018; 13: 757-72.

29. Sharma V, Collins LB, Chen TH, et al. Oxidative stress at low levels can induce clustered DNA lesions leading to NHEJ mediated mutations. Oncotarget 2016; 7: 25377-90.

30. Dubois-deruy E, Peugnet V, Turkieh A, Pinet F. Oxidative stress in cardiovascular diseases. Antioxidants 2020; 9: 1-15.

31. Hayes JD, Dinkova-Kostova AT, Tew KD. Oxidative stress in cancer. Cancer Cell 2020; 38: 167-97.

32. Sergent O, Griffon B, Cillard P, Cillard J. [Alcool et stress oxydatif]. Pathol Biol (Paris) 2001; 49: 689-95.

33. Albano E. Alcohol, oxidative stress and free radical damage. Proc Nutr Soc 2006; 65: 278-90.

34. Petrella C, Di Certo MG, Gabanella F, et al. Mediterranean diet, brain and muscle: olive polyphenols and resveratrol protection in neurodegenerative and neuromuscular disorders. Curr Med Chem 2021; 28: 7595-613.

35. Carito V, Ceccanti M, Tarani L, Ferraguti G, N. Chaldakov G, Fiore M. Neurotrophins’ modulation by olive polyphenols. Curr Med Chem 2016; 23: 3189-97.

36. De Nicolò S, Tarani L, Ceccanti M, et al. Effects of olive polyphenols administration on nerve growth factor and brain-derived neurotrophic factor in the mouse brain. Nutrition 2013; 29: 681-7.

37. Carito V, Ceccanti M, Cestari V, et al. Olive polyphenol effects in a mouse model of chronic ethanol addiction. Nutrition 2017; 33: 65-9.

38. Carito V, Venditti A, Bianco A, et al. Effects of olive leaf polyphenols on male mouse brain NGF, BDNF and their receptors TrkA, TrkB and p75. Nat Prod Res 2014; 28: 1970-84.

39. Petrella C, Carito V, Carere C, et al. Oxidative stress inhibition by resveratrol in alcohol-dependent mice. Nutrition 2020; 79-80: 110783.

40. Mittal N, Fleming SM, Martinez A, et al. Sex differences in cognitive performance and alcohol consumption in High Alcohol-Drinking (HAD-1) rats. Behav Brain Res 2020; 381: 112456.

41. Ferraguti G, Pascale E, Lucarelli M. Alcohol addiction: a molecular biology perspective. Curr Med Chem 2015; 22: 670-84.

42. WHO Regional Office for Europe. Status report on alcohol consumption, harm and policy responses in 30 European countries 2019. WHO Reg Off Eur 2019.

43. Peng B, Yang Q, Joshi RB, et al. Role of alcohol drinking in Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Int J Mol Sci 2020; 21: 2316.

44. Toda A, Tagata Y, Nakada T, Komatsu M, Shibata N, Arai H. Changes in Mini-Mental State Examination score in Alzheimer’s disease patients after stopping habitual drinking. Psychogeriatrics 2013; 13: 94-8.

45. Molina PE, Happel KI, Zhang P, Kolls JK, Nelson S. Focus on: alcohol and the immune system. Alcohol Res Heal 2010; 33: 97-108.

46. Bellentani S, Saccoccio G, Costa G, et al. Drinking habits as cofactors of risk for alcohol induced liver damage. Gut 1997; 41: 845-50.

47. Day CP. Who gets alcoholic liver disease: nature or nurture? (extended abstract). Acta Gastroenterol Belg 2003; 66: 290-1.

48. Rumgay H, Shield K, Charvat H, et al. Global burden of cancer in 2020 attributable to alcohol consumption: a population-based study. Lancet Oncol 2021; 22: 1071-80.

49. Fiore M, Petrella C, Coriale G, et al. Markers of neuroinflammation in the serum of prepubertal children with fetal alcohol spectrum disorders. CNS Neurol Disord Drug Targets 2021. doi:10.2174/1871527320666211201154839.

50. Terracina S, Ferraguti G, Tarani L, et al. Transgenerational abnormalities induced by paternal preconceptual alcohol drinking. Findings from humans and animal models. Curr Neuropharmacol 2021. doi:10.2174/1570159x19666211101111430.

51. Messina MP, D’Angelo A, Battagliese G, et al. Fetal alcohol spectrum disorders awareness in health professionals: implications for psychiatry. Riv Psichiatr 2020; 55: 79-89.

52. Jones KL, Smith DW. Recognition of the fetal alcohol syndrome in early infancy. Lancet 1973; 302: 999-1001.

53. Carito V, Ceccanti M, Ferraguti G, et al. NGF and BDNF alterations by prenatal alcohol exposure. Curr Neuropharmacol 2019; 17: 308-17.

54. Ceccanti M, Coccurello R, Carito V, et al. Paternal alcohol exposure in mice alters brain NGF and BDNF and increases ethanol-elicited preference in male offspring. Addict Biol 2016; 21: 776-87.

55. Ceci FM, Fiore M, Agostinelli E, et al. Urinary ethyl glucuronide for the assessment of alcohol consumption during pregnancy: comparison between biochemical data and screening questionnaires. Curr Med Chem 2021. doi: 10.2174/0929867328666211125100329.

56. Ferraguti G, Merlino L, Battagliese G, et al. Fetus morphology changes by second-trimester ultrasound in pregnant women drinking alcohol. Addict Biol 2020; 25: e12724.

57. Coriale G, Fiorentino D, Di Lauro F, et al. Fetal Alcohol Spectrum Disorder (FASD): neurobehavioral profile, indications for diagnosis and treatment. Riv Psichiatr 2013; 48: 359-69.

58. Ciafrè S, Ferraguti G, Tirassa P, et al. Nerve growth factor in the psychiatric brain. Riv Psichiatr 2020; 55: 4-15.

59. Fiore M, Korf J, Angelucci F, Talamini L, Aloe L. Prenatal exposure to methylazoxymethanol acetate in the rat alters neurotrophin levels and behavior: considerations for neurodevelopmental diseases. Physiol Behav 2000; 71: 57-67.

60. Manni L, Aloe L, Fiore M. Changes in cognition induced by social isolation in the mouse are restored by electro-acupuncture. Physiol Behav 2009; 98: 537-42.

61. Fiore M, Korf J, Antonelli A, Talamini L, Aloe L. Long-lasting effects of prenatal MAM treatment on water maze performance in rats: associations with altered brain development and neurotrophin levels. Neurotoxicol Teratol 2002; 24: 179-91.

62. Ceci FM, Ferraguti G, Petrella C, et al. Nerve Growth Factor, stress and diseases. Curr Med Chem 2020; 28: 2943-59.

63. Rehm J, Hasan OSM, Black SE, Shield KD, Schwarzinger M. Alcohol use and dementia: a systematic scoping review. Alzheimers Res Ther 2019; 11: 1.

64. Bolton JM, Robinson J, Sareen J. Self-medication of mood disorders with alcohol and drugs in the National Epidemiologic Survey on Alcohol and Related Conditions. J Affect Disord 2009; 115: 367-75.

65. Clarke T-K, Treutlein J, Zimmermann US, et al. HPA-axis activity in alcoholism: examples for a gene-environment interaction. Addict Biol 2008; 13: 1-14.

66. Mueser KT, McGurk SR. Schizophrenia. Lancet 2004; 363: 2063-72.

67. Archibald L, Brunette MF, Wallin DJ, Green AI. Alcohol use disorder and schizophrenia or schizoaffective disorder. Alcohol Res Curr Rev 2019; 40: e1-9.

68. Caton CLM, Drake RE, Hasin DS, et al. Differences between early-phase primary psychotic disorders with concurrent substance use and substance-induced psychoses. Arch Gen Psychiatry 2005; 62: 137-45.

69. Cheng C, Huang C-L, Tsai C-J, Chou P-H, Lin C-C, Chang C-K. Alcohol-Related Dementia: a systemic review of epidemiological studies. Psychosomatics 2017; 58: 331-42.

70. Gutwinski S, Schreiter S, Priller J, Henssler J, Wiers CE, Heinz A. Drink and think: impact of alcohol on cognitive functions and dementia - Evidence of dose-related effects. Pharmacopsychiatry 2018; 51: 136-43.

71. Solfrizzi V, D’Introno A, Colacicco AM, et al. Alcohol consumption, mild cognitive impairment, and progression to dementia. Neurology 2007; 68: 1790-9.

72. NIMH. Bipolar Disorder Available at: [last accessed 2022 January 17].

73. Li C, Palka JM, Brown ES. Cognitive impairment in individuals with bipolar disorder with and without comorbid alcohol and/or cocaine use disorders. J Affect Disord 2020; 272: 355-62.

74. Cerullo MA, Strakowski SM. The prevalence and significance of substance use disorders in bipolar type I and II disorder. Subst Abuse Treat Prev Policy 2007; 2: 29.

75. Chakravorty S, Chaudhary NS, Brower KJ. Alcohol dependence and its relationship with insomnia and other sleep disorders. Alcohol Clin Exp Res 2016; 40: 2271-82.

76. He S, Brooks AT, Kampman KM, Chakravorty S. The relationship between alcohol craving and insomnia symptoms in alcohol-dependent individuals. Alcohol Alcohol 2019; 54: 287-94.

77. Anker JJ, Kushner MG. Co-occurring alcohol use disorder and anxiety: bridging psychiatric, psychological, and neurobiological perspectives. Alcohol Res 2019; 40: arcr.v40.1.03.

78. Lepola U. Alcohol and depression in panic disorder. Acta Psychiatr Scand Suppl 1994; 377: 33-5.

79. Gilpin NW, Koob GF. Neurobiology of alcohol dependence: focus on motivational mechanisms. Alcohol Res Health 2008; 31: 185-95.

80. Vitali M, Mistretta M, Alessandrini G, et al. Pharmacological treatment for dual diagnosis: a literature update and a proposal of intervention. Riv Psichiatr 2018; 53: 160-9.

81. Chukwueke CC, Le Foll B. The human laboratory and drug development in Alcohol Use Disorder: recent updates. Methods Mol Biol 2019; 2011: 195-219.

82. Kranzler HR, Soyka M. Diagnosis and pharmacotherapy of alcohol use disorder a review. JAMA 2018; 320: 815-24.

83. Jonas DE, Amick HR, Feltner C, et al. Pharmacotherapy for adults with alcohol use disorders in outpatient settings: a systematic review and meta-analysis. JAMA 2014; 311: 1889-900.

84. Brent DA, Kolko DJ. Psychotherapy: definitions, mechanisms of action, and relationship to etiological models. J Abnorm Child Psychol 1998; 26: 17-25.

85. Ritvo RZ, Papilsky SB. Effectiveness of psychotherapy. Curr Opin Pediatr 1999; 11: 323-7.

86. Coriale G, Fiorentino D, De Rosa F, et al. Diagnosis of alcohol use disorder from a psychological point of view. Riv Psichiatr 2018; 53: 128-40.

87. Lamster F, Jäger M. [Psychotherapy of psychotic disorders]. Ther Umsch 2018; 75: 67-75.

88. Clark DB, Bukstein O, Cornelius J. Alcohol use disorders in adolescents: epidemiology, diagnosis, psychosocial interventions, and pharmacological treatment. Paediatr Drugs 2002; 4: 493-502.

89. Jaurigue MM, Cappell MS. Therapy for alcoholic liver disease. World J Gastroenterol 2014; 20: 2143-58.

90. Nowinski J, Baker S, Carroll KM. Twelve step facilitation therapy manual: a clinical research guide for therapists treating individuals with alcohol abuse and dependence. US Department of Health and Human Services, Public Health Service, National Institutes of Health 1995.

91. Spaeth M, Bleich S, Hillemacher T. [Motivational interviewing with alcohol-dependent patients]. Fortschr Neurol Psychiatr 2017; 85: 549-65.

92. Mann K, Hermann D. Individualised treatment in alcohol-dependent patients. Eur Arch Psychiatry Clin Neurosci 2010; 260 Suppl 2: S 116-20.

93. Miller WR, Rollnick S. The effectiveness and ineffectiveness of complex behavioral interventions: impact of treatment fidelity. Contemp Clin Trials 2014; 37: 234-41.

94. Allen J, Anton RF, Babor TF, et al. Matching patients with alcohol disorders to treatments: clinical implications from project MATCH. J Ment Heal 1998; 7: 589-602.

95. UKATT Research Team. UK Alcohol Treatment Trial: client-treatment matching effects. Addiction 2008; 103: 228-38.

96. Miller WR, Rose GS. Toward a theory of motivational interviewing. Am Psychol 2009; 64: 527-37.

97. Allen JP, Mattson ME, Miller WR, et al. Matching alcoholism treatments to client heterogeneity: project MATCH posttreatment drinking outcomes. J Stud Alcohol 1997; 58: 7-29.

98. Miller WR, Rollnick S. Motivational interviewing: helping people change. New York: Guilford Press, 2012.

99. Amrhein PC, Miller WR, Yahne CE, Palmer M, Fulcher L. Client commitment language during motivational interviewing predicts drug use outcomes. J Consult Clin Psychol 2003; 71: 862-78.

100. Madson MB, Schumacher JA, Baer JS, Martino S. Motivational interviewing for substance use: mapping out the next generation of research. J Subst Abuse Treat 2016; 65: 1-5.

101. Testing combined pharmacotherapies and behavioral interventions for alcohol dependence (the COMBINE study): a pilot feasibility study. Alcohol Clin Exp Res 2003; 27: 1123-31.

102. Moyers TB, Martin T, Houck JM, Christopher PJ, Tonigan JS. From in-session behaviors to drinking outcomes: a causal chain for motivational interviewing. J Consult Clin Psychol 2009; 77: 1113-24.

103. Carroll KM, Ball SA, Nich C, et al. Motivational interviewing to improve treatment engagement and outcome in individuals seeking treatment for substance abuse: a multisite effectiveness study. Drug Alcohol Depend 2006; 81: 301-12.

104. Hodgins DC, Ching LE, McEwen J. Strength of commitment language in motivational interviewing and gambling outcomes. Psychol Addict Behav J Soc Psychol Addict Behav 2009; 23: 122-30.

105. Perry CJ, Lawrence AJ. Addiction, cognitive decline and therapy: seeking ways to escape a vicious cycle. Genes Brain Behav 2017; 16: 205-18.

106. Flanagan JC, Jones JL, Jarnecke AM, Back SE. Behavioral treatments for alcohol use disorder and post-traumatic stress disorder. Alcohol Res 2018; 39: 181-92.

107. Marlatt GA, Witkiewitz K. Harm reduction approaches to alcohol use: health promotion, prevention, and treatment. Addict Behav 2002; 27: 867-86.

108. Kadden R. Cognitive-behavioral coping skills therapy manual: a clinical research guide for therapists treating individuals with alcohol abuse and dependence. US Department of Health and Human Services, Public Health Service, National Institutes of Health, 1995.

109. Carroll KM, Onken LS. Behavioral therapies for drug abuse. Am J Psychiatry 2005; 162: 1452-60.

110. Miller WR, Taylor CA. Relative effectiveness of bibliotherapy, individual and group self-control training in the treatment of problem drinkers. Addict Behav 1980; 5: 13-24.

111. Hester RK. Behavioral self-control training. In: Hester RK, Miller WR (eds). Handbook of alcoholism treatment approaches: effective alternatives. Boston: Allyn & Bacon, 1995.

112. Carroll KM, Kiluk BD. Cognitive behavioral interventions for alcohol and drug use disorders: through the stage model and back again. Psychol Addict Behav 2017; 31: 847-61.

113. Rawson RA, Huber A, McCann M, et al. A comparison of contingency management and cognitive-behavioral approaches during methadone maintenance treatment for cocaine dependence. Arch Gen Psychiatry 2002; 59: 817-24.

114. Magill M, Ray LA. Cognitive-behavioral treatment with adult alcohol and illicit drug users: a meta-analysis of randomized controlled trials. J Stud Alcohol Drugs 2009; 70: 516-27.

115. Series CYT. Motivational Enhancement Therapy and Cognitive Behavioral Therapy for adolescent cannabis users: 5 Sessions n.d.

116. Gonzalez VM, Dulin PL. Comparison of a smartphone app for alcohol use disorders with an internet-based intervention plus bibliotherapy: a pilot study. J Consult Clin Psychol 2015; 83: 335-45.

117. Wu SS, Schoenfelder E, Hsiao RC-J. Cognitive behavioral therapy and Motivational enhancement therapy. Child Adolesc Psychiatr Clin N Am 2016; 25: 629-43.

118. Butler AC, Chapman JE, Forman EM, Beck AT. The empirical status of cognitive-behavioral therapy: a review of meta-analyses. Clin Psychol Rev 2006; 26: 17-31.

119. UKATT Research Team. Cost effectiveness of treatment for alcohol problems: findings of the randomised UK alcohol treatment trial (UKATT). BMJ 2005; 331: 544.

120. Coriale G, De Rosa F, Battagliese G, et al. Motivational enhancement therapy versus Cognitive behavioral therapy in a cohort of men and women with alcohol use disorder. Biomed Rev 2019; 30: 125-35.

121. Martín-Pérez C, Navas JF, Perales JC, et al. Brief group-delivered motivational interviewing is equally effective as brief group-delivered cognitive-behavioral therapy at reducing alcohol use in risky college drinkers. PLoS One 2019; 14: e0226271.

122. Khan A, Tansel A, White DL, et al. Efficacy of psychosocial interventions in inducing and maintaining alcohol abstinence in patients with chronic liver disease: a systematic review. Clin Gastroenterol Hepatol 2016; 14: 191-202.