Alcohol and Alcoholism Advance Access published March 13, 2008

Alcohol & Alcoholism Vol. 0, No. 0, pp. 16, 2008 doi: 10.1093/alcalc/agn016

NEUROBIOLOGY AND TREATMENT IN ALCOHOLISMRECENT FINDINGS REGARDING

LESCHS TYPOLOGY OF ALCOHOL DEPENDENCE
THOMAS HILLEMACHER and STEFAN BLEICH
Department of Psychiatry and Psychotherapy, University Hospital Erlangen, Germany

(Received 00 2008; in revised form 00 2008; accepted 00 2008)

Abstract Subtyping in alcohol dependence has become an important issue as studies have proposed different neurobiological
mechanisms in alcoholism in the recent years. Studies have shown that alcohol dependence reflects a wide range of different phenotypes,
including psychological, social, and neurobiological factors. Different ways of subtyping have been proposed in the last decades, one of
them being Leschs typology of alcohol dependence. Recent investigations have shown that different subtypes of Leschs typology are
associated with specific neurobiological factors which may have important implications for clinical practice. This applies in particular for
genetic and neuroendocrinological factors, differences in the regulation of NMDA receptor-mediated glutamatergic neurotransmission,
and in response to acamprosate and naltrexone treatment.

INTRODUCTION
Alcohol dependence is a highly relevant disease in clinical
medicine. Social, psychological, and biological factors influ-
encing the etiogenesis of alcohol dependence are manifold and
subject to intensive research worldwide. Moreover, alcohol de-
pendence is a disease particularly characterized by frequent but
very different comorbidities. These comorbidities range from
medical conditions associated with alcohol consumption such
as liver cirrhosis or esophagus varices to psychiatric disor-
ders such as depression, ADHS, personality disorders, or anx-
iety disorders. Many attempts to classify patients with alcohol
dependence have been made in the past. These include bio-
logically orientated typologies (Cloninger et al., 1988; Babor
et al., 1992; Babor and Caetano, 2006) and classifications fo-
cusing on behavioral characteristics (Jellinek, 1960). The Lesch
typology, which is widely used in Europe and especially in
German-speaking countries, tries to integrate biological, social,
and psychological factors in one classification (Lesch et al.,
1990; Lesch and Walter, 1996). The typology differentiates
four subtypes: type 1 (model of allergy) consists of patients
with heavy alcohol withdrawal symptoms who tend to use al-
cohol to weaken detoxification symptoms. Patients of type 2
(model of anxiety or conflict) are characterized by using alco-
hol as self-medication because of anxiolytic effects. The main
characteristic in type 3 patients is an underlying affective disor-
der (alcohol as an antidepressant) (Kiefer and Barocka, 1999).
Type 4 patients (alcohol as adaptation) show pre-morbid cere-
bral defects, behavioral disorders, and a high social burden.
Patients are usually classified at admission for detoxification
treatment according to the decision tree developed in 1990
(Lesch et al., 1990). If it is not possible to determine an appro-
priate medical history at admission, a time period of 5 days is
allowed before classification into the referring type.
Leschs typology has been used in many research projects
focusing on very different aspects of alcoholism research. This
Author to whom correspondence should be addressed at: Department of
Psychiatry and Psychotherapy, University Hospital Erlangen, Schwabachan-
lage 6, D-91054 Erlangen, Germany. Tel: +49-9131-8533001; Fax:
+49-9131-8534105; E-mail: thomas.hillemacher@uk-erlangen.de
review will try to give an overview of the recent findings fo-
cusing on neurobiological aspects and treatment implications
regarding the subtypes of Leschs typology.
Homocysteine and the glutamate system
Various recent studies have shown that elevated serum levels of
the sulfur-containing amino acid homocysteine play a crucial
role in the neurobiology of alcoholism (Bleich et al., 2005),
particularly regarding withdrawal symptoms such as seizures
(Bleich et al., 2000a, 2006), cognitive impairment (Wilhelm
et al., 2006), and brain atrophy (Bleich et al., 2000b, 2003a).
Homocysteine is an excitatory amino acid and leads to an in-
crease of glutamatergic neurotransmission via overstimulation
of NMDA receptors (Bleich et al., 2003b, 2004b; Bigal et al.,
2007).
Regarding Leschs typology, it is known that patients of
Lesch type 1 tend to suffer from seizures and more prominent
withdrawal symptoms than patients of other types of Leschs
typology. In a recent study, it has been shown that homocysteine
serum levels are elevated in patients of Leschs type 1, espe-
cially in patients with a history of alcohol withdrawal seizures
(Bleich et al., 2004a). As homocysteine acts as a glutamate ag-
onist at the NMDA receptor, it is interesting whether there are
differences regarding serum levels of glutamic acid between
the different types of Leschs typology. In a recently published
work Walter et al. showed that blood levels of glutamic acid
differ between patients of Leschs typology. In this study, the
authors investigated a sample of 159 alcoholics, measuring glu-
tamic acid in peripheral blood and assessing the type of alcohol
dependence according to Leschs typology. As a main finding,
patients of types 1 and 4 showed significantly higher levels
of glutamic acid than patients of types 2 and 3. The authors
interpret these findings in type 1 patients as a kindling phe-
nomenon while in type 4 patients elevated glutamic acid values
may be related either to compulsivity and/or to the frequent
repetition of drinking and withdrawal (Walter et al., 2006).
Taken together, these findings show that particularly patients
of Leschs type 1 and possibly patients of type 4 seem to suffer
from changes in glutamatergic pathways which might underline
the marked withdrawal symptoms in these groups.


C The Author 2008. Published by Oxford University Press on behalf of Medical Council on Alcohol. All rights reserved
2 T. HILLEMACHER AND S. BLEICH
Genetics and Leschs typology
Many different candidate genes have been identified which
may be associated with alcoholism or with specific features of
the disease (e.g., withdrawal seizures). However, most of these
reports did not include subtyping of alcohol patients. Most re-
cently, a first study investigated Leschs typology in respect to
genetic investigations (Bonsch et al., 2006). Bonsch et al. inves-
tigated a sample of 134 alcoholics admitted for detoxification
treatment with respect to different MTHFR (methylene-tetra-
hydrofolate reductase) genotypes. MTHFR is of crucial impor-
tance in the homocysteine pathway, acting as a carbon donator
in the remethylation of homocysteine to methionine. Findings
of this study revealed a significantly higher frequency of the
thermolabile MTHFR (C677T) variant in patients of Leschs
type 4 compared to type 2 and 3 patients. This first study points
towards a genetic determination of Leschs typology.
Another recent study that focused on genetic variants in
different subgroups of Leschs typology found no evidence
for a role of different polymorphisms in patients of Leschs
types 1 and 2 (Samochowiec et al., 2008). This investiga-
tion included the dopamine transporter (DAT), the D2 receptor
(DRD2), the serotonin transporter (5HTT), and the catechol-
O-methyltransferase (COMT) polymorphism. However, this
study could not provide any results regarding Leschs type 3
and 4 patients as the number of included subjects was too small
for analysis. In conclusion, this second study shows that further
studies including larger numbers of patients are necessary to
verify these first results and to investigate other candidate genes
in respect to different subtypes of Leschs typology.
Neuroendocrinological findings
Endocrinological changes have particularly been associated
with alcohol craving, including changes of the hypothalamus-
pituitary-adrenocortical axis (HPA-axis), changes of appetite
regulating peptides, and other hormones associated with stress
response and dopaminergic neurotransmission.
Several studies have shown that the HPA-axis is disturbed
during active drinking, withdrawal, and abstinence (Kiefer
et al., 2002b; Kiefer and Wiedemann, 2004). For example, de-
creased CRH (corticotropin releasing hormone) is associated
with elevated craving in alcohol dependence (Fahlke et al.,
1994; Olive et al., 2003). Furthermore, studies found low cor-
tisol and ACTH (adrenocorticotropic hormone) serum levels to
be associated with increased craving and higher relapse rates
(Kiefer et al., 2002b; Junghanns et al., 2003).
Also, other endocrinological changes have been described
in alcoholism. Prolactin secretion is closely connected to
dopaminergic transmission, reflecting changes of the tuberoin-
fundibular dopamine pathway. Furthermore, prolactin is known
to be elevated in stress situations. A recent study investigated
possible associations between prolactin serum levels and alco-
hol craving during alcohol withdrawal differentiating alcohol-
dependent patients using Leschs typology (Hillemacher et al.,
2006b). This study assessed 115 male patients suffering from
alcohol dependence according to ICD-10 criteria with the Ob-
sessive Compulsive Drinking Scale (OCDS) during early al-
cohol withdrawal. Results revealed a significant association
between prolactin serum levels and extent of craving measured
by the OCDS particularly in Leschs type 2 patients. This is in-
teresting because patients of Leschs type 2 are characterized to
suffer from anxiety and to use alcohol because of its anxiolytic
effects. Anxiety disorders are also known to be associated with
elevated stress levels and prolactin elevation (Hollander et al.,
1989; Apostolopoulos et al., 1993). This finding may therefore
reflect a shared pathophysiological pathway between anxiety
disorder and alcohol craving in patients of Leschs type 2.
Another important neuroendocrinological pathway in the
pathogenesis of alcohol craving seems to be the appetite-
regulating system. In this context the endocrinological peptides
leptin and ghrelin have received most attention. Kiefer et al.
firstly described that increased plasma concentrations of leptin
may be associated with increased subjective rates of alcohol
craving (Kiefer et al., 2001a, 2001b). Other studies showed
that leptin plasma concentrations were elevated during chronic
alcohol consumption (Nicolas et al., 2001), normalized dur-
ing withdrawal and abstinence (Wurst et al., 2003). Using a
large study sample a recent investigation provided evidence
that leptin serum levels are associated with the extent of alco-
hol craving during early alcohol withdrawal (Hillemacher et al.,
2007a). Also, the gastrointestinal peptide ghrelin was shown to
be increased in alcohol dependence. Kim et al. found higher
ghrelin levels in alcohol abstainers and a positive association
with the duration of abstinence (Kim et al., 2005). Other studies
described an involvement of ghrelin in the brain reward systems
in an animal-experimental study (Jerlhag et al., 2006). A re-
cent investigation described ghrelin levels to be elevated during
alcohol withdrawal. However, this study found no association
between ghrelin serum levels and alcohol craving (Kraus et al.,
2005). In contrast to these findings, another recent investiga-
tion from Addolorato and colleagues found significantly lower
plasma ghrelin levels in alcoholics and a significant relationship
between ghrelin levels and alcohol craving scores (Addolorato
et al., 2006).
A recent investigation analyzed the role of these peptides
in alcohol craving in respect to Leschs typology (Hillemacher
et al., 2007b). This investigation was based on a sample of
188 patients with alcohol dependence, admitted for alcohol
detoxification. Craving was measured using the OCDS. Using
general linear models the authors found a significant positive
association for leptin in patients of Leschs types 1 and 2, while
ghrelin showed a trend regarding an association with craving in
patients of Leschs type 1. These findings show that appetite-
regulating peptides which obviously play an important role in
alcohol craving may be of special interest in particular subtypes
of patients.
Volume regulating mechanisms and alcohol craving
Other studies focused on differences regarding the association
of drinking behavior and alcohol craving between subtypes of
Leschs typology. Different studies have indicated a beverage-
dependent influence on craving apart from the association with
alcohol intake itself.
Consumption of low alcoholic drinks such as so-called
alcohol free beer was found to be associated with increased
craving (Long and Cohen, 1989). A recent study found that
craving is not only associated with alcohol intake itself but also
with the type of consumed alcoholic beverage (Hillemacher
et al., 2005). Furthermore, changes in volume-regulating pep-
tides during alcohol intoxication and withdrawal were de-
scribed recently in various studies (Eisenhofer et al., 1985;
 NEUROBIOLOGY AND LESCHS TYPOLOGY
Trabert et al., 1992; Taivainen et al., 1995; Kiefer et al.,
2002a). These alterations persist in long-term abstinent alco-
holics (Doring et al., 2003; Jahn et al., 2004) and an associ-
ation between craving and changes in volume regulation has
been postulated (van Ree et al., 1994; Doring et al., 2003).
However, these studies did not perform an analysis regarding
different subtypes of alcoholism. A recent investigation ana-
lyzed data of 158 male alcoholics to investigate an association
between volume intake of alcoholic beverage and alcohol crav-
ing in respect to Leschs typology (Hillemacher et al., 2006d).
This preliminary study should help to assess, whether volume-
regulating mechanisms may be of different importance in sub-
types of Lesch. This investigation found that the daily volume
intake of alcoholic beverages correlated significantly with the
extent of the OCDS. The effect was strongest in patients of
Lesch type 2. These results show that volume intake is asso-
ciated with alcohol craving and suggest a pathophysiological
role of volume-regulating peptides like vasopressin or ANP.
These mechanisms may be of special importance in patients
of Leschs type 2 which is interesting because ANP was de-
scribed to have anxiolytic effects (Bhattacharya et al., 1995;
Wiedemann et al., 2001; Herrmann-Lingen et al., 2003).
The kindling effect and other important findings
A recent study showed that recurrent detoxifications are asso-
ciated with elevated alcohol craving (Malcolm et al., 2000),
reflecting a kindling effect which has also been associated
with the elevated risk of alcohol-related seizures after multiple
detoxifications (Lechtenberg and Worner, 1991; Becker and
Hale, 1993; Anton et al., 1996; Worner, 1996; Boothby and
Doering, 2005). However, other investigations found contra-
dictory results (Duka et al., 2002).
A recent study investigated a large patients sample regard-
ing the role of recurrent detoxifications in alcohol craving in
respect to the subtyping of Lesch (Hillemacher et al., 2006a).
This study examined a sample of 192 patients, using the OCDS
to assess the extent of craving during early alcohol withdrawal.
Regarding a possible association between the number of previ-
ous detoxifications and alcohol craving, findings show a signif-
icant correlation for the whole population but particularly for
patients of Leschs type 1. This suggests that the kindling effect
may be particularly important in a subgroup of patients. These
findings may also help to interpret the previous contradictory
findings and underline the importance of subtyping patients
with alcohol dependence.
Another interesting investigation focused on the concept of
abnormal hemispheric organization in alcoholism. This concept
was studied previously in the area of endogenous psychosis and
focuses on the frequency of left-handedness (Sperling et al.,
2000). In a sample of 250 alcoholic inpatients, Sperling et al.
found a significantly higher frequency of left-handedness in
type 4 patients of Leschs typology. According to the authors,
left-handedness and therefore abnormal hemispheric organiza-
tion may be a sign of the cerebral damage which is a charac-
teristic of type 4 patients.
Association with nicotine dependence
Many studies document the well-known association be-
tween alcohol and nicotine dependence. Epidemiological
investigations found a consistent association between alcohol
3
and nicotine consumption (Zacny, 1990). A recent investiga-
tion demonstrated that in alcohol-dependent patients obsessive-
compulsive craving is associated with the extent of nicotine
dependence (Hillemacher et al., 2006c). We further analyzed
these data, comparing patients regarding Leschs typology of
alcohol dependence. The severity of nicotine dependence was
assessed using the Fagerstrom Test for Nicotine Dependence
(FTND) (Fagerstrom et al., 1990; Heatherton et al., 1991), and
the extent of alcohol craving was measured using the OCDS
(Anton et al., 1996). All patients included in the study suffered
from alcohol dependence according to DSM-IV and were as-
sessed after admittance to the detoxification unit. Findings of
the Spearmans correlation analysis revealed significant asso-
ciations particularly in patients of Leschs type 2 (OCDS total
score: r = 0.274, P = 0.045, N = 54; OCDS compulsive sub-
scale: r = 0.319, P = 0.019) and of Leschs type 4 (OCDS
total score: r = 0.527, P = 0.20; N = 19; OCDS compul-
sive subscale: r = 0.472, P = 0.041). We found no significant
associations for Leschs type 1 (N = 27) and Leschs type 3
patients (N = 22). Also, no significant correlations with the ob-
sessive subscale of the OCDS could be observed. In conclusion,
these findings show that the subtyping of patients with alcohol
dependence is also important when investigating associations
with other comorbidities like nicotine dependence. Differences
in brain pathophysiology between specific patients groups
particularly in the prefrontal and the orbitofrontal cortex-may
help to explain these results as these circuits have been associ-
ated with compulsive behavior and drug use which may be the
link between nicotine dependence and alcohol craving (Volkow
et al., 1999; George et al., 2001; Grusser et al., 2004). The cur-
rent findings should lead to further investigations regarding the
involvement of these circuits in specific patient groups, which
may also be of importance for differential treatment strategies.
Implications for therapy
Various studies have investigated different treatment options in
respect to Leschs typology. The United Kingdom Multicen-
tre Acamprosate Study (UKMAS) found no differences in the
response to acamprosate regarding Leschs typology (Chick
et al., 2000). However, in this study patients of types 3 and 4
were overrepresented. In the Austrian Acamprosate trial results
show a better response to acamprosate in patients of types 1
and 2 (Lesch et al., 2001). Kiefer et al. found that acamprosate
was particularly efficacious in patients of Leschs type 1 while
naltrexone was more effective in type 3 and type 4 patients
(Kiefer et al., 2005). Also studies on other agents like flu-
penthixol have been performed. In a large study it was shown
that flupenthixol is not only beneficial but also increases relapse
rated in abstinent patients (Wiesbeck et al., 2001). In respect
to Leschs typology, Walter et al. showed that flupenthixol has
this detrimental effect only in patients of types 1 and 3 (Walter
et al., 2001). These findings demonstrate that different types
of alcohol-dependent patients do respond to pharmacological
interventions in a distinct manner, which should be consid-
ered when treating patients with anticraving substances such as
acamprosate or naltrexone. Furthermore, a specific subtyping
is useful when investigating new treatment options for relapse
prevention, such as topiramate or baclofen (Addolorato et al.,
2002; Johnson et al., 2003).
4 T. HILLEMACHER AND S. BLEICH
Figure 1. Neurobiological findings regarding Leschs typology.
CONCLUSION
The presented findings may lead to two important conclusions.
The different studies focusing on very different aspects in al-
coholism show that the Lesch typology has a biological and
genetic basis (see Fig. 1). Furthermore, dividing patients into
subgroups has an important impact for further research strate-
gies as completely different findings might be found regarding
neurobiological mechanisms as well as the efficacy of pharma-
cological treatment. Testing new pharmacological options and
psychotherapeutical or psychosocial interventions, it is impor-
tant to take into account that these may have different efficacy
when used in patients of different subgroups. Of course, also
other typologies are of high interest in research and therapy
(Babor and Caetano, 2006). A recent analysis comparing dif-
ferent typologies of alcohol dependence supports the concept
of four homogeneous types of alcoholism (Hesselbrock and
Hesselbrock, 2006). Therefore, Leschs typology offers a good
basis for research and for a better understanding of alcoholism.
Further investigations (e.g., a large European multicenter study)
should be performed to assess whether Leschs subtypes of
alcoholism are associated with specific electrophysiological,
neuroendocrine, genetic, and cognitive markers to confirm that
this typology may be useful to define endophenotypes of alco-
holism. Approaches for specific typologies are also necessary
in other areas of addiction such as nicotine dependence (Lesch
et al., 2004).
REFERENCES
Addolorato, G., Capristo, E., Leggio, L. et al. (2006) Relationship
between ghrelin levels, alcohol craving and nutritional status in
current alcoholics. Alcoholism: Clinical and Experimental Research
30, 19331937.
Addolorato, G., Caputo, F., Capristo, E. et al. (2002) Baclofen efficacy
in reducing alcohol craving and intake: A preliminary double-blind
randomized controlled study. Alcohol and Alcoholism 37, 504508.
Anton, R. F., Moak, D. H. and Latham, P. K. (1996) The obsessive
compulsive drinking scale: A new method of assessing outcome in
alcoholism treatment studies. Archives of General Psychiatry 53,
225231.
Apostolopoulos, M., Judd, F. K., Burrows, G. D. and Norman, T. R.
(1993) Prolactin response to dl-fenfluramine in panic disorder. Psy-
choneuroendocrinology 18, 337342.
Babor, T. F. and Caetano, R. (2006). Subtypes of substance dependence
and abuse: Implications for diagnostic classification and empirical
research. Addiction 101 (Suppl 1), 104110.
Babor, T. F., Hofmann, M., DelBoca, F. K. et al. (1992) Types of
alcoholics: I. Evidence for an empirically derived typology based
on indicators of vulnerability and severity. Archives of General
Psychiatry 49, 599608.
Becker, H. C. and Hale, R. L. (1993) Repeated episodes of
ethanol withdrawal potentiate the severity of subsequent withdrawal
 NEUROBIOLOGY AND LESCHS TYPOLOGY
seizures: An animal model of alcohol withdrawal kindling. Alco-
holism: Clinical and Experimental Research 17, 9498.
Bhattacharya, S. K., Chakrabarti, A., Sandler, M. and Glover, V.
(1995). Rat brain monoamine oxidase A and B inhibitory (tribu-
lin) activity during drug withdrawal anxiety. Neuroscience Letters
199, 103106.
Bigal, M. E., Lipton, R. B., Holland, P. R. and Goadsby, P. J. (2007)
Obesity, migraine, and chronic migraine: Possible mechanisms of
interaction. Neurology 68, 185161.
Bleich, S., Bandelow, B., Javaheripour, K. et al. (2003a) Hyperhomo-
cysteinemia as a new risk factor for brain shrinkage in patients with
alcoholism. Neuroscience Letters 335, 179182.
Bleich, S., Bayerlein, K., Hillemacher, T., Degner, D., Kornhuber, J.
and Frieling, H. (2006) An assessment of the potential value of
elevated homocysteine in predicting alcohol-withdrawal seizures.
Epilepsia 47, 934938.
Bleich, S., Bayerlein, K., Reulbach, U. et al. (2004a) Homocysteine
levels in patients classified according to Leschs typology. Alcohol
and Alcoholism 39, 493498.
Bleich, S., Carl, M., Bayerlein, K. et al. (2005) Evidence of increased
homocysteine levels in alcoholism: The Franconian alcoholism re-
search studies (FARS). Alcoholism: Clinical and Experimental Re-
search 29, 334336.
Bleich, S., Degner, D., Bandelow, B., von Ahsen, N., Ruther, E. and
Kornhuber, J. (2000a) Plasma homocysteine is a predictor of alcohol
withdrawal seizures. Neuroreport 11, 27492752.
Bleich, S., Degner, D., Javaheripour, K., Kurth, C. and Kornhuber, J.
(2000b) Homocysteine and alcoholism. Journal of Neural Trans-
mission Supplement 60, 187196.
Bleich, S., Degner, D., Sperling, W., Bonsch, D., Thurauf, N. and
Kornhuber, J. (2004b) Homocysteine as a neurotoxin in chronic
alcoholism. Progress in Neuropsychopharmacology and Biological
Psychiatry 28, 453464.
Bleich, S., Wiltfang, J. and Kornhuber, J. (2003b). Memantine in
moderate-to-severe Alzheimers disease. New England Journal of
Medicine 349, 609610.
Bonsch, D., Bayerlein, K., Reulbach, U. et al. (2006) Different allele-
distribution of Mthfr 677 C T and Mthfr 393 C a in patients
classified according to subtypes of Leschs typology. Alcohol and
Alcoholism 41, 364367.
Boothby, L. A. and Doering, P. L. (2005) Acamprosate for the
treatment of alcohol dependence. Clinical Therapeutics 27, 695
714.
Chick, J., Howlett, H., Morgan, M. Y. and Ritson, B. (2000) United
Kingdom Multicentre Acamprosate Study (UKMAS): A 6-month
prospective study of acamprosate versus placebo in preventing re-
lapse after withdrawal from alcohol. Alcohol and Alcoholism 35,
176187.
Cloninger, C. R., Sigvardsson, S., Gilligan, S. B., von Knorring, A.
L., Reich, T. and Bohman, M. (1988) Genetic heterogeneity and the
classification of alcoholism. Advances in Alcohol and Substance
Abuse 7, 316.
Doring, W. K., Herzenstiel, M. N., Krampe, H. et al. (2003) Persistent
alterations of vasopressin and N-terminal proatrial natriuretic pep-
tide plasma levels in long-term abstinent alcoholics. Alcoholism:
Clinical and Experimental Research 27, 849861.
Duka, T., Townshend, J. M., Collier, K. and Stephens, D. N. (2002)
Kindling of withdrawal: A study of craving and anxiety after multi-
ple detoxifications in alcoholic inpatients. Alcoholism: Clinical and
Experimental Research 26, 785795.
Eisenhofer, G., Lambie, D. G., Whiteside, E. A. and Johnson, R.
H. (1985) Vasopressin concentrations during alcohol withdrawal.
British Journal of Addiction 80, 195199.
Fagerstrom, K. O., Heatherton, T. F. and Kozlowski, L. T. (1990) Nico-
tine addiction and its assessment. Ear, Nose, and Throat Journal 69,
763765.
Fahlke, C., Hard, E., Thomasson, R., Engel, J. A. and Hansen, S.
(1994) Metyrapone-induced suppression of corticosterone synthe-
sis reduces ethanol consumption in high-preferring rats. Pharma-
cology, Biochemistry, and Behavior 48, 977981.
George, M. S., Anton, R. F., Bloomer, C. et al. (2001) Activation
of prefrontal cortex and anterior thalamus in alcoholic subjects on
exposure to alcohol-specific cues. Archives of General Psychiatry
58, 345352.
5
Grusser, S. M., Wrase, J., Klein, S. et al. (2004) Cue-induced activa-
tion of the striatum and medial prefrontal cortex is associated with
subsequent relapse in abstinent alcoholics. Psychopharmacology
(Berl) 175, 296302.
Heatherton, T. F., Kozlowski, L. T., Frecker, R. C. and Fagerstrom,
K. O. (1991) The Fagerstrom Test for Nicotine Dependence: A
revision of the Fagerstrom Tolerance Questionnaire. British Journal
of Addiction 86, 11191127.
Herrmann-Lingen, C., Binder, L., Klinge, M. et al. (2003). High
plasma levels of N-terminal pro-atrial natriuretic peptide associated
with low anxiety in severe heart failure. Psychosomatic Medicine
65, 517522.
Hesselbrock, V. M. and Hesselbrock, M. N. (2006) Are there empir-
ically supported and clinically useful subtypes of alcohol depen-
dence? Addiction 101 (Suppl 1), 97103.
Hillemacher, T., Bayerlein, K., Reulbach, U. et al. (2005) Influence of
beer, wine and spirits consumption on craving. Addiction Biology
10, 181186.
Hillemacher, T., Bayerlein, K., Wilhelm, J. et al. (2006a) Recurrent
detoxifications are associated with craving in patients classified as
type 1 according to Leschs typology. Alcohol and Alcoholism 41,
6669.
Hillemacher, T., Bayerlein, K., Wilhelm, J. et al. (2006b) Prolactin
serum levels and alcohol cravingAn analysis using Leschs ty-
pology. Neuropsychobiology 53, 133136.
Hillemacher, T., Bayerlein, K., Wilhelm, J. et al. (2006c) Nicotine de-
pendence is associated with compulsive alcohol craving. Addiction
101, 892897.
Hillemacher, T., Bayerlein, K., Wilhelm, J. et al. (2006d) Volume
intake and craving in alcohol withdrawal. Alcohol and Alcoholism
41, 6165.
Hillemacher, T., Bleich, S., Frieling, H. et al. (2007a) Evidence of
an association of leptin serum levels and craving in alcohol depen-
dence. Psychoneuroendocrinology 32, 8790.
Hillemacher, T., Kraus, T., Rauh, J. et al. (2007b) Role of appetite-
regulating peptides in alcohol craving: An analysis in respect to
subtypes and different consumption patterns in alcoholism. Alco-
holism: Clinical and Experimental Research 31, 950954.
Hollander, E., Liebowitz, M. R., Cohen, B. et al. (1989) Prolactin and
sodium lactate-induced panic. Psychiatry Research 28, 181191.
Jahn, H., Doring, W. K., Krampe, H. et al. (2004) Preserved va-
sopressing response to osmostimulation despite decreased basal
vasopressin levels in long-term abstinent alcoholics. Alcoholism:
Clinical and Experimental Research 28, 19251930.
Jellinek, E. M. (1960) The Disease Concept of Alcoholism. New
Haven, CT: Hillhouse.
Jerlhag, E., Egecioglu, E., Dickson, S. L., Andersson, M., Svensson,
L. and Engel, J. A. (2006) Ghrelin stimulates locomotor activity
and accumbal dopamine-overflow via central cholinergic systems
in mice: Implications for its involvement in brain reward. Addiction
Biology 11, 4554.
Johnson, B. A., Ait-Daoud, N., Bowden, C. L. et al. (2003) Oral topira-
mate for treatment of alcohol dependence: A randomised controlled
trial. Lancet 361, 16771685.
Junghanns, K., Backhaus, J., Tietz, U. et al. (2003) Impaired serum
cortisol stress response is a predictor of early relapse. Alcohol and
Alcoholism 38, 189193.
Kiefer, F., Andersohn, F., Jahn, H., Wolf, K., Raedler, T. J. and
Wiedemann, K. (2002a) Involvement of plasma atrial natriuretic
peptide in protracted alcohol withdrawal. Acta Psychiatrica Scan-
dinavica 105, 6570.
Kiefer, F. and Barocka, A. (1999) Secondary depression in weaned
alcoholics: Implications of Leschs typology of chronic alcoholism.
Alcohol and Alcoholism 34, 916917.
Kiefer, F., Helwig, H., Tarnaske, T., Otte, C., Jahn, H. and Wiedemann,
K. (2005) Pharmacological relapse prevention of alcoholism: Clini-
cal predictors of outcome. European Addiction Research 11, 8391.
Kiefer, F., Jahn, H., Jaschinski, M. et al. (2001a) Leptin: A modulator
of alcohol craving? Biological Psychiatry 49, 782787.
Kiefer, F., Jahn, H., Schick, M. and Wiedemann, K. (2002b) Alcohol
self-administration, craving and HPA-axis activity: An intriguing
relationship. Psychopharmacology (Berl) 164, 239240.
Kiefer, F., Jahn, H., Wolf, K., Kampf, P., Knaudt, K. and Wiede-
mann, K. (2001b) Free-choice alcohol consumption in mice after
6 T. HILLEMACHER AND S. BLEICH
application of the appetite regulating peptide leptin. Alcoholism:
Clinical and Experimental Research 25, 787789.
Kiefer, F. and Wiedemann, K. (2004) Neuroendocrine pathways of
addictive behaviour. Addiction Biology 9, 205212.
Kim, D. J., Yoon, S. J., Choi, B. et al. (2005) Increased fasting plasma
ghrelin levels during alcohol abstinence. Alcohol and Alcoholism
40, 7679.
Kraus, T., Schanze, A., Groschl, M. et al. (2005) Ghrelin levels are
increased in alcoholism. Alcoholism: Clinical and Experimental
Research 29, 21542157.
Lechtenberg, R. and Worner, T. M. (1991) Relative kindling effect
of detoxification and non-detoxification admissions in alcoholics.
Alcohol and Alcoholism 26: 221225.
Lesch, O. M., Dvorak, A., Hertling, I. et al. (2004) The Austrian
multicentre study on smoking: Subgroups of nicotine dependence
and their craving. Neuropsychobiology 50, 7888.
Lesch, O. M., Kefer, J., Lentner, S. et al. (1990) Diagnosis of chronic
alcoholismClassificatory problems. Psychopathology 23, 88
96.
Lesch, O. M., Riegler, A., Gutierrez, K. et al. (2001) The European
acamprosate trials: Conclusions for research and therapy. Journal
of Biomedical Science 8, 8995.
Lesch, O. M. and Walter, H. (1996) Subtypes of alcoholism and
their role in therapy. Alcohol and Alcoholism 31 (Suppl 1), 63
67.
Long, C. G. and Cohen, E. M. (1989). Low alcohol beers and wines:
Attitudes of problem drinkers to their use and their effect on craving.
British Journal of Addiction 84, 777783.
Malcolm, R., Herron, J. E., Anton, R. F., Roberts, J. and Moore,
J. (2000) Recurrent detoxification may elevate alcohol craving as
measured by the Obsessive Compulsive Drinking scale. Alcohol 20,
181185.
Nicolas, J. M., Fernandez-Sola, J., Fatjo, F. et al. (2001) Increased
circulating leptin levels in chronic alcoholism. Alcoholism: Clinical
and Experimental Research 25: 8388.
Olive, M. F., Mehmert, K. K., Koenig, H. N. et al. (2003) A role
for corticotropin releasing factor (CRF) in ethanol consumption,
sensitivity, and reward as revealed by CRF-deficient mice. Psy-
chopharmacology (Berl) 165, 181187.
Samochowiec, J., Kucharska-Mazur, J., Grzywacz, A. et al.
(2008) Genetics of Leschs typology of alcoholism. Progress in
Neuro-Psychopharmacology and Biological Psychiatry 32, 423
427.
Sperling, W., Frank, H., Martus, P. et al. (2000) The concept of abnor-
mal hemispheric organization in addiction research. Alcohol and
Alcoholism 35, 394399.
Taivainen, H., Laitinen, K., Tahtela, R., Kilanmaa, K. and Valimaki,
M. J. (1995) Role of plasma vasopressin in changes of water balance
accompanying acute alcohol intoxication. Alcoholism: Clinical and
Experimental Research 19, 759762.
Trabert, W., Caspari, D., Bernhard, P. and Biro, G. (1992) Inappropri-
ate vasopressin secretion in severe alcohol withdrawal. Acta Psy-
chiatrica Scandinavica 85, 376379.
van Ree, J. M., Kornet, M. and Goosen, C. (1994) Neuropeptides and
alcohol addiction in monkeys. EXS 71, 165174.
Volkow, N. D., Wang, G. J., Fowler, J. S. et al. (1999) Association
of methylphenidate-induced craving with changes in right striato-
orbitofrontal metabolism in cocaine abusers: Implications in addic-
tion. American Journal of Psychiatry 156, 1926.
Walter, H., Ramskogler-Skala, K., Dvorak, A. et al. (2006) Glutamic
acid in withdrawal and weaning in patients classified according to
Cloningers and Leschs typologies. Alcohol and Alcoholism 41,
505511.
Walter, H., Ramskogler, K., Semler, B., Lesch, O. M. and Platz, W.
(2001) Dopamine and alcohol relapse: D1 and D2 antagonists in-
crease relapse rates in animal studies and in clinical trials. Journal
of Biomedical Science 8, 8388.
Wiedemann, K., Jahn, H., Yassouridis, A. and Kellner, M. (2001) Anx-
iolyticlike effects of atrial natriuretic peptide on cholecystokinin
tetrapeptide-induced panic attacks: Preliminary findings. Archives
of General Psychiatry 58, 371377.
Wiesbeck, G. A., Weijers, H. G., Lesch, O. M., Glaser, T., Toennes,
P. J. and Boening, J. (2001) Flupenthixol decanoate and relapse
prevention in alcoholics: Results from a placebo-controlled study.
Alcohol and Alcoholism 36, 329334.
Wilhelm, J., Bayerlein, K., Hillemacher, T. et al. (2006) Short-term
cognition deficits during early alcohol withdrawal are associated
with elevated plasma homocysteine levels in patients with alco-
holism. Journal of Neural Transmission 113, 357363.
Worner, T. M. (1996) Relative kindling effect of readmissions in al-
coholics. Alcohol and Alcoholism 31, 375380.
Wurst, F. M., Bechtel, G., Forster, S. et al. (2003) Leptin levels of alco-
hol abstainers and detoxification patients are not different. Alcohol
and Alcoholism 38, 364368.
Zacny, J. P. (1990) Behavioral aspects of alcohol-tobacco interactions.
Recent Developments in Alcoholism 8, 205219.