© Med Sci Monit, 2007; 13(12): CR543-547 WWW. M ED S CI M ONIT.

COM
PMID: 18049433 Clinical Research

Received: 2007.10.25
Accepted: 2007.11.08 Alcohol craving, limbic irritability, and stress CR
Published: 2007.12.01

Authors’ Contribution:
A Study Design
B Data Collection
C Statistical Analysis
D Data Interpretation
E Manuscript Preparation
F Literature Search
G Funds Collection
Denisa Jasova1 ABCDEF, Petr Bob1 ACDEFG, Peter Fedor-Freybergh1,2 DF
1
Department of Psychiatry, 1st Faculty of Medicine, Charles University, Prague, Czech Republic
2
St. Elisabeth University College of Health and Social Work, Bratislava, Slovak Republic
Source of support: This work was supported by research grants MSM0021620849 and MSM0021622404 and
by support of the research project of Center for Neuropsychiatric Research of Traumatic Stress 1M06039 by the
Czech Ministry of Education

Summary
Background: Recent findings indicate that craving during alcohol withdrawal, also in abstinent patients, can re-
late to kindling phenomena caused by sensitization in temporo-limbic structures. Because limbic
structures are involved in stress, anxiety, and emotional processing, kindling and temporolimbic
seizure-like activity are also closely related to various psychiatric symptoms frequently presented
without seizure disorders. Recent findings also show that these seizure-like processes are related
to limbic irritability, which may also be significantly influenced by stressful life events.
Material/Methods: The hypothesis tested in the present study is that limbic irritability could be closely related to crav-
ing symptoms. Therefore, limbic irritability and craving were assessed using psychometric mea-
sures in 40 alcohol-dependent patients and the results were compared with those of 40 healthy
controls.
Results: Statistical analysis showed highly significant correlation (r=0.75, p<0.0000001) between limbic ir-
ritability (LSCL-33) and craving (ACQ-R) and highly increased limbic irritability scores in the pa-
tients compared with the healthy controls.
Conclusions: The results indicate that craving symptoms are related to the kindling process presented in the
form of cognitive, affective, sensory, somatic, behavioral, and memory symptoms linked to limbic
irritability and temporo-limbic seizure-like activity.

key words: alcohol • kindling • limbic irritability • craving

Full-text PDF: http://www.medscimonit.com/abstract/index/idArt/563763

Word count: 1795
Tables: 1
Figures: 1
References: 51

Author’s address: Petr Bob, Charles University, Psychiatry Department, Ke Karlovu 11, 128 00 Prague, Czech Republic,
e-mail: Petr.Bob@lf1.cuni.cz

Current Contents/Clinical Medicine • IF(2006)=1.595 • Index Medicus/MEDLINE • EMBASE/Excerpta Medica • Chemical Abstracts CR543
Clinical Research
Background
Alcohol craving presents an irresistible need for alcohol in-
take that is most often understood as a subjective experience
that motivates people to use alcohol; it plays a major role in
the development and maintenance of dependent behavior
[1]. According to recent findings, alcohol craving during al-
cohol withdrawal, also in abstinent patients, is related to kin-
dling phenomena caused by sensitization [2–8]. Application
of the kindling model to alcohol withdrawal also suggests
that neuroadaptation of the CNS to repeated detoxification
may also cause neurobehavioral alterations that may affect
craving, and these findings emphasize the need to address
craving and other psychological variables with respect to the
treatment of alcohol withdrawal syndrome [2–4]. Both clin-
ical and experimental evidence support the view that the se-
verity of craving and other withdrawal symptoms increases
after repeated withdrawal episodes [2–8]. Kindling also may
play a significant role in the risk of relapse, alcohol-related
brain damage, and cognitive impairment [5–8]. This pro-
cess causes abnormalities in a number of neurotransmitter
systems and leads to reduced inhibitory functions and in-
creased activity of excitatory systems [7,8]. Recent findings
show the kindling mechanism to be one of the most wide-
ly used models of seizures and epilepsy, especially human
limbic or temporal lobe epilepsy [9–12]. These data strong-
ly suggest that the animal model of amygdala kindling pro-
vides insight into the intracellular, synaptic, and microstruc-
tural changes that have been shown to be related to both
the primary pathophysiology of kindling development and
compensatory adaptation processes [9–12].
Because limbic structures are also involved in stress, anxiety,
and emotion modulation, the development of neurochemi-
cal alterations associated with kindling in temporolimbic sei-
zures is closely related to the various psychiatric symptoms
that may also be present without seizure disorders and de-
termines limbic irritability, which may also be significantly
influenced by stressful life events [13–15]. Anderson et al.
[15] found a reciprocal relationship between symptoms of
limbic irritability measured by the LSCL-33 (Limbic System
Checklist) questionnaire and activity in the cerebellar ver-
mis assessed by fMRI T2 relaxometry. They reported a sig-
nificant correlation between T2 relaxation time and the de-
gree of limbic irritability (LSCL-33) in healthy young adult
controls (r=–0.67) and also in young adults who had a his-
tory of repeated sexual abuse (r=–0.71). The results were
consistent with findings that the cerebellar vermis controls
limbic activation and inhibition and also influences the on-
set and spread of seizures [13,14,16–18] as well as with find-
ings that alcohol addiction is frequently related to cerebel-
lar dysfunctions, especially in the vermis [19–22]. These
findings suggest that the cognitive and emotional dysreg-
ulation related to kindling is linked to defective inhibitory
functions that may also lead to temporo-limbic seizure-like
activity. This epileptic-like process may emerge in the form
of symptoms similar to ictal temporal lobe epilepsy, such as
somatic, sensory, behavioral, and memory symptoms that
may also occur in nonepileptic conditions [13,14,23–28].
These findings suggest the hypothesis that limbic irritabili-
ty could be closely related to craving symptoms. According
to a PubMed search, this is the first study that used mea-
surement of limbic irritability for the purpose of assessing
its relationship to alcohol addiction with the aim to iden-
CR544
Med Sci Monit, 2007; 13(12): CR543-547
tify the relationship between craving and limbic irritability
related to kindling using psychological measures.
Material and Methods
Participants
For empirical examination of the suggested hypothesis, the
methods of psychometric measures were used in 40 alcohol-
dependent outpatients of a university outpatient center (mean
age: 39.2, age range: 32-50, SD=5.18 years) and 40 healthy con-
trols selected from the general population by advertisement
(mean age: 37.8, age range: 37–49, SD=4.85 years). The pa-
tients had a diagnosis of alcohol dependence with abstinence
periods of one to six months from the beginning of alcohol
withdrawal and treatment. The majority of the patients man-
ifested comorbidities, i.e. anxiety (N=4), affective disorders
(N=8), or personality disorders (N=17) confirmed accord-
ing to DSM IV criteria [29], and were also assessed by the
structured psychiatric interview M.I.N.I. version 5.0.0 [30].
Thirty-two patients of the cohort were also smokers. The pa-
tients’ treatment at the time of recruitment was based only
on anxiolytic or antidepressant medication and disulfiram.
Disulfiram treatment was used in 24 patients of the cohort,
with the beginning of disulfiram therapy approximately four
weeks after the beginning of alcohol withdrawal. Anamnestic
data showed that 22 patients had a history of detoxification
treatment (mean number of detoxification treatments for
the whole group: 1.54, SD=1.45), but only two patients also
had a history of alcohol withdrawal seizures. Exclusion crite-
ria were alcohol addiction lasting more than 15 years, alco-
hol dementia, current alcohol withdrawal seizures and de-
toxification therapy, acute stage of alcohol withdrawal with
abstinence symptoms, treatment lasting more than 6 months
from the beginning of alcohol withdrawal, drug abuse, or-
ganic illnesses involving the central nervous system, psychot-
ic disorders, electroconvulsive therapy, any form of epilepsy,
and mental retardation (IQ Raven higher than 90). The same
exclusion criteria regarding CNS disorders were applied to
the healthy controls together with the criterion that all the
controls must be psychiatrically healthy and must be free of
alcohol and other drug abuse according to M.I.N.I. The pa-
tients were 20 males and 20 females and the control group
involved 19 males and 21 females, both groups predominant-
ly with high-school education. All the patients and controls
gave written informed consent and the clinical study was ap-
proved by the university ethics committee.
Psychometric measures
For the assessment of alcohol craving the revised version of
the alcohol craving questionnaire (ACQ-R) was used [31].
The ACQ-R is a 30-item questionnaire for assessing craving
that reflects the main dimensions of alcohol craving, such as
urges and desires to use alcohol, intent to use alcohol, antic-
ipation of positive outcome, anticipation of relief from with-
drawal or negative outcome, and lack of control over alcohol
consumption [31]. Subjects indicate the degree of their expe-
rience on a seven-point Likert scale (from strongly agree to
strongly disagree). The ACQ shows psychometric properties
well and internal consistency (Cronbach’s alpha: 0.93).
Symptoms of limbic irritability linked to temporal lobe
epileptiform activity were assessed by the Limbic System
Med Sci Monit, 2007; 13(12): CR543-547
Table 1. Descriptive statistics for the psychometric measures in the patients and healthy controls.
Patients
Mean SD
LSCL-33 31.9 20.29 17.03
ACQ-R 28.63 19.98 0.0
Checklist, LSCL-33 [32]. LSCL-33 is designed to measure
temporo-limbic activity in the form of somatic, sensory, be-
havioral, and memory symptoms known to be associated
with phenomena of ictal temporal lobe epilepsy. LSCL-33
shows psychometric properties well and internal consisten-
cy (Cronbach’s alpha: 0.90). These symptoms may be gen-
erally described as brief hallucinations, paroxysmal somat-
ic disturbances, automatisms, and dissociative disturbances.
Subjects indicate the degree of their experience on a four-
point Likert scale (never, rarely, sometimes, often).
The psychometric measures were administered individually
with the help of a physician and in a quiet room.
Data analysis
Statistical evaluation of the results of the psychometric mea-
sures included common methods of descriptive and infer-
ential statistics, i.e. mean and standard deviation, Pearson’s
product-moment correlation, and the t-test for indepen-
dent samples. For statistical evaluation the software pack-
age Statistica version 6 was used.
Results
The results of the present study confirm the stated hy-
pothesis of a close relationship between limbic irritability
measured by LSCL-33 and craving symptoms measured by
ACQ-R. The data also indicate a statistically significant dif-
ference between the patients and healthy controls because
the t-test showed that the alcohol-dependent patients had
significantly higher LSCL-33 scores than the healthy con-
trols (Table 1).
Statistical analysis showed highly significant correlation be-
tween LSCL-33 and ACQ-R (r=0.75, p<0.0000001), indicat-
ing that craving symptoms reflect with high probability the
kindling process that causes typical cognitive, affective, sen-
sory, somatic, behavioral, and memory symptoms linked to
temporo-limbic seizure-like activity (Figure 1).
Anamnestic data regarding the history of detoxification treat-
ment did not show any significant relationships with limbic
irritability and alcohol craving. Statistical analysis of these
data showed non-significant correlation between ACQ-R and
the number of detoxifications (r=0.25, p=0.12) and between
LSCL-33 and the number of detoxifications (r=0.30, p=0.06).
Discussion
The objective of the present study was to document the re-
lationship between symptoms of limbic irritability and crav-
ing symptoms. The results indicate that symptoms of lim-
Jasova D et al – Alcohol craving, limbic irritability, and stress
Controls Patients-Controls
Mean SD t-test (df=78)
9.27 4.217, p=0.00007 CR
0.0 –
90
80
70
60
50
ACQ-R
40
30
20
10
0
–10
–20 0 20 40 60 80 100
LSCL-33
Figure 1. Dependency graph between ACQ-R and LSCL-33 (r=0.75,
p<0.0000001).
bic irritability produced by a temporal-limbic seizure-like
mechanism are significantly related to alcohol craving and
support the kindling/withdrawal theory. Statistically signifi-
cant relationships of the history of detoxification treatment
with limbic irritability and alcohol craving were not found
in the present study. In this context, several previous find-
ings suggest that repeated detoxification may intensify sub-
jective feelings of craving based on the sensitizing effects of
repeated withdrawal depending on the type of subjectively
experienced process of the urge to drink [2–4].
LSCL-33 is an easy clinical instrument that may help in treat-
ment strategy and also could be a helpful criterion for deci-
sions regarding anticonvulsant treatment, which has been
found promising [33,34]. In this context we could expect
that patients with high scores of limbic irritability assessed
by LSCL-33 in the form of a careful clinical interview could
be indicated for anticonvulsant treatment with the aim to
prevent relapse. Recent findings also indicate that limbic ir-
ritability is significantly related to stress [13–15,32]. For ex-
ample, Teicher et al. [32] found in a cohort of 253 patients
that adult outpatients with a self-reported history of physi-
cal or sexual abuse had increased LSCL-33 scores that were
dramatically elevated in patients with a history of combined
abuse, both physical and sexual. In this context, the data of
this study suggest that the problem of neural adaptation to
stress stimuli and its relationship to alcohol addiction could
be important in principle. Limbic irritability is significant-
ly related to stress and is also likely related to activity in the
cerebellar vermis that may be damaged by stress hormones
[13–15]. These data imply that stress could represent a sig-
nificant predisposing factor to addiction, because limbic
CR545
Clinical Research
irritability may be attenuated for short-periods of time by
alcohol and this stress-related vulnerability may cause alco-
hol-seeking behavior because of the gratifying effect of al-
cohol via its influence on GABA transmission [35,36].
Conclusions
In this context, sensitization during alcohol withdrawal may
represent exposure to the consequences of previously ex-
perienced stressors, which at the time of withdrawal or lat-
er in abstinence are not compensated by alcohol’s sedative
effect. Because previously experienced stressors are pres-
ent not only at the level of functional or structural damage
[13,14,38–41], but also cause consolidation of traumatic
memories [28,42,43], alcohol consumption and addiction
21. Manzardo AM, Penick EC, Knop J et al: Developmental differences
may represent an active process that facilitates forgetting
and dissociation of traumatic and stressful memories and
the inhibition of limbic irritability. This is consistent with
findings that irritability in limbic structures and reduced
functional activity of the cerebellar vermis are related to
functional defects in the hippocampus determined by stress
that cause decreasing inhibitory control of the hippocam-
pus on the HPA axis, and significant neuroendocrine dys-
regulation [44,45]. Conversely, recent findings indicate
that these changes may be significantly influenced by vari-
ous therapeutic methods [46–51] that may break down the
circulus vitiosus between alcohol and stress, in which stress
produces addiction and alcohol addiction or its withdraw-
al sequentially causes stressful life events.
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