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Journal of Psychoactive Drugs
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Long-Term Therapy using GHB (Sodium Gamma
Hydroxybutyrate) for Treatment-Resistant Chronic
Alcoholics
Icro Marremmani a , Francesco Lamanna a & Alessandro Tagliamonte b
a Department of Psychiatry , Neurobiology, Pharmacology and Biotechnology , University
of Pisa, Italy
b Department of Neurosciences , University of Siena , Italy
Published online: 06 Sep 2011.
To cite this article: Icro Marremmani , Francesco Lamanna & Alessandro Tagliamonte (2001) Long-Term Therapy using
GHB (Sodium Gamma Hydroxybutyrate) for Treatment-Resistant Chronic Alcoholics, Journal of Psychoactive Drugs, 33:2,
135-142, DOI: 10.1080/02791072.2001.10400478
To link to this article: http://dx.doi.org/10.1080/02791072.2001.10400478
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Long-Terꢀ Therapy using Gꢁ
(Sodiuꢀ Gaꢂꢃla Hydroxybutyrate) for
ꢄeatment-Resistant Chronic Alcoholics
Icro Maremmani, M.D.*; Francesco Lamanna, M.D.** & Alessandro Tagliamonte, M.D.***
Abstract-Thirty-five alcohol-dependent patients accoꢄding to DSM-IV cꢄiteꢄia who also met cꢄiteria
foꢄ tꢄeatment ꢄesistance were tꢄeated with doses of gamma hydꢄoxybutyꢄate (GHB) ranging between
25 and 1 00 mglkgldie in an open one-yeaꢄ study. The ꢄesults show that no patients discontinued the
pꢄogꢄam duꢄing the fiꢄst month of tꢄeatment. Sixty peꢄcent of these patients successfully completed
the pꢄotocol; 1 1 .4% showed complete abstinence (full respondeꢄ patients); 1 4.3% stꢄongly ꢄeduced
theiꢄ alcohol intake (paꢄtial ꢄespondeꢄ patients) and 34.3% of the patients weꢄe still under tꢄeatment
after one yeaꢄ. Foꢀy percent of the patients weꢄe nonꢄesponders. The ꢄetention ꢄate undeꢄ tꢁatment
of the studied sample was statistically higheꢄ than that found duꢄing the last tꢄeatment of the same
subjects. No significant diffeꢄences weꢄe found between full ꢄespondeꢄ and paꢂiaꢃ ꢄespondeꢄ patients
ꢄegꢅding changes in clinical featuꢄes, alcohol intake oꢄ social adjustment. Patients stilꢃ in tꢄeatment
afteꢄ one year significantꢃy diffeꢄed from nonꢄesponder patients on aꢃl the variabꢃes investigated. A
six-times/daiꢃy fꢄactionated administꢄation ofthe GHB dose was the only significant pꢄedictoꢄ ofthe
ꢄetention ꢄate.
Keywords-anticꢄaving dꢄugs, contꢄolled use of ethanoꢃ, gamma hydꢄoxybutyꢄate (GHB).
phaꢄmacological tꢄeatment of alcoholism
Studies of pharmacological treatment for chronic
alcoholism have proven more complex than other areas of
clinical psychopharmacology research. These studies
often suffer from a high dropout rate of patients in the
early stage of treatment. The presence of medical
contraindications associated with alcoholism limits the
kinds of drugs that can be used in some patient popula-
tions. There is a need to define specific measures of
treatment efficacy, rather than to rely on general param-
eters of treatment outcome. If the target is a moderate
drinking outcome, self-report measures may not be valid
enough to confirm that outcome.
Gamma hydroxybutyrate (GHB) is an obsolete gen-
eral anesthetic which was introduced into clinical practice
in the 1950s. GHB has several interesting pharmacological
effects (Ferrara et al. 1 992; Tunnicliff 1 992; Serra et al.
1 99 1 ; Snead 199 1 ; Mamelak 1 989; Scrima et al. 1989;
Crosby et al. 1 983). At anesthetic doses it induces a selec-
tive increase in dopamine concentrations in various brain
areas, related to a fall in the spontaneous neuronal firing;
at lower doses it has been reported to increase the firing of
dopaminergic neurons in the ventral tegmental area (VTA)
*Professoꢄ ofAddiction Medicine, Medical Diꢄector of PISA-SIA
Gꢄoup (Study and Inteꢆention on Addictions), Depaꢂment ofPsychiatꢄy,
Neuꢄobioꢃogy, Pharmacoꢃogy and Biotechnology, Univeꢄsity ofPisa, Italy.
**Research Candidate, PISA-SIA Group (Study and Inteꢄvention
on Addictions). Depaꢇment of Psychiatꢄy, Neuꢄobioꢃogy, Phaꢄmacology
and Biotechnology, University of Pisa, Italy.
***Pꢄofessor of Phaꢄmacology, Depaꢄtment of Neuꢄosciences,
Univeꢄsity of Siena, Itaꢃy.
Pꢃease address coꢄꢄespondence and reprint ꢄequests to lcꢄo
Maꢄemmani, M.D., University of Pisa, Dipartimento di Psichiatria,
Neurobiologia, Farmacologia e B iotecnologie, Unita Opeꢄativa di
Psichiatria, via Roma 67, 561ꢀ Pisa, Italy.
Vo ꢃume 33 (2), Apriꢃ - June ꢂꢃꢄ
1 35
Jouꢁal of Psychoactive Drugs

Maremmani, Lamanna & Tagliamonte
Long-Term GHB Therapy for Alcohoꢀꢁm
TABLE 1
Demographic Characteristics, Clinical Features and Previous Pharmacological Treatments
Demographic characteristics
Age (M±s)
Sex
4 1 . 83±1 1 .55
1 7 (48.6)
20 (57.2)
8 (22.9)
Males N(%)
Education
Less than high school N(%)
Marital status
Single N(%)
Job status N(%)
White collar
8 (22.8)
14 (40.0)
1 3 (37.2)
2.4 1±.95
Blue collar
Unemployed
Income ( 1 - low ; 4 high) (M±s)
Years of addiction (M±s)
6±3
5.26±1 .01
40.35±10.4
Severity of illness (M±s)
Social adjustment (DSM-IV GAF) (M±s)
Previous pharmacological treatments
(29 subjects)
Imipramine (mg/day; M±s)
Clomipramine
95±35
38±20
50±30
26±1 0
1 25±70
520±90
5ꢀ±250
6±6
Trimipramine
Fluoxetine
Fluvoxamine
Carbamazepine
Valproic Acid
Clonazepam
1 ±0.25
Alprazolam
although this finding was not confirmed in some laborato-
METHODS
ries. GHB has specific binding sites in discrete brain areas;
it is not related to GABA-A receptors, but it becomes bound
to GABA-B receptors. It is a substitute for ethanol in
alcohol-preferring rats.
GHB has been reported to decrease ethanol intake in
alcoholics in the short term (Zolesi et al. 1995; Biggio et al.
1 992; Gallimberti et al. 1992; Gallimberti et al. 1 989). Aims
of the present study were:
Sample
Patients included in the present study were chronic
alcoholics attending the Outpatient Service of the Psychi-
atric Clinic of the University of Pisa, Italy, during a
six-month period. The Psychiatric Clinic of the University
of Pisa is affiliated to the Drug Addiction Unit of the Post-
Doctoral Research Program of the Universities of Siena,
Pisa and Cagliari. Inclusion criteria were:
I . To evaluate the efficacy of a long-term (one-year)
anticraving GHB treatment with regards to the etha-
nol intake of chronic alcoholics who met criteria for
treatment resistance (the target outcomes being con-
trolled use or complete abstinence).
2. To verify whether such a potential efficacy would
outlast the suspension of the therapy, and, if so, for
how long.
This study compared retention in treatment following
seven days of inpatient treatment with GHB to
retention for the same subjects during a later outpa-
tient treatment with GHB for up to one year.
1 . Diagnosis ofalcohol dependenceaccording to DSM-
IV (APA 1994) criteria, whether complicated or not
by psychiatric comorbidity.
2. Treatment resistance, as determined by the follow-
ing criteria: (a) at least two periods of treatment in
the preceding two years. Patients were treated with
the standard therapeutic protocols for alcohol
dependence and for psychiatric comorbidity, when
present (GHB-assisted alcohol detoxification as
inpatient-see first phase on procedure section-
followed by self-help group therapy, use of tryciclics
1 36
Volume 33 (2), April - June 2ꢈ1
Jꢅuꢆꢇꢈ ꢅf Psychoꢇctive Drugs

Maremmani, Lamanna & Tagliamonte
Long-Term GHB Therapy for Alcoholism
FIGURE 1
Psychiatric Comorbidi�y
·
Substance
Related
n = 1
Personality
Disorders .
Delirium
Dementia
n = 2
Mood
Disorders
n = 9
Anxiety
Disorders
n = 4
Anxiety
Disorders
n = 1
Anxiety
Disorders
n = 1
Anxiety
Disorders
n=2
Anxiety
Mood
Mood
Disorders
Disorders
Disorders
n=2
n=2
Substance
Related
n=2
Substance
Related
n=2
Mood
Disorders
n = 1
and/or SSRis, mood stabilizers, and occasionally
benzodiazepines); (b) relapses into alcohol abuse
during the last treatment period (self-help group
therapy) which ranged between one and six months;
and (c) presence of multiple psychosocial or envi-
ronmental problems within the pasttwo years. Scores
for social functioning at the end of the last treat-
ment period were used as the baseline ratings for
the study.
Positive outcome in the outpatient treatment consisted of
complete compliance with the rules of the program,
improved social adjustment, complete abstinence (full
responder patients) or controlled ethanol drinking (partial
responder patients). Controlled drinking was defined as a
maximum daily intake during meals of 1mi!Kg. A failure
to achieve these criteria and a voluntary dropout from
the program were eval uated as a negative outcome
(nonresponder patients).
3. Patients consuming more than 2cc/kg/day of ethanol.
4. Patients living with their families.
Exclusion criteria were:
Psychiatric comorbidity was separately diagnosed by
two residents in psychiatry and confirmed by a senior
psychiatrist (I.M.).
I . Serious liver disorders and chronic diseases.
2. Any structured psychotherapy during the last year.
The sample consisted of 35 patients ( 18 males), mean
age 4 1 ± 1 1 . Demographic characteristics, psychiatric
comorbidity and previous pharmacological treatment are
reported in Table I. Patients were mostly married males
with average economic conditions, but experiencing diffi-
culties as to social adjustment. Most ofthem (n=29) showed
one or more (up to three) psychiatric comorbidities. Six-
teen patients showed one additional psychiatric diagnosis,
eight patients showed two additional psychiatric diagnoses,
and five patients showed three additional psychiatric diag-
noses (see Figure 1 for details).
Severity of illness, global improvement and efficacy
index were evaluated by Clinical Global Impressions (CGI)
(Guy 1976). The items "severity of illness" and "global
improvement" ranged between zero (not assessed) and
seven, which were classified as "among the most extremely
ill patients" and "very much worse," respectively; in the
lattercase a score ofone represents "very much improved."
The efficacy index requires a rating of the interaction of
therapeutic effectiveness and adverse reactions that ranges
between one ("vast improvement, no side effect") and 16
("unchanged or worse, side effects outweighs therapeutic
effect"). These indices have an ordinal relationship.
Social adjustment was evaluated by means of the Glo-
balAssessmentofFunctioning (DSM-IV GAF; APA 1994).
The GAF reports the clinician'sjudgment ofthe individual
overall level of functioning. The maximum level (scores
of 91 to 100) indicates efficient functioning in a wide range
of activities. Scores between 41 and 50 signify the pres-
ence of serious psychopathological symptoms or any
serious impairment in social, occupational, or school func-
tioning. The minimum score (one to l O) indicates the
persistent inability to maintain minimal personal hygiene
or thepresence ofsevere violence or suicidal thoughts. Ten
ASSESSMENT
Alcohol intake was evaluated in terms of total daily
milliliters ofethanol, distinguishing between consumption
during meals and consumption between meals. The varia-
tion in alcohol intake was assessed as percentfall in drinking
volume through self-evaluation as confirmed by family
observer evaluation. One or two members of the family
were responsible for detecting patient alcohol intake.
Vo lume 33 (2), April - June 2001
ꢄ 37
Journal of Psychoactive Drugs

Mꢀmmꢁ, Lamanna & Tagliꢂonte
Long-Teꢃ Gꢂ Therapy for Aꢄcohoꢄꢅꢆ
TABLE 2
Retention Rate Under ꢀeatment
Interval
Number
at Start of
Interval
Number
Number
Cumulative
Percent
Hazard
Rate
Start Time
(month)
Withdrawing
During
Leaving
Program
Survival
at End
(ꢁ±SD)
Inteꢀal
(Nonrespondent)
0
I
2
3
4
5
6
7
35
35
26
23
1 9
1 7
1 6
14
1 2
1 2
12
1 2
1 2
0
3
0
2
0.0
6.6±.3
4. 1±. 1
3.2±.2
1 .9±.2
0.0
2.2±.2
2.6±.3
0.0
0
6
3
2
I
0
I
I
1 .ꢀ
0.82
0.72
0.66
0.62
0.62
0.58
0.54
0.54
0.54
0.54
0.54
0.54
I
I
8
9
10
1 1
1 2
0
0
0
0
0
0
0
0
0
0
0.0
0
.0
0.0
0.0
ꢋeveꢋs oꢍ ꢍꢆnꢂꢈioning ꢅre pꢀovided. Inꢈeꢀmediꢅꢈe ꢂodes ꢅre
ꢅvꢅiꢋꢅbꢋe wꢃen ꢅppꢀopꢀiꢅꢈe.
STATISTICAL ANALYSIS
A ꢀeseꢅꢀꢂꢃeꢀ wꢃo wꢅs noꢈ inꢍormed ꢅs ꢈo vꢅꢀiꢅtions in
sꢆbjeꢂꢈs' ꢅꢋꢂoꢃoꢋ inꢈꢅke ꢅdminisꢈeꢀed ꢈꢃe CGI ꢅnd GAF. Iꢈ
wꢅs pꢀeꢍeꢀꢀed ꢈꢃꢅꢈ ꢈꢃe ꢀeseꢁꢂꢃeꢀ noꢈ be inꢍormed in oꢀdeꢀ
ꢈo beꢈꢈeꢀ ꢂompꢅꢀe ꢍꢆꢋꢋ ꢀespondeꢀ pꢅꢈienꢈs ꢅnd pꢅrꢈiꢅꢋ ꢀe-
spondeꢀ pꢅꢈienꢈs; tꢃis wꢅs ꢅppꢀopꢀiꢅꢈe ꢄꢂꢅꢆse CGI ꢅnd GAF
scꢅꢋes ꢅꢀe ꢈo be ꢀꢅꢈed wiꢈꢃ ꢀespeꢂꢈ onꢋꢉ ꢈo psꢉꢂꢃoꢋogiꢂꢅꢋ,
psꢉchopꢅꢈꢃoꢋogiꢂꢅꢋ, sociꢅꢋ, ꢅnd ocꢂꢆpꢅꢈionꢅꢋ ꢍꢆnꢂꢈioning.
e ꢅꢆꢈꢃoꢀs sꢈꢆdied ꢈꢃe ꢀeꢈenꢈion ꢀꢅꢈe ꢆndeꢀ ꢈꢀeꢅꢈmenꢈ
ꢆsing ꢈꢃe "ꢋiꢍe-ꢈꢅbꢋe ꢅnꢅꢋꢉsis" ꢅꢂꢂoꢀding ꢈo Leeꢊdesꢆ sꢈꢅ-
ꢈisꢈiꢂs. Fiꢀsꢈ ꢈꢃe ꢀeꢈenꢈion ꢀꢅꢈe oꢍ ꢈhe enꢈiꢀe gꢀoꢆp wꢅs
ꢂompꢅꢀed wiꢈh ꢈꢃꢅꢈ dꢆꢀing ꢈꢃeiꢀ ꢋꢅsꢈ ꢈꢀeꢅꢈmenꢈ. Then ꢈhe
pꢀediꢂꢈoꢀs oꢍꢈꢃe ꢀesponse ꢈo GHB tꢀeꢅꢈmenꢈ weꢀe ꢅnꢅꢋꢉzed
in ꢈꢃe sꢅme wꢅꢉ. The ꢋiꢍeꢊꢈꢅbꢋe oꢍ sꢆbgꢀoꢆps divided bꢉ
sex (mꢅꢋeꢊꢍemꢅꢋe), ꢅge (ꢆp ꢈo 40 ꢉeaꢀs oꢋd veꢀsꢆs oveꢀ 40),
psꢉꢂꢃiꢅꢈꢀiꢂ ꢂomoꢀbidiꢈꢉ (ꢅbsence veꢀsꢆs pꢀesence), seveꢀ-
iꢈꢉ oꢍ iꢋꢋness (CGI Iꢈem 1 ꢈo 5 veꢀsꢆs oveꢀ 5), GHB dꢅilꢉ
inꢈꢅke (ꢈꢃree ꢈimes veꢀsꢆs six ꢈimes) weꢀe comparedꢑ Dif-
ꢍeꢀenꢂes in ꢂꢋiniꢂꢅꢋ gꢋobꢅꢋ impꢀessions ꢅnd in sociꢅꢋ
ꢅdjꢆsꢈmenꢈ beꢈween diꢍꢍeꢀenꢈ oꢆꢈꢂome gꢀoꢆps weꢀe ꢈesꢈed
bꢉ one-wꢅꢉ vꢅꢀiꢅnꢂe ꢅnꢅꢋꢉsis wiꢈꢃ posꢈeꢀioꢀ conꢈꢀꢅsꢈ
ꢅꢂꢂoꢀding ꢈoꢈꢃe Sꢂꢃeffeemeꢈhod. Sꢈꢅꢈisꢈicꢅꢋ ꢀoꢆꢈines weꢀe
ꢂꢅrꢀied oꢆꢈ ꢅꢂꢂoꢀding ꢈo ꢈꢃe SPSS sꢉsꢈem.
PROCEDURE
The expeꢀimenꢈꢅꢋ pꢀoꢈoꢂoꢋ consisꢈed oꢍ ꢈꢃree ꢂonseꢂꢆ-
ꢈive pꢃꢅses. Wiꢈꢃin ꢈꢃe ꢍiꢀsꢈ seven dꢅꢉs oꢍꢈꢀeꢅꢈmenꢈ, 50mg/
kg/dꢅꢉ oꢍ GHB, divided inꢈo ꢈꢃꢀee doses ꢈꢅken eveꢀꢉ ꢍoꢆꢀ
ꢃoꢆꢀs, weꢀe ꢅdminisꢈeꢀed ꢈo ꢀeꢋieve ꢅꢋꢂoꢃoꢋ wiꢈꢃdꢀꢅwꢅꢋ
sꢉmpꢈoms ꢅnd ꢈo ꢍꢅciꢋiꢈꢅꢈe ꢈꢃe ꢂessꢅꢈion oꢍ eꢈꢃꢅnoꢋ ꢂon-
sꢆmpꢈion. In tꢃe second sꢈep, ꢈꢃe dose wꢅs pꢀogꢀessiveꢋꢉ
ꢅdjꢆsꢈed ꢈo ꢅ mꢅximꢆm oꢍ 100 mglkg/dꢅꢉ on ꢈꢃe bꢅsis oꢍ
ꢈhe pꢅꢈienꢈ's ꢀesponse. In consideꢀꢅꢈion oꢍ ꢈꢃe sꢃoꢀꢈ ꢃꢅꢋꢍ-
ꢋiꢍe oꢍ GHB (Leꢈtieꢀi & Fꢆng 1 979), pꢅꢈienꢈs weꢀe given
ꢈꢃe dꢅiꢋꢉ dosꢅge oꢍ GHB ꢅꢂꢂoꢀding ꢈo ꢈꢃe ꢈwo ꢍoꢋꢋowing
modꢅꢋiꢈies: eiꢈꢃeꢀ ꢈꢃꢀee doses ꢈꢅken eveꢀꢉ ꢍoꢆꢀ ꢃoꢆꢀs, oꢀ six
doses ꢈꢅken eveꢀꢉ ꢈwo ꢅnd oneꢊhꢅꢋꢍ ꢃoꢆꢀs. Pꢅꢈienꢈs weꢀe
ꢅꢋꢋowed ꢈo inꢂꢀeꢅse ꢈꢃeiꢀ inꢈake bꢉ ꢈꢃemseꢋves (wiꢈꢃ medi-
cꢅꢋ ꢅppꢀovꢅꢋ). Tꢃe ꢈꢃiꢀd sꢈep is ꢂꢃꢅꢀꢅꢂꢈeꢀized bꢉ ꢆp ꢈo one
ꢉeꢅꢀ oꢍ ꢍoꢋꢋow-ꢆp ꢈꢀeꢅꢈmenꢈ, wiꢈꢃ some pꢅꢈienꢈs ꢂonꢈinꢆing
ꢅꢈ ꢈhe opꢈimized dose whiꢋe oꢈꢃeꢀs voꢋꢆnꢈꢅꢀiꢋꢉ sꢆspended
ꢈꢃe ꢈꢀeꢅꢈmenꢈ. No psꢉꢂꢃoꢈꢃeꢀꢅpꢉ oꢀ coꢆnseꢋing wꢅs pꢀo-
vided dꢆꢀing ꢅn ꢆnpꢋꢅnned sꢂꢃedꢆꢋe oꢍ visiꢈs. Geneꢀꢅꢋꢋꢉ
pꢅꢈienꢈs weꢀe seen ꢈwiꢂe oꢀ moꢀe monꢈꢃꢋꢉ. Aꢋꢋ pꢅꢈienꢈs gꢅve
ꢈꢃeiꢀ inꢍoꢀmed ꢂonsenꢈ beꢍoꢀe ꢈꢅking ꢅnꢉ mediꢂꢅꢈion.
RESULTS
ꢇenꢈꢉꢊone pꢅꢈienꢈs (60%) sꢆcꢂessꢍꢆꢋꢋꢉ compꢋeꢈed the
pꢀoꢈoꢂoꢋ ꢅnd weꢀe ꢂonsideꢀed ꢈo be ꢀespondeꢀs; 14 (40%)
ꢋeꢌ tꢃe pꢀogꢀꢅms ꢅnd weꢀe consideꢀed ꢈo be nonꢀespondeꢀsꢑ
Among ꢀespondeꢀs, ꢍoꢆꢀ ( 1 1 .4%) sꢆccessꢍꢆꢋꢋꢉ concꢋꢆded
ꢈꢃe pꢀogꢀꢅm ꢅnd weꢀe consideꢀed ꢍꢆꢋꢋ ꢀespondeꢀs (com-
pꢋeꢈe ꢅbsꢈinence ꢅnd good soꢂiꢅꢋ ꢅdjꢆsꢈmenꢈ), 5 ( 14.3%)
ꢀedꢆced tꢃeiꢀ ꢅꢋꢂoꢃoꢋ inꢈꢅke bꢆꢈdid noꢈ ꢅcꢃieve ꢅbsꢈinence
ꢄꢍoꢀe ꢋeꢅving tꢃe ꢎeꢅꢏenꢈ (pꢅꢀꢈiꢅꢋ ꢀespondeꢀs). Moꢀeoveꢀ,
12 pꢅꢈienꢈs (34.3%) weꢀe sꢈiꢋꢋ ꢆndeꢀ ꢎeꢅꢏenꢈ ꢅꢍꢈeꢀ one ꢉeꢐꢑ
Tꢅbꢋe 2 sꢃows ꢈꢃe ꢀeꢈenꢈion ꢀꢅꢈe ꢆndeꢀ ꢈꢀeꢅꢈmenꢈ. The
ꢂoꢋꢆmn "nꢆmbeꢀ oꢍ pꢅꢈienꢈs wiꢈꢃdꢀꢅwing dꢆꢀing ꢈhe in-
Jouꢀal ofPsychoactive Drugs
138
Volume 33 (2), Apꢀl- June 2ꢀ 1

Maremmani, Lamanna & Tagliamonte
Long-Te rm GHB Therapy for Alcoholism
FꢀGUꢁ 2
Retent.ion Rate in Treatment Compared with Last Previous Treatment
teꢀval" shows those sꢆbjects who left tꢀeatment withoꢆt
and patients still ꢆndeꢀ tꢀeatment significantly diffeꢀ (posi-
tively) fꢀom nonꢀesponding patients.
being consideꢀed nonꢀespondeꢀs; they weꢀe eitheꢀ fꢆll
ꢀespondeꢀs oꢀ paꢀtial ꢀespondeꢀs. Theꢀe was slow sample
attꢀition in months two thꢀoꢆgh seven. Afteꢀ the eighth
month of tꢀeatment, no patients left the pꢀogꢀam. Figꢆꢀe 2
shows the ꢀetention ꢀate of the entiꢀe gꢀoꢆp compaꢀed with
theiꢀ last pꢀevioꢆs tꢀeatment (GHB-assisted alcohol detoxi-
fi cation as inpatients foꢀ seven days, followed by self-help
gꢀoꢆp theꢀapy). Patients ꢆndeꢀ long-teꢀm tꢀeatment with
GHB (as anticꢀaving theꢀapy) stayed in tꢀeatment longeꢀ
(compaꢀison: statistic 26.028, DF1 , p <.001) than when they
weꢀe detoxified and tꢀeated with self-help gꢀoꢆp theꢀapy.
Moꢀe specifically, the gꢀeatest ꢀisk of leaving the self-help
gꢀoꢆp theꢀapy aꢒeꢀ GHB-assisted alcohol detoxification
tꢀeatment dꢆꢀing theiꢀ last pꢀevioꢆs theꢀapeꢆtic pꢀogꢀam
occꢆꢀꢀed dꢆꢀing the 1 80-2 10 day inteꢀval (6.6±. 1%o); the
next most cꢀꢆcial peꢀiods weꢀe, in oꢀdeꢀ, the 60-90 day
inteꢀval (3.4±.9%o); the 90- 1 20 day inteꢀval (2.8±. 1 .%o),
the 1 50- 1 80 day inteꢀval (2.2±.2%o), the 30-60 day inteꢀval
( 1 .4±.2%o), and the 0-30 days inteꢀval ( 1 . 1±.2%o). Afteꢀ the
seventh month oftꢀeatment, no patients in the pꢀevioꢆs tꢀeat-
ment pꢀogꢀam stayed in the pꢀogꢀam.
Table 3 shows endpoint clinical diffeꢀences in diffeꢀ-
ent oꢆtcome gꢀoꢆps. Seveꢀity of illness at endpoint is the
lowest in fꢆll ꢀespondeꢀs, bꢆt no significant diffeꢀences weꢀe
foꢆnd between fꢆll ꢀespondeꢀs and paꢀtial ꢀespondeꢀs.
Patients still ꢆndeꢀ tꢀeatment afteꢀ one yeaꢀdo significantly
diffeꢀ fꢀom fꢆ ll oꢀ paꢀtial ꢀespondeꢀs, bꢆt also fꢀom
nonꢀesponding patients. Regaꢀding global impꢀovement, the
efficacy index, the peꢀcent ꢀedꢆction in alcohol intake and
the ꢀate of social adjꢆstment, fꢆll and paꢀtial ꢀespondeꢀs
Table 4 shows pꢀedictoꢀs ofꢀesponse to tꢀeatment. Sex,
age, pꢀesence of a psychiatꢀic comoꢀbidity, and seveꢀity of
illness at baseline all failed to show any effect on ꢀetention
ꢀate. Only GHB intake (oveꢀ thꢀee times a day) pꢀedicts a
betteꢀ ꢀetention ꢀate (94. 12% veꢀsꢆs 27.78%).
DISCUSSION
Afteꢀ one yeaꢀ oftꢀeatment, 34.3% ofthe patients weꢀe
still in the pꢀogꢀam; they weꢀe not complete abstaineꢀs, bꢆt
they weꢀe at least able to contꢀol theiꢀ ꢆse of alcohol. They
did, in fact, ꢀedꢆce theiꢀ baseline ꢆse ofethanol by appꢀoxi-
mately 40%. This oꢆtcome is closeꢀ to the figꢆꢀes foꢀ
methadone maintenance tꢀeatment pꢀogꢀams than to those
of any known type of pꢀogꢀam foꢀ alcoholics. In ꢀeality,
the psychosocial tꢀeatment of alcoholism is associated with
limited sꢆccess ꢀates. Appꢀoximately half of the alcohol-
dependentpatients who ꢀeceive psychosocial tꢀeatment and
stop dꢀinking expeꢀience ꢀelapses and ꢀesꢆme excessive
alcohol consꢆmption within thꢀee months (Nathan 1986).
As ꢀegaꢀds otheꢀ psychoactive dꢀꢆgs ꢆsed in tꢀeating
alcoholism, naltꢀexone is cꢆꢀꢀently effective in maintain-
ing dꢀꢆg fꢀee statꢆs afteꢀ detoxification. Moꢀeoveꢀ the
obseꢀvation peꢀiod is geneꢀally no longeꢀ than 12 weeks
and the ꢀesꢆlts aꢀe betteꢀ when patients also ꢀeceive psy-
chosocial tꢀeatment (Cꢀoop, Faꢆlkneꢀ & Labꢀiola 1997;
Volpicelli et al. 1 997; Volpicelli et al. 1995; O'Malley et
al. 1992; Vo lpicelli et al. 1 992). Howeveꢀ, some aꢆthoꢀs
ꢀepoꢀted a misꢆse of naltꢀexone (Measom 1 996). Clinical
Volume 33 (ꢂ), April - June ꢂꢃꢋ
1 39
Joꢉꢁꢊl of Psychoꢊctive Drꢉgs

Maremmani, Lamanna & Tagliamonte
Long-ꢇeꢃ GHB ꢇherapy for Alcoholism
TABLE 3
Endpoint Clinicꢆl Diꢁeꢂencꢃ in Diꢁeꢄnt Outcome Gꢂoups
Non-
Full
Parꢃial
Responders
(n=S)
Sꢃill
in ꢂeaꢃmenꢃ
(n=12)
Responder
(n=14)
Responders
(n=4)
ꢄ.7 1 ±ꢂ6
4ꢂ79±ꢂ7
1 ꢁꢂ93±1.ꢄ
87ꢂꢄ0±1 3ꢂ4
47.3 1 ±9.ꢁ
ꢁꢂꢁꢄ±.ꢄ
3.00± 1 .0
ꢁꢂ6ꢃ0ꢂꢄ
ꢄꢂ60±.ꢄ
4.33±.4*
ꢁ.67±.4**
6ꢂ00±1ꢂ8***
4ꢁꢂꢄ0±1 1 . 1 ****
68ꢂ93+8. 1 *****
Severity of illness
Global improvement
Efficacy index
ꢁꢂ00±ꢂ8ꢁ
ꢁꢂꢄ0± 1 ꢂ7
0.00ꢅ
Percent drinking
DSM-IV GAF scores
Statistics:
ꢁ9ꢂꢆ8.9
7 1 ꢂ0ꢃ8ꢇꢁ
78ꢂ33±7ꢂ6
*F-test
**F-test
***F-test
=
44.ꢃ3
37.49
p < ꢀꢁ
Scheffe F-Test (.05)
Scheffe F-Test (.05)
Scheffe F-Test (.05)
Scheffe F-Test (.05)
Scheffe F-Test (.05)
(2) (3) VS (4) VS ( I )
( I) VS (2,3,4)
(I) vs (2,3,4)
(I) vs (2,3,4)
=
p < ꢁꢂꢃ
p < ꢄꢂꢃ
p < ꢁꢂꢃ
p < .ꢂꢅ
=
7 ꢅ ꢁ60
****F-test
=
82ꢁ22
*****F-test
=
2 ꢅ .26
( I) vs (2,3,4)
TABLE 4
Pꢂedictoꢂs of Response to ꢅeꢆtment
Percenꢃ
Overall
Group Clusꢃer
Number
Uncensored
Censored
Censored
Sꢃaꢃisꢃics
p
Sex
8
1 3
47ꢂ06
7ꢁ.ꢁꢁ
1 7
1 8
9
ꢄ
Males
0ꢂ07ꢁ
0.78
Females
Age
1 6
1 9
6
8
10
I I
6ꢁ.ꢄ0
ꢄ7.89
ꢈ 40
> 40
0ꢂ7 1 7
0.037
1 ꢂ 1 ꢁ4
0.39
Psychiatric comorbidity
Absent
4
1 7
66ꢂ67
ꢄ8ꢂ6ꢁ
ꢁ
1 ꢁ
6
ꢁ9
Present
0.84
0.ꢁ8
Baseline severity
CGI ꢉꢄ
1 ꢄ
ꢁ0
ꢄ
9
10
I I
66ꢂ67
ꢄꢄꢂ00
CGI > 5
GHB Intake
3 times/day
6 times/day
ꢄ
1 6
ꢁ7.78
94. 1 ꢁ
1 8
1 7
1 3
I
1 ꢄ.46 1
<.001
also suggested a possible anticraving effect. Tꢃis ꢃꢉpoth-
esis is supported bꢉ tꢃe observation tꢃat no patients ꢋeft
tꢃe program after tꢃe eigꢃtꢃ montꢃ.
Cꢋinicaꢋ globaꢋ impressions and tꢃe rate of social
adjustment, wꢃicꢃ sꢃowed no significant diffe rences
between fulꢋ responders and partial responders, favor the
concept tꢃat a controlled use of etꢃanol is possible utiliz-
ing GHB as an anticraving tꢃerapꢉ. In a previous article
(Biancꢃi et aꢋ. 1 992) tꢃe autꢃors demonstrated that satis-
factorꢉ sociaꢋ adjustment and a ꢋow criminaꢋitꢉ score could
experience suggests tꢃat tꢃe vast majoritꢉ ofꢃeroin addicts
refuse to take naꢋtrexone, but tꢃat it can be usefuꢋ in ꢃigꢃꢋꢉ
motivated individuals. It is possibꢋe tꢃat naꢋtrexone wouꢋd
be usefuꢋ in a simiꢋarlꢉ seꢋected subgroup of alcoꢃoꢋic
patients. Tꢃe clinicaꢋ impact oftꢃe present studꢉ is furtꢃer
strengtꢃened bꢉ tꢃe complete absence of anꢉ concurrent
psꢉchosociaꢋ treatment and bꢉ tꢃe seriousness of patients'
baseline conditions. In addition, no patients discontinued
tꢃe program during tꢃe first montꢃ ofꢈreaꢈment, wꢃicꢃ dem-
onstrated tꢃe efficacꢉ ofGHB on witꢃdrawaꢋ sꢉmptoms and
ꢅ40
Volume 33 (2), April- June 2ꢆ ꢅ
ꢌꢍꢎꢏꢊꢐ of Psychoꢊctive Drꢎgs

Maremmani, Lamanna & Tagliamonte
Long-Term Gꢂ Therapy for Alcoholism
be achieved under strictly controlled methadone mainte-
nance therapy, independently of the complete cessation of
heroin use. Certainly, the controlled use ofheroin may raise
ethical issues, but the controlled use of ethanol is accept-
able in patients whose social role is impaired when they
have no pharmacological support. In other words, GHB
may be able to dissociate alcohol use from poor social func-
tioning in alcoholic patients.
compound is more likely to act as a nonspecific anticraving
agent than as a replacement therapy.
The major limitation of this study is the fact that the
patients served as their own controls, but they were only
included because they had failed their previous detoxifica-
tion program. So the bias that any subsequent treatment
will be superior to one that has failed should be consid-
ered.
A good anticraving drug should have the following
characteristics: it should be able to prevent or reduce with-
drawal symptoms andcraving, prevent relapses, andrestore
to normality each physiological function disrupted by the
use of the substance. Moreover, it should be effective taken
orally, have a long half-life (greater than 24 hours), and
have only slight side-effects, even ifadministered fora long
time; be safe, that is, display no real toxicity or serious
contrary reactions; and be effective with a satisfactory per-
centage of patients (more than 1 5-20%).
The results of this study favor the use of GBH as an
anticraving drug, because they satisfy all the criteria listed
above, but they also reveal its greatest limits. In fact age,
sex, psychiatric comorbidity, and baseline severity of CGI
did not interfere with the efficacy of GHB in controlling
alcohol consumption. The only variable significantly cor-
relating with a better control of ethanol consumption was a
six times/daily fractionated administration ofthe GHB dose.
It should be borne in mind that the anticraving effects of
the GHB may be limited by the short half-life of the com-
pound (Addolorato et al. 1998; Maremmani et al. 1998;
Lettieri & Fung 1979). Three doses per day may not be
sufficient to produce a stable mood concentration during
the 8:00 a.m. to 8:00 p.m. period. Six doses per day should
permit a more stable mood concentration with a higher
anticraving effect.
CONCLUSIONS
The treatment of drug addiction by means of "other
substances" is considered to be an incorrect practice by
some experts. Their view is that drug addiction should be
treated in a different way from other chronic diseases (such
as diabetes and hypertension) i.e., without drugs.
The present results favor the use of GHB not only for
relief of the withdrawal symptoms, but also for alcohol-
craving symptoms. It has a good retention rate during
outpatient treatment, so reducing the social costs of this
illness. The usefulness of GHB in providing an opportu-
nity enabling patients to get the proper psychosocial help
in order to keep the risk of relapse to a minimum remains
to be verified. Lastly, GHB should be useful in the long-
term treatment of patients who cannot have an adequate
life without medication, but are able to have a productive
life when they continue to take it.
It should also be useful to patients who are unable to
discontinue treatment. When GHB therapy continues over
a whole year, it leads to a reduction in the use of the sub-
stance, to the control or reduction of associated and
previously uncontrollable psychiatric symptoms, and to an
improvement in the general state of health. This is verified
by a better level of social adjustment in the workplace and
within the family, bearing in mind that these subjects have
no structured psychosocial setting.
Responsive patients did not show any tolerance to GHB
even after one year of treatment; which suggests that this
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Voꢂume 33 (ꢂ), Aprꢄl - June ꢂ00ꢋ
ꢄ 4 ꢄ
ꢑꢒuꢁꢇl of Psychoꢇctivꢕ Drugs

Mꢈꢉmmꢈnꢊꢋ Lꢈmꢈnnꢈ & Tꢈglꢊꢈmꢏnte
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CꢗPꢗ ꢥ 997. Nꢇꢉtꢈexoꢌe ꢊd ꢇꢉꢏoꢕoꢉ deꢚꢌdeꢌꢏeꢁ Archꢚves ꢖf Geꢛerꢇl
ꢞsꢟꢜhꢚꢊꢠꢡ 54: 737-4ꢤ.
Voꢉpiꢏeꢉꢉi, Jꢁ Rꢒ; Cꢉꢇy, KꢁLꢒ; Wꢇtsoꢌꢛ NꢁTꢒ
&
OꢘBrieꢌꢛ C. P. ꢅ995
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Meꢎom, MꢗOꢁ 1996. Misuse of ꢌꢇꢉtꢍxoꢌeꢁ ꢌꢖꢉrꢗl ꢖf ꢘꢙꢚꢛꢚꢜꢊlꢝꢞsꢟꢜhꢚꢊꢠꢡ
57: 488-89.
Nꢇtꢕꢇꢌ, PꢁE. ꢥ986. Outꢏomes of tꢈeꢇtmeꢌt foꢈ ꢇlꢏoꢕoꢉism: ꢏuꢐeꢌt dꢇtꢇꢁ
Aꢛꢛꢊls ꢖf Behꢊvꢚꢖrꢊl Medꢚꢜꢚꢛe 8: 40-46.
O'Mꢇꢉꢉey, SꢗSꢁ; Jꢇffe,AꢁJꢁ; Cꢕꢇꢌg, Gꢁ; Sꢏꢕotteꢌfeꢉd, R.Sꢁ; Meyeꢈ, RꢁEꢁ &
Rouꢌsꢇviꢉꢉe, B. ꢥ 99ꢤ. Nꢇꢉtꢈexoꢌe ꢊd ꢏopiꢌg skiꢉꢉs tꢕeꢈꢇpy foꢈ
ꢇꢉꢏoꢕoꢉ depeꢌdeꢌꢏe: A ꢏoꢌtꢈoꢉꢉed study. Arꢜhꢚves ꢖf Geꢛerꢊl
ꢞsꢟꢜhꢚꢊꢠꢢ 49: 881-87.
Sꢏꢈimꢇ, Lꢁ; Hꢇꢈtmꢊ, PꢁGꢁ; Joꢕꢌsoꢌ Jꢈ., ꢑHꢁ & Hiꢉꢉeꢈꢛ FꢁC. ꢥ989. Effiꢏꢇꢏy
of gꢇmmꢇ-ꢕydꢈoxibutyꢈꢈꢇte vs pꢉꢇꢏebo iꢌ tꢈeꢇtiꢌg ꢌꢇꢈꢏoꢉepsy
ꢏꢇtꢇpꢉexy; Doubꢉe-bꢉiꢌd subjeꢏtive meꢇsuꢍsꢒ Bꢚꢖlꢖgꢚꢜꢊl ꢞsꢟꢜhꢚꢊꢠꢡ
ꢤ6: 33ꢥ-43.
Nꢇꢉtꢈexoꢌe iꢌ tꢕe treꢇtmeꢌt of ꢇlꢏoꢕoꢉism: Pꢈediꢏtiꢌg ꢈespoꢌse to
ꢌꢇꢉtꢈexoꢌe. ꢌꢖꢉꢏꢊl ꢖf ꢘlꢚꢛꢚꢜꢊl ꢞsꢟꢜhꢚꢊꢠrꢟ 56 (Suppꢉ 7): 39-44.
Voꢉpiꢏeꢉꢉi, JꢁRꢁ; Aꢉteꢈmꢇꢌ, Aꢁꢉꢗ; Hꢇyꢇsꢕidꢇ, M. & OꢘBꢈieꢌ. C.Pꢒ 199ꢤ.
Nꢇꢉtꢈexoꢌe iꢌ tꢕe tꢈeꢇtmeꢌt of ꢇꢉꢏoꢕoꢉ depeꢌdeꢌꢏe. Arꢜhꢚves ꢍf
Geꢛerꢊl ꢞsꢟꢜhꢚꢊꢠry 49: 876-80.
Zoꢉesi, 0.; Dꢇiꢌi, Lꢁ;· Cꢇpoꢌe, MꢗR.; Agꢉiettiꢛ Mꢒ; Rꢇimoꢌdiꢛ Fꢁ&
Mꢖemmꢇꢌiꢛ Iꢁ ꢥ 995. Tꢕe use of GHB iꢌ ꢇꢌtiꢏꢈꢇviꢌg tꢕerꢇpy.
Pꢈeꢉimiꢌꢇꢈy expeꢈimeꢌtꢇꢉ dꢇtꢇ of its use iꢌ ꢇlꢏoꢕol ꢇꢌd ꢕeꢈoiꢌ
depeꢌdeꢌꢏeꢁ Iꢌ: Aꢗ Tꢇgꢉiꢇmoꢌte & 1ꢗ Mꢇremmꢇꢌi (Eds.) Drꢉg
Addꢚꢜꢠꢚꢖꢛ ꢊꢛd Relꢊꢠed ꢘlꢚꢛꢚꢜꢊl ꢞrꢖblems. Vieꢌꢌꢇ & New York:
SpꢈiꢌgeꢈꢔVeꢈꢉꢇgꢁ
ꢥ4ꢤ
Voꢉume 33 (ꢤ), April- Juꢌe ꢤꢀꢥ
Jꢖꢉꢆꢊl ꢖf ꢞsꢟꢜhꢖꢊꢜꢠꢚve Drꢉgs