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New treatments for cocaine dependence:
a focused review
Laurent Karila
1
, David Gorelick
2
, Aviv Weinstein
3
, Florence Noble
4
, Amine Benyamina
5
,
Sarah Coscas
5
, Lisa Blecha
5
, William Lowenstein
6
, Jean Luc Martinot
7
, Michel Reynaud
5
*
and Jean Pierre Le
´
pine
8
*
1
INSERM, U797, Research Unit ‘Neuroimaging & Psychiatry’, IFR49 – CEA, ‘Neuroimaging & Psychiatry’ Unit, Hospital
Department Fre
´
de
´
ric Joliot, 12BM, Orsay, France – Univ Paris-Sud and Univ Paris V Rene Descartes; AP-HP, Ho
ˆ
pital
Universitaire Paul Brousse, Centre d’Enseignement, de Recherche et de Traitement des Addictions, Villejuif F-94808, France
2
Intramural Research Program, Nati onal Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, USA
3
Department of Medical Biophysics and Nuclear Medicine, Hadassah Hospital Ein Kerem, Jerusalem, Israel
4
Universite
´
Paris Descartes, Faculte
´
de Pharmacie, Neuropsychopharmacologie des addictions, CNRS, UMR7157, France
5
Universite
´
Paris-Sud – INSERM U669 Paris, F-75014 – AP-HP, Ho
ˆ
pital Universitaire Paul Brousse, Centre d’Enseignement,
de Recherche et de Traitement des Addictions, Villejuif F-94808, France
6
Montevideo Clinic, Boulogne-Billancourt, France
7
INSERM, U797, Research Unit ‘Neuroimaging & Psychiatry’, IFR49 – CEA, ‘Neuroimaging & Psychiatry’ Unit, Hospital
Department Fre
´
de
´
ric Joliot, 12BM, Orsay, France – Univ Paris-Sud and Univ Paris V Rene Descartes; France
8
Universite
´
Paris Descartes, Faculte
´
de Pharmacie, Neuropsychopharmacologie des addictions, CNRS, UMR7157 et Universite
´
Paris 7 – INSERM, U705 – AP-HP, Ho
ˆ
pital Fernand Widal, Service de Psychiatrie, Paris F-75010, France
Abstract
Cocaine, already a significant drug problem in North and South America, has become a more prominent
part of the European drug scene. Cocaine dependence has major somatic, psychological, psychiatric,
socio-economic, and legal implications. No specific effective pharmacological treatment exists for cocaine
dependence. Recent advances in neurobiology have identified various neuronal mechanisms implicated
in cocaine addiction and suggested several promising pharmacological approaches. Data were obtained
from Medline, EMBASE, and PsycINFO searches of English-language articles published between 1985 and
June 2007 using the key words: cocaine, addiction, cocaine dependence, clinical trials, pharmacother-
apy(ies) singly and in combination. Large well-controlled studies with appropriate statistical methods
were preferred. Pharmacological agents such as GABA agents (topiramate, tiagabine, baclofen and viga-
batrin) and agonist replacement agents (modafinil, disulfiram, methylphenidate) seem to be the most
promising in treatment of cocaine dependence. The results from trials of first- and second-generation
neuroleptics are largely negative. Aripiprazole, a partial dopaminergic agonist that may modulate the
serotonergic system, shows some promise. Preliminary results of human studies with anti-cocaine vac-
cine, N-acetylcysteine, and ondansetron, are promising, as are several compounds in preclinical devel-
opment. While no medication has received regulatory approval for the treatment of cocaine dependence,
several medications marketed for other indications have shown efficacy in clinical trials. An anti-cocaine
vaccine and several compounds in preclinical development have also shown promise. Findings from early
clinical trials must be confirmed in larger, less selective patient populations.
Received 11 January 2007; Reviewed 22 February 2007; Revised 16 July 2007; Accepted 22 August 2007
Key words: Addiction, clinical trials, cocaine, dependence, pharmacotherapy(ies).
Introduction
Cocaine dependence is a chronic, relapsing disorder
characterized by compulsive drug-seeking and drug
use despite negative consequences (Dackis and
O’Brien, 2001; Goldstein and Volkow, 2002). Cocaine
dependence is a significant worldwide public health
problem with somatic, psychological, socio-economic,
and legal complications. Associated public health
risks include infectious diseases (viral hepatitis, HIV)
Address for correspondence: Dr L. Karila, Ho
ˆ
pital Paul Brousse, CERTA (Centre d’Enseignement, de Recherche, de Traitement des Addictions),
12 Avenue Paul Vaillant-Couturier, Villejuif 94800, France.
Tel.: 00 33 1 45593961 Fax: 00 33 1 45593863 E-mail: laurent.karila@pbr.aphp.fr
* These authors contributed equally to this paper.
International Journal of Neuropsychopharmacology, Page 1 of 14. Copyright f 2007 CINP
doi:10.1017/S1461145707008097
REVIEW ARTICLE
CINP
(Friedman et al., 2006) and increased crime and viol-
ence (Hoaken and Stewart, 2003).
This psychostimulant has become a noticeable part
of the European drug scene. The European Monitoring
Centre for Drugs and Drug Abuse estimates that about
3.5 million Europeans (approximately 1% of the adult
population) had used cocaine at least once during the
past year, a substantial increase over the past decade.
Only 13 % of lifetime cocaine users had used cocaine in
the previous month (EMCDDA, 2006), suggesting that
many users do not become chronic users. Cocaine use
varies widely by country, with the highest past year
rates in Spain (2.7%) and the United Kingdom (2%),
comparable to the 2.4 % past year use rate in the USA
in 2004 (Substance Abuse and Mental Health Services
Administration, 2005). As with most illegal drugs,
the highest rates of cocaine use are among young
males aged 15–24 years. Cocaine use has become
the third commonest reason (after opiate and cannabis
use) for patients in the European Union to enter drug
abuse treatment, accounting for approximately 8% of
all treatment admissions in 2004 (EMCDDA, 2006).
Almost all psychoactive drugs causing addiction in
humans activate the meso-cortico-limbic system by
increasing dopamine release within the nucleus ac-
cumbens (Cami and Farre, 2003; Koob and Le Moal,
2001; Nestler, 2001; Wise, 2002). This dopamine sys-
tem plays a critical role in motivational, emotional,
contextual, and affective information processing of
behaviour and drug reinforcement mechanisms.
Cocaine directly increases synaptic dopamine levels in
this meso-cortico-limbic system by blocking the
transporter that pumps dopamine out of the synapse
into the presynaptic nerve terminal. There is strong
evidence from animal and human studies (including
brain imaging by positron emission tomography; PET)
that increased dopamine transmission contributes
significantly to the reinforcing effects of cocaine
(Volkow et al., 2006). However, the original hypothesis
of a simple dysfunction of the meso-cortico-limbic
dopaminergic system is no longer adequate to explain
all aspects of cocaine addiction. Cocaine also blocks
the serotonin and norepinephrine presynaptic trans-
porters. The rewarding cocaine subjective experience
(‘high’) is mediated by increases in both synaptic dop-
amine and norepinephrine levels (Filip et al., 2005;
Wee et al., 2006). Cocaine withdrawal alters function
of both serotonin and dopamine neurons. All three
of these biogenic amine transporters are targets of in-
terest for the development of therapeutic compounds.
Cocaine influences other neurotransmitter systems
including glutamate, GABA, endocannabinoid, and
corticotrophin-releasing hormone (Arnold, 2005;
Backstrom and Hyytia, 2006; Lee et al., 2003; Lhuillier
et al., 2007). These other neurotransmitter systems
interact with and modulate the reward, motivation,
and memory systems in the brain (Kalivas et al.,
2005; Lingford-Hughes and Nutt, 2003). Adaptations
of these neurotransmission systems are observed after
repeated cocaine administration in rats (Kalivas, 2004).
Currently, there is no specific pharmacological
therapy with established efficacy for the treatment of
cocaine dependence, nor is any medication approved
by regulatory authorities for such treatment. Recent
advances in neurobiology have identified various
neuronal mechanisms implicated in cocaine addiction
(Goldstein and Volkow, 2002; Koob, 2000) and sug-
gested several promising pharmacological approaches.
Preliminary clinical trials, including the Cocaine
Rapid Efficacy Screening Trial (CREST) programme
conducted by the United States National Institute
on Drug Abuse (NIDA) (Leiderman et al., 2005),
point to medications affecting the GABAergic and
glutamatergic systems as holding substantial promise.
Recent reviews on pharmacotherapy for cocaine de-
pendence have been published (Gorelick et al., 2004;
Sofuoglu and Kosten, 2005; Vocci and Elkashef, 2005),
but this is a quickly evolving area with new clinical
trials and preclinical findings being reported fre-
quently.
This review will focus on medications which have
been clinically evaluated (Dackis, 2004; Vocci and
Elkashef, 2005) and shown efficacy in published clinical
trials, especially agents affecting the neurotransmitter
systems mentioned above. While glutamatergic agents
show promise in animal studies (Kalivas, 2004), we are
not aware of any published clinical trials showing ef-
ficacy of purely glutamatergic medication (Berger et al.,
2005; Ciraulo et al., 2005). We also discuss preliminary
human studies results with anti-cocaine vaccine,
N-acetylcysteine, and promising compounds based on
preclinical data. We will not discuss other medications
that have been tested as treatment for cocaine depen-
dence in patients with comorbid psychiatric disorders.
This review is based on Medline, EMBASE, and
PsycINFO searches of English-language articles pub-
lished between 1985 and June, 2007.
Clinical pharmacology and efficacy data of current
medications
GABA agents
Topiramate
Topiramate is an anticonvulsant that is also used
clinically to prevent migraine headaches. It has several
2 L. Karila et al.
neuropharmacological actions: blockade of voltage-
dependent sodium channels, enhancement of GABA
neurotransmission at GABA
A
receptors, blockade of
glutamate receptors (AMPA/kainate subtype), and
inhibition of carbonic anhydrase.
Clinical pharmacology. Topiramate is well absorbed
after oral administration (80 % bioavailability), with
peak plasma concentrations achieved after 2 h. Its half-
life is around 21 h, with plasma steady state reached
after 4 d. Topiramate is weakly bound to plasma
proteins (15–40%). Approximately 70 % is excreted
unchanged in the urine.
Efficacy data. In animal studies, topiramate reduces
cocaine self-administration and the dopaminergic
response to cocaine administration and exposure to
cocaine-associated cues (Johnson, 2005).
An open-label pilot study involved six cocaine-
dependent outpatients (also alcohol users) who re-
ceived increasing doses of topiramate (up to 300 mg/d)
for 6 wk, along with weekly cognitive-behavioural
therapy (CBT) (Johnson, 2005). Urine tests remained
negative for cocaine and alcohol consumption was
reduced throughout the study.
The first randomized, double-blind clinical trial in-
volved 40 cocaine-dependent outpatients who received
topiramate (up to 200 mg/d) or placebo for 13 wk, in
conjunction with twice weekly CBT (Kampman et al.,
2004).The topiramate group had significantly less co-
caine use than the placebo group; 59% maintained
continuous abstinence for at least 3 wk.
Baclofen
Baclofen is a GABA
B
receptor agonist which inhibits
mono- and poly-synaptic reflexes at the spinal cord
level, but does not affect neuromuscular transmission.
It is primarily used to reduce muscle spasticity in
neurological diseases such as multiple sclerosis.
Clinical pharmacology. Baclofen has good absorption
after oral administration (75%), with peak serum
concentrations achieved in 2–4 h. Its half-life is 3–4 h.
Baclofen is weakly bound (30 %) to plasma proteins. It
is eliminated primarily via the kidneys, 85 % as the
unchanged parent compound.
Efficacy data. Baclofen reduces ongoing cocaine self-
administration (Roberts, 2005; Roberts and Brebner,
2000), reinstatement of cocaine self-administration
after extinction (Campbell et al., 1999), and cocaine-
seeking behaviour (Di Ciano and Everitt, 2003) in rats.
These behavioural effects may be mediated by its an-
tagonism of cocaine-induced dopamine release in the
nucleus accumbens (Fadda et al., 2003). In preliminary
clinical studies, baclofen (20 –40 mg/d) significantly
reduced cocaine craving in cocaine-dependent sub-
jects (Brebner et al., 2002; Ling et al., 1998). The first
randomized, double-blind clinical trial involved 70
cocaine-dependent outpatients who received 60 mg/d
baclofen or placebo for 16 wk. While there was no
significant overall difference between the two groups,
baclofen significantly reduced cocaine use in the sub-
group of patients who had heavier cocaine use
(Shoptaw et al., 2003). A recent human laboratory
study showed that 60 mg/d baclofen reduced cocaine
self-administration in non-opioid-dependent, non-
treatment-seeking cocaine addicts (Haney et al., 2006).
Baclofen may have clinical utility beyond any anti-
addiction effect. Cocaine-dependent patients have
high rates of psychiatric comorbidity; there is pre-
liminary evidence that baclofen has some anxiolytic
(Breslow et al., 1989; Drake et al., 2003) and anti-
depressant (Krupitsky et al., 1993) effects.
Tiagabine
Tiagabine is an anticonvulsant that increases GABA
neurotransmission by blocking the presynaptic re-
uptake of GABA.
Clinical pharmacology. Tiagabine is rapidly and almost
completely (>90 %) absorbed after oral adminis-
tration, with peak plasma concentration achieved after
45 min. The elimination half-life is 7–9 h, which
shortens to 2–5 h with chronic dosing because of in-
duction of drug-metabolizing enzymes. Tiagabine is
96% bound to plasma proteins. Only 2% is excreted as
parent compound in urine and faeces.
Efficacy data. Tiagabine (20 mg/d) showed a trend
towards reduced cocaine use in a 10-wk screening trial
(Winhusen et al., 2005). Two randomized, placebo-
controlled clinical trials in cocaine-dependent out-
patients maintained on methadone to treat concurrent
opiate dependence confirmed the efficacy of tiagabine.
The first trial involved 45 patients who received
12 mg/d, 24 mg/d, or placebo for 10 wk, along
with weekly CBT (Gonzalez et al., 2003). Tiagabine
dose-dependently decreased cocaine use compared
with placebo. The second trial involved 50 patients
who received 24 mg/d or placebo for 10 wk, along
with weekly individual CBT (Gonzalez et al., 2006).
Tiagabine again significantly decreased cocaine use.
Tiagabine may have clinical utility beyond its anti-
addiction effect. There is clinical evidence that it
New treatments for cocaine dependence 3
may be an anxiolytic agent (Schwartz and Nihalani,
2006).
Vigabatrin (c-vinyl-GABA)
Vigabatrin (c-vinyl-GABA) is an anticonvulsant that
increases GABA neurotransmission by inhibiting
GABA transaminase, an enzyme that breaks
down GABA. In animals, it reduces cocaine self-
administration and cocaine-induced dopamine release
in the nucleus accumbens (Gerasimov et al., 2001;
Kushner et al., 1999). In three open-label studies
involving 78 cocaine- and/or methamphetamine-
dependent outpatients receiving medication for up to
9 wk, vigabatrin (1.5–3 g/d) was well tolerated and
associated with substantial drug abstinence, albeit
with about a 50% dropout rate (Brodie et al., 2003,
2005; Fechtner et al., 2006). Vigabatrin is not marketed
in some countries (e.g. USA) because of concern over
ophthalmological side-effects, but none were observed
during these short-term studies (Fechtner et al., 2006).
Dopamine agents
Bupropion: a dopamine reuptake inhibitor
Bupropion is an antidepressant also approved as
treatment for nicotine (tobacco) dependence. It has
stimulant-like effects in animals and is a weak inhibi-
tor of the presynaptic dopamine transporter, but the
mechanism of its therapeutic action is unclear.
Bupropion (300 mg/d), along with weekly or bi-
weekly individual counselling, was not effective in
reducing cocaine use in a 12-wk, multi-site, controlled
clinical trial in outpatients also maintained on methad-
one for the treatment of concurrent opiate dependence
(Margolin et al., 1995). A post-hoc analysis of this
study showed a significant beneficial effect in the
patients with comorbid depression.
In a recent controlled clinical trial also conducted in
outpatients maintained on methadone for the treat-
ment of concurrent opiate dependence, bupropion
(300 mg/d) potentiated the effect of contingency
management (i.e. reward for producing a cocaine-free
urine specimen) in reducing cocaine use, while having
no effect in patients receiving non-contingent reward
(Poling et al., 2006).
Levodopa/carbidopa
The combination of levodopa (
L-dopa) and carbidopa
is approved for the treatment of Parkinson’s disease.
Clinical pharmacology.
L-dopa, the precursor of dop-
amine, readily crosses the blood–brain barrier into the
central nervous system (CNS), where it is metabolized
to dopamine by aromatic-
L-amino-acid decarbxylase.
This conversion also occurs in peripheral tissues,
causing adverse effects and decreasing the dopamine
available to the CNS.
Carbidopa inhibits decarboxylation of
L-dopa
but does not cross the blood–brain barrier. Hence,
co-administration of carbidopa makes more
L-dopa
available for transport into the brain and its conver-
sion there to dopamine.
Efficacy data.
L-dopa–carbidopa is a dopamine replen-
ishment treatment strategy. In three randomized,
double-blind, placebo-controlled trials in cocaine-
dependent outpatients,
L-dopa–carbidopa (300/75 mg/d,
400/100 mg/d, or 800/200 mg/d) did not signifi-
cantly reduce cocaine use or craving (Mooney et al.,
2007; Shoptaw et al., 2005).
Dopamine antagonists and partial agonists
Cocaine acts directly on the dopaminergic system,
so blockade of dopamine receptors is a plausible
therapeutic approach for cocaine dependence. Con-
ventional (first-generation) neuroleptics, which act
chiefly as dopamine D
2
receptor antagonists, are not
effective in reducing cocaine use in patients with major
psychiatric comorbidity (e.g. schizophrenia) (Green,
2005). Newer second-generation neuroleptics, which
also act on serotonin receptors, are currently being
evaluated.
Efficacy data. Several human laboratory studies found
that the second-generation neuroleptics risperidone
or olanzapine reduced cocaine-induced euphoria or
cue-induced cocaine craving (Newton et al., 2001;
Smelson et al., 1997, 2002, 2004, 2006). One case- series
of 21 outpatients on methadone maintenance for opi-
ate dependence found that olanzapine (5–10 mg/d)
substantially reduced cocaine use (Bano et al., 2001).
However, several outpatient clinical trials found that
neither olanzapine (10 mg/d for 8 wk or 12 wk)
(Kampma, et al., 2003; Reid et al., 2005) nor risper-
idone (2–8 mg/d for 12 wk or 2–4 mg/d for 26 wk)
(Grabowski et al., 2000, 2004a), always in com-
bination with weekly or twice-weekly CBT, signi-
ficantly reduced cocaine use in patients without
psychiatric comorbidity. Aripiprazole is a second-
generation neuroleptic which acts as a partial antag-
onist at both the dopamine D
2
and 5-HT
1
A
receptors
(which regulate dopamine release) (El-Sayeh et al.,
2006). It blocked reinstatement of cocaine self-
administration after extinction, an animal model
of relapse (Feltenstein et al., 2006). Aripiprazole
4 L. Karila et al.
decreased cocaine craving in an 8-wk open-label
pilot study involving 10 cocaine-dependent patients
with comorbid schizophrenia (Beresford et al., 2005).
Clinical trials in cocaine-dependent patients are cur-
rently underway to evaluate these promising findings.
Agonist replacement therapy
Agonist replacement therapy uses a drug from
the same pharmacological family as the abused
drug to suppress withdrawal and drug craving
(Grabowski et al., 2004b). A clinical example is
methadone treatment of heroin dependence. The
abused drug itself can be used in treatment, especially
in a slower onset formulation which has less abuse
liability (Gorelick, 1998). An example of such use
is nicotine gum or skin patch to treat tobacco depen-
dence.
The World Health Organization (WHO) is ex-
ploring the use of agonist replacement medication;
several countries are developing programmes to pur-
sue this approach. Potential agonist medications
include methylphenidate, modafinil, disulfiram,
d-amphetamine, and oral cocaine.
Methylphenidate
Methylphenidate is approved for the treatment of
attention deficit hyperactivity disorder (ADHD).
Clinical pharmacology. Methylphenidate binds to both
the dopamine and norepinephrine presynaptic trans-
porters, but not to the serotonin transporter. The
functional effect is to block catecholamine reuptake
from and increase catecholamine release into the
synapse.
Methylphenidate is rapidly and extensively ab-
sorbed following oral administration. Owing to ex-
tensive first-pass metabolism, oral bioavailability is
around 30%. Peak plasma concentrations of 7.8 ng/ml
were observed 2 h after administration of 0.30 mg/kg
as the standard tablet. The extended-release formu-
lation has similar bioavailability with a broader peak
plasma concentration lasting 2–6 h after adminis-
tration. Methylphenidate has a mean plasma half-
life of around 3.5 h. Following oral administration,
78–97% of the dose is excreted in urine and 1–3% in
faeces within 48–96 h.
The commonest adverse effects are nervousness,
insomnia, and decreased appetite.
Efficacy data. Methylphenidate (5 mg+20 mg sus-
tained release) was no better than placebo in an
11-wk, double-blind, placebo-controlled trial in 24
cocaine-dependent outpatients without psychiatric
comorbidity (Grabowski et al., 1997). However, ADHD
is a common psychiatric comorbidity among cocaine-
dependent persons, occurring in up to 30 % in
some studies (Schubiner, 2005). Because methyl-
phenidate is an effective treatment for ADHD, it
was hypothesized that it might have a beneficial
effect in cocaine-using patients with this comorbid
disorder.
Controlled clinical trials of methylphenidate in this
population have shown mixed results. In a 12-wk,
double-blind, placebo-controlled trial of methyl-
phenidate (90 mg/d immediate-release formulation)
in 48 cocaine-dependent adults with comorbid ADHD,
methylphenidate was no better than placebo for
cocaine use and craving, but did improve subjective
reports of ADHD symptoms (Schubiner et al., 2002).
A recent 14-wk, double-blind, placebo-controlled trial
of sustained-release methylphenidate (60 mg/d) in
106 cocaine-dependent outpatients with comorbid
ADHD found a significant decrease in cocaine use
compared with placebo, with most of the benefit
occurring in patients who had improvement in ADHD
symptoms (Levin et al., 2007). This pattern of findings
suggests that sustained-release methylphenidate may
be more effective than immediate-release, and that
the beneficial effect may be mediated, in part, by a
reduction in ADHD symptoms.
Methylphenidate, like cocaine, is a cardiovascular
stimulant with the potential to cause cardiac adverse
events. A placebo-controlled, cross-over oral methyl-
phenidate (placebo, 60 mg, 90 mg immediate-release
formulation)–intravenous cocaine (saline, 20 mg, 40
mg) interaction study in seven cocaine-dependent
adults found no significant effect of methylphenidate
on the cardiovascular response to cocaine or cocaine
pharmacokinetics (Winhusen et al., 2006). A similar
placebo-controlled, cross-over interaction study in
seven adult cocaine abusers with comorbid ADHD
found that sustained-release oral methylphenidate
(40 mg or 60 mg) increased the cardiovascular
response to intravenous cocaine (16 mg or 48 mg/
70 kg every 14 min for four doses), but not to a de-
gree that required termination of study sessions
(Collins et al., 2006). In both studies, methylphenidate
pretreatment reduced the positive subjective effects of
cocaine. These findings suggest that methylphenidate
may be safe to use in outpatient cocaine abusers.
Oral methylphenidate in the immediate-release
formulation has potential for abuse (Arria and Wish,
2006; White et al., 2006), while the sustained-release
formulation has much less abuse potential (Greenhill,
2006).
New treatments for cocaine dependence 5
Modafinil
Modafinil, a functional stimulant, is used to treat
disorders of excessive sleepiness, such as narcolepsy
or idiopathic hypersomnia (Bastuji and Jouvet, 1988;
Billiard et al., 1994; Laffont et al., 1994).
Clinical pharmacology. Neurochemical mechanisms
underlying modafinil’s therapeutic actions remain
unresolved. This drug has been demonstrated to
occupy both the dopamine and norepinephrine trans-
porter at clinically relevant doses (Madras et al., 2006;
Mignot et al., 1994), consistent with stimulant-like
action In addition, modafinil appears to increase re-
lease of glutamate, an excitatory neurotransmitter, and
decrease release of GABA, an inhibitory neurotrans-
mitter (Ballon and Feifel, 2006).
Modafinil has good absorption following oral
administration, with peak plasma concentrations
attained after 2–4 h. Modafinil is moderately bound to
plasma proteins (60 %), with little evidence of dis-
placement of other medications. Modafinil acid, the
primary metabolite, is pharmacologically inactive.
Modafinil and its metabolites are primarily excreted
by the kidneys; only a small proportion (<10%) is
excreted as the unchanged parent compound.
Modafinil has a half-life of about 15 h, with steady
state reached after 2–4 d of dosing. Thus, once- or
twice-daily dosing is adequate. In clinical trials for
sleep disorders, up to 3% of patients experienced
cardiovascular side-effects such as hypertension,
tachycardia, and palpitations. Patients with mitral
valve prolapse or left ventricular hypertrophy may be
at increased risk of chest pain or ischaemic ECG
changes.
Efficacy data. Modafinil’s stimulant-like activity may
diminish the symptoms of cocaine withdrawal, in-
cluding hypersomnia, lethargy, dysphoric mood, cog-
nitive impairment, and increased appetite (Dackis
et al., 2003), thereby reducing the desire to use cocaine.
It has weak cocaine-like reinforcement effects in ani-
mals (Deroche-Gamonet et al., 2002) and stimulant-
like subjective effects in humans (Rush et al., 2002a,b).
In this light, modafinil may be envisaged as a ‘substi-
tution treatment’ for cocaine dependence, analogous
to methadone or buprenorphine treatment of heroin
dependence.
The first randomized, double-blind clinical trial
involved 62 cocaine-dependent outpatients who
received either a single 400-mg dose of modafinil (n=
32) or of placebo (n=30) daily for 8 wk in conjunction
with CBT (Dackis et al., 2005). Patients taking
modafinil had significantly less cocaine use (measured
by urine drug testing) than did patients treated with
placebo. No significant adverse effects were noted.
A recently completed multi-site, controlled clinical
trial involved 210 cocaine-dependent outpatients who
received either modafinil (200 mg/d or 400 mg/d)
or placebo (Elkashef and Vocci, 2007). Modafinil
significantly reduced cocaine use only in the subgroup
of patients without alcohol dependence. Additional
clinical trials are needed to evaluate the efficacy and
clinical role of modafinil treatment.
Modafinil does not appear to produce euphoria or
evoke cocaine craving (Ballon and Feifel, 2006; O’Brien
et al., 2006), suggesting that it has low abuse potential
(Jasinski, 2000; Jasinski and Kovacevic-Ristanovic,
2000). Chronic cocaine users are capable of discrimi-
nating between cocaine and modafinil effects and re-
port no euphoric effects from the latter (Rush et al.,
2002b). Human laboratory studies report no clinically
significant adverse interactions between modafinil
and cocaine (Dackis et al., 2003; Donovan et al., 2005;
Hart et al., 2007; Malcolm et al., 2006). Post-marketing
surveillance studies have reported no evidence of sig-
nificant abuse liability (Myrick et al., 2004).
Disulfiram: a dopamine metabolism inhibitor
Disulfiram has been used for more than half a century
in the treatment of alcoholism (Suh et al., 2006). It
inhibits aldehyde dehydrogenase, the enzyme that
transforms acetaldehyde into acetate during alcohol
metabolism. When a person drinks alcohol while tak-
ing disulfiram, the resulting acetylaldehyde accumu-
lation causes an aversive reaction (flushing, sweating,
headache, nausea, tachycardia, palpitations, arterial
hypotension, hyperventilation) which discourages
further drinking.
Disulfiram also inhibits dopamine b-hydroxylase,
the enzyme that transforms dopamine into nor-
epinephrine. Such inhibition would increase dop-
amine levels and decrease norepinephrine levels in the
nervous system. This effect is considered to be thera-
peutic for cocaine dependence. In addition, a di-
sulfiram metabolite may block glutamatergic receptors
(Ningaraj et al., 2001).
Clinical pharmacology. Disulfiram is readily absorbed
after oral administration, but then rapidly reduced
to diethyldithiocarbamate, which in turn is broken
down into several metabolites, some of which may be
pharmacologically active. The elimination half-life is
about 7 h, but enzyme inhibition may persist for at
least a week after discontinuation of chronic dosing.
Disulfiram is excreted in urine almost entirely as
metabolites.
6 L. Karila et al.
Efficacy data. The initial impetus for the use of
disulfiram to treat cocaine dependence was the high
rate of comorbidity between cocaine abuse or depen-
dence and alcohol abuse or dependence, up to 85% in
some studies (Gossop and Carroll, 2006). It was hoped
that reduction in alcohol use would lead to secondary
reduction in cocaine use. Abstinence from alcohol
would also prevent formation of cocaethylene, a
metabolite formed when alcohol and cocaine are
present together. Cocaethylene has pharmacological
actions similar to cocaine, but may be longer acting
(Hart et al., 2000). A recent 12-wk open study in out-
patients abusing both cocaine and alcohol found that
the four patients receiving disulfiram (400 mg/d)
along with CBT had fewer urine samples positive for
cocaine and cocaethylene than did the four patients
receiving CBT alone (Grassi et al., 2007).
Several short-term clinical trials in outpatients using
both cocaine and alcohol showed that disulfiram
(250–500 mg/d), along with CBT or a 12-step self-help
group, significantly reduced cocaine and alcohol use
(Carroll et al., 1998; Higgins et al., 1993). In one study,
the reduction in cocaine use was still present one year
after treatment (Carroll et al., 2000).
Three published randomized, placebo-controlled
clinical trials have found that disulfiram has a direct
effect in reducing cocaine use, i.e. in outpatients
who are not also abusing alcohol. Two of these
studies involved outpatients who were also opiate-
dependent and receiving opiate agonist maintenance
treatment (either methadone or buprenorphine)
(George et al., 2000; Petrakis et al., 2000). A larger
trial in outpatients without concurrent opiate de-
pendence found that disulfiram (250 mg/d), along
with CBT or interpersonal therapy, significantly re-
duced cocaine use over the 12-wk study (Carroll
et al., 2004).
Caution has been raised regarding the clinical
use of disulfiram. In human laboratory studies,
disulfiram inhibits cocaine metabolism, increasing
cocaine plasma levels when the two are administered
together (Baker et al., 2006). In some studies, this
has been associated with enhanced cardiovascu-
lar response to cocaine. Both cocaine and the di-
sulfiram–alcohol interaction can produce severe
cardiovascular effects. A patient who relapsed to
cocaine and/or alcohol use while taking disulfiram
might be at risk for serious, perhaps life-threatening,
adverse events. This might limit the use of disulfiram
to patients who are highly motivated for abstinence,
have an active social support network for early de-
tection of relapse, and are in good cardiovascular
health.
Dextroamphetamine (d-amphetamine)
Dextroamphetamine binds to presynaptic dopamine
and norepinephrine transporters and promotes
release of these neurotransmitters. d-amphetamine
decreases cocaine self-administration by rhesus mon-
keys (Negus and Mello, 2003). Three double-blind,
placebo-controlled studies using d-amphetamine
(15–60 mg/d sustained-release formulation) in co-
caine-dependent or in cocaine- and heroin-dependent
patients showed decreased cocaine use at the higher
doses (30 –60 mg/d) (Grabowski et al., 2001, 2004a;
Shearer et al., 2003).
Oral formulations of cocaine
Coca leaf chewing is common among indigenous
inhabitants of the Andean region (Bolivia, Peru,
Colombia). Oral formulations of cocaine, such as coca
tea (infusions of the leaf) and tablets, are also used in
this region.
Clinical pharmacology. Cocaine is a crystalline tropane
alkaloid found in leaves of the coca plant. About a
third of an oral dose is systemically absorbed, with
detectable blood levels appearing after about 30 min.
Physiological and psychotropic effects typically ap-
pear approximately 1 h after ingestion. Cocaine is
rapidly and extensively metabolized, with only about
1% excreted unchanged in the urine. The major
metabolic process is hydrolysis, either by butyryl-
cholinesterase in plasma, brain, and lung (resulting in
ecgonine methylester) or by carboxyesterases in the
liver (resulting in benzoylecgonine) (Warner and
Norman, 2000).
Efficacy data. A human laboratory study found that
pretreatment with oral cocaine (400 mg/d in capsules)
decreased the subjective and physiological responses
to an intravenous cocaine challenge (25 mg or 50 mg)
(Walsh et al., 2000). Anecdotal reports suggest that
coca tea may have anti-craving effects in cocaine users
(Siegel et al., 1986; Weil, 1978). A case- series of 23
coca-paste smokers in Lima, Peru found that coca
tea (20–60 mg/d cocaine) plus counselling reduced
cocaine craving and relapse (Llosa, 1994).
Future studies including controlled clinical trials
are needed to evaluate the efficacy of this treatment
approach.
Promising medications for the future
Several other promising compounds are undergoing
clinical trials or are in preclinical development.
New treatments for cocaine dependence 7
Promising compounds in clinical trials
Vaccine pharmacotherapy
Vaccine pharmacotherapy uses anti-cocaine anti-
bodies to sequester cocaine molecules in the periph-
eral circulation. The cocaine-antibody complexes are
too large to cross the blood–brain barrier, thus keeping
cocaine from its site of action in the CNS (Kosten and
Biegel, 2002). The cocaine molecule by itself is too
small to be antigenic (i.e. to evoke an antibody re-
sponse), so it (or a stable congener) must be coupled
to a larger antigenic molecule, e.g. cholera B toxin
(Heading, 2002). Cocaine vaccines significantly reduce
the behavioural effects of cocaine in animals (Fox et al.,
1996; Kantak et al., 2000). An anti-cocaine vaccine
might have two advantages over conventional medi-
cation: (1) no direct psychoactive effects and, there-
fore, no abuse liability and (2) therapeutic effects
persisting for months, improving patient adherence to
treatment (Kosten and Owens, 2005). A disadvantage
might be a lag time of up to several months before
therapeutic antibody levels were achieved.
A phase I, randomized, double-blind placebo-
controlled trial of vaccine in 34 cocaine abusers over
12 months found that cocaine-specific IgG cocaine
antibodies were induced in a time- and dose-
dependent manner. The vaccine was well tolerated
with no serious adverse effects (Kosten et al., 2002).
More recently, the cocaine vaccine was tested in 18
cocaine-dependent subjects in an open label, 14-wk,
dose-escalation study (Martell et al., 2005). Ten subjects
received four 100 mg injections over 8 wk; eight sub-
jects received five 400 mg vaccinations over 12 wk. The
vaccine was well tolerated. There was a significantly
higher mean antibody titre response in the 2000- mg
group than in the 400-mg group, with detectable anti-
body titres still present after 6 months. Despite relapse
in both groups, most subjects reported attenuation of
cocaine-induced euphoria (‘ high’) (Martell et al., 2005).
N-acetyl cysteine
N-acetyl cysteine is approved for the treatment of
pulmonary complications of cystic fibrosis and para-
cetamol (acetaminophen) overdose.
As the N-acetyl derivative of the amino acid
L-cysteine, it is a major precursor to the antioxidant
glutathione. N-acetyl cysteine is rapidly absorbed
from the gastrointestinal tract, but has low bioavail-
ability due to first-pass metabolism. Peak plasma
concentrations are observed 0.5–1 h following oral
administration of 200–600 mg. Its terminal half-life is
approximately 6 h.
Chronic cocaine use decreases basal levels of gluta-
mate within the nucleus accumbens in rats (Baker
et al., 2003a). N-acetyl cysteine can exchange extra-
cellular cysteine for intracellular glutamate, resulting
in increased levels of glutamate. N-acetyl cysteine
treatment reduces cocaine-induced reinstatement of
cocaine self-administration in rats (an animal model
of relapse) (Baker et al., 2003b).
A double-blind, placebo-controlled, cross-over in-
patient study in 13 non-treatment-seeking cocaine-
dependent subjects found N-acetyl cysteine well
tolerated, with some evidence of decreased cocaine
craving and withdrawal symptoms (LaRowe et al.,
2006).
A 4-wk, open-label pilot study of three doses
of N-acetyl cysteine (1200, 2400, or 3600 mg/d) in
23 treatment-seeking cocaine-dependent outpatients
found all doses safe and well tolerated (Mardikian
et al., 2007). The majority of subjects reduced their
cocaine use; treatment retention was longer for the
two higher-dose groups. Controlled clinical trials are
currently underway to evaluate the promise of this
compound.
Ondansetron
Ondansetron, a serotonin 5-HT
3
receptor antagonist, is
approved as an anti-emetic agent. 5-HT
3
receptor ac-
tivation increases dopamine activity in the nucleus
accumbens (Dremencov et al., 2006), making blockade
of these receptors a potential treatment approach.
A recent 10-wk, double-blind, placebo-controlled trial
in 63 cocaine-dependent outpatients receiving ondan-
setron (0.25 mg, 1.0 mg, or 4.0 mg twice daily) or
placebo plus weekly CBT found that ondansetron
was well tolerated. The 4.0-mg ondansetron group
had a lower dropout rate and higher percentage of
participants with a cocaine-free week than the other
three groups (Johnson et al., 2006).
Promising compounds in preclinical development
Selective dopamine reuptake inhibitor
Dopamine reuptake inhibitors with a slower onset
of effect and longer duration of action than cocaine
might act as functional cocaine antagonists. One such
compound, the 3-phenyltropane analogue RTI-336,
reduced cocaine self-administration in rat and rhesus
monkey models (Carroll et al., 2006).
D
3
receptor ligands
D
3
selective antagonists may influence the ability
of drug-associated cues to induce drug-seeking
8 L. Karila et al.
behaviour (Cervo et al., 2007). They inhibit cocaine-
induced drug seeking and decrease cocaine self-
administration in rodents (Cervo et al., 2007), but not in
rhesus monkeys (Martelle et al., 2007). The D
3
partial
agonist CJB090 blocks the discriminative and reinfor-
cing stimulus effects of cocaine in rhesus monkeys,
without producing cocaine-like effects (Martelle et al.,
2007).
Dual dopamine-serotonin releasers
Medications that release both dopamine and serotonin
are plausible candidates for the treatment of co-
caine addiction, based on several lines of evidence
(Rothman et al., 2006). Withdrawal from chronic co-
caine use produces a dual deficit of both neuro-
transmitters in the brain; drug-seeking behaviour is
reduced by the administration of dopamine and
serotonin releasing agents separately or together;
increased levels of extracellular serotonin can antag-
onize psychomotor stimulant actions of dopamine
releasers, and dual dopamine-serotonin releasers have
low abuse ability. One such candidate medication,
PAL287, is minimally reinforcing itself and suppres-
ses cocaine self-administration in rhesus monkeys
(Rothman et al., 2005).
Cannabinoid CB
1
receptor antagonists
Cannabinoid CB
1
receptors are expressed in the brain
reward circuit, modulate the dopamine-releasing
effects of drugs of abuse, and are involved in relapse
to drug seeking for many addictive drugs (Maldonado
et al., 2006). Blockade of cannabinoid CB
1
receptors
inhibits cocaine- or cocaine cue-induced reinstatement
of cocaine seeking in animals (Xi et al., 2006). CB
1
recep-
tor antagonists are not themselves self-administered
by animals, suggesting little or no abuse liability
(Beardsley et al., 2002). These preclinical findings
suggest that CB
1
receptor antagonists may be a useful
target for medication development.
Corticotropin-releasing factor (CRF) receptor antagonists
CRF is a neuropeptide that evokes release of ACTH
in response to physiological or behavioural stress.
Cocaine self-administration by rhesus monkeys
stimulates ACTH release and activates the hypo-
thalamic–pituitary–adrenal (HPA) axis (Broadbear
et al., 2004), while administration of CRF promotes
reinstatement of cocaine self-administration after ex-
tinction in rats (Erb and Brown, 2006). Stress-induced
activation of the HPA axis during in-patient treat-
ment was negatively correlated with time to relapse
to cocaine use during a 90-d outpatient follow-up
period in a recent study of 49 cocaine-dependent
patients (Sinha et al., 2006). These findings suggest
the HPA axis as a useful target for medication devel-
opment.
The selective CRF
1
receptor antagonist CP154,526
decreased cocaine-induced reinstatement of cocaine
self-administration in rats, while not affecting ongoing
cocaine self-administration or cocaine discrimination
(Przegalinski et al., 2005). Another selective CRF
1
re-
ceptor antagonist, antalarmin, had no effect on cocaine
discrimination or self-administration in rhesus mon-
keys (reinstatement was not studied) (Mello et al.,
2006).
Conclusions
Given that cocaine has become a more prominent part
of the European drug scene, pharmacological treat-
ment has become important for combating this in-
creasingly popular drug of abuse. No pharmacological
treatment has yet proven broadly effective for cocaine
addiction. The studies reviewed in this paper reveal
some promising findings, although most studies were
of short duration and in selected patients.
Recent controlled clinical trials have highlighted the
promise of several medications, especially GABAergic
agents, agonist replacement therapy (amphetamine
or perhaps modafinil) which modulate the cortico-
meso-limbic dopaminergic brain circuits on which
cocaine acts. Partial agonists at the dopamine D
2
re-
ceptor, the 5-HT
3
receptor antagonist ondansetron and
anti-cocaine vaccines are other promising treatment
approaches.
Recent studies suggest that the targets of interest in
developing new treatments for cocaine dependence
should include all three biogenic amine neuro-
transmitters (not only dopamine), as well as the
GABAergic, glutamatergic, and endocannabinoid sys-
tems.
Finally, several issues beyond the scope of this
review, such as integrating pharmacological with
psychosocial treatment, psychiatric comorbidity, and
concurrent dependence (on alcohol or other sub-
stances), should be taken into consideration when
implementing pharmacological treatment for cocaine
dependence.
Acknowledgements
Preparation of this review was supported in part by
the Intramural Research Program, US National
Institutes of Health, National Institute on Drug Abuse.
New treatments for cocaine dependence 9
Dr Weinstein (Israel) and Dr Karila (France) are sup-
ported by the Fondation Rashi (Israel).
Statement of Interest
None.
References
Arnold JC (2005). The role of endocannabinoid transmission
in cocaine addiction. Pharmacology, Biochemistry and
Behavior 81, 396–406.
Arria AM, Wish ED (2006). Nonmedical use of prescription
stimulants among students. Pediatric Annals 35, 565–571.
Backstrom P, Hyytia P (2006). Ionotropic and metabotropic
glutamate receptor antagonism attenuates cue-induced
cocaine seeking. Neuropsychopharmacology 31, 778–786.
Baker DA, McFarland K, Lake RW, Shen H, Tang XC,
Toda S, Kalivas PW (2003a). Neuroadaptations in
cystine-glutamate exchange underlie cocaine relapse.
Nature Neuroscience 6, 743–749.
Baker DA, McFarland K, Lake RW, Shen H, Toda S,
Kalivas PW (2003b). N-acetyl cysteine-induced blockade
of cocaine-induced reinstatement. Annals of the New York
Academy of Sciences 1003, 349–351.
Baker JR, Jatlow P, McCance-Katz EF (2006). Disulfiram
effects on responses to intravenous cocaine administration.
Drug and Alcohol Dependence 87, 202–209.
Ballon JS, Feifel D (2006). A systematic review of modafinil:
potential clinical uses and mechanisms of action. Journal of
Clinical Psychiatry 67, 554–566.
Bano MD, Mico JA, Agujetas M, Lopez ML, Guillen JL
(2001). Olanzapine efficacy in the treatment of cocaine
abuse in methadone maintenance patients. Interaction
with plasma levels [in Spanish]. Actas Espanolas de
Psiquiatria 29, 215–220.
Bastuji H, Jouvet M (1988). Successful treatment of
idiopathic hypersomnia and narcolepsy with modafinil.
Progress in Neuropsychopharmacology and Biological
Psychiatry 12, 695–700.
Beardsley PM, Dance M, Balster RL, Munzar P (2002).
Evaluation of the reinforcing effects of the cannabinoid
CB1 receptor antagonist, SR141716, in rhesus monkeys.
European Journal of Pharmacology 435, 209–216.
Beresford TP, Clapp L, Martin B, Wiberg JL, Alfers J,
Beresford HF (2005). Aripiprazole in schizophrenia with
cocaine dependence: a pilot study. Journal of Clinical
Psychopharmacology 25, 363–366.
Berger S, Winhusen T, Somoza E, Harrer J, Mezinskis J,
Leiderman D, Montgomery MA, Goldsmith RJ, Bloch
DA, Singal BM, Elkashef A (2005). A medication
screening trial evaluation of reserpine, gabapentin and
lamotrigine pharmacotherapy of cocaine dependence.
Addiction 100, 58–67.
Billiard M, Besset A, Montplaisir J, Laffont F, Goldenberg
F, Weill JS, Lubin S (1994). Modafinil: a double-blind
multicentric study. Sleep 17, S107–112.
Brebner K, Childress AR, Roberts DC (2002). A potential
role for GABA (B) agonists in the treatment of
psychostimulant addiction. Alcohol and Alcoholism 37,
478–484.
Breslow MF, Fankhauser MP, Potter RL, Meredith KE,
Misiaszek J, Hope Jr. DG (1989). Role of
gamma-aminobutyric acid in antipanic drug efficacy.
American Journal of Psychiatry 146, 353–356.
Broadbear J, Winger G, Woods J (2004). Self-administration
of fentanyl, cocaine and ketamine: effects on
pituitary-adrenal axis in rhesus monkeys.
Psychopharmacology (Berlin) 176, 398–406.
Brodie JD, Figueroa E, Dewey SL (2003). Treating cocaine
addiction: from preclinical to clinical trial experience with
gamma-vinyl GABA. Synapse 50, 261–265.
Brodie JD, Figueroa E, Laska EM, Dewey SL (2005). Safety
and efficacy of gamma-vinyl GABA (GVG) for the
treatment of methamphetamine and/or cocaine addiction.
Synapse 55, 122–125.
Cami J, Farre M (2003). Drug addiction. New England Journal
of Medicine 349, 975–986.
Campbell UC, Lac ST, Carroll ME (1999). Effects of baclofen
on maintenance and reinstatement of intravenous cocaine
self-administration in rats. Psychopharmacology (Berlin) 143,
209–214.
Carroll FI, Howard JL, Howell LL, Fox BS, Kuhar MJ (2006).
Development of the dopamine transporter selective
RTI-336 as a pharmacotherapy for cocaine dependence.
American Association of Pharmaceutical Scientists Journal 8,
196–203.
Carroll KM, Fenton LR, Ball SA, Nich C, Frankforter TL,
Shi J, Rounsaville BJ (2004). Efficacy of disulfiram and
cognitive behavior therapy in cocaine-dependent
outpatients: a randomized placebo-controlled trial.
Archives of General Psychiatry 61, 264–272.
Carroll KM, Nich C, Ball SA, McCance E, Frankforter TL,
Rounsaville BJ (2000). One-year follow-up of disulfiram
and psychotherapy for cocaine-alcohol users: sustained
effects of treatment. Addiction 95, 1335–1349.
Carroll KM, Nich C, Ball SA, McCance E, Rounsavile BJ
(1998). Treatment of cocaine and alcohol dependence with
psychotherapy and disulfiram. Addiction 93, 713–727.
Cervo L, Cocco A, Petrella C, Heidbreder CA (2007).
Selective antagonism at dopamine D3 receptors attenuates
cocaine-seeking behaviour in the rat. International Journal of
Neuropsychopharmacology 10, 167–181.
Ciraulo DA, Sarid-Segal O, Knapp CM, Ciraulo AM,
LoCastro J, Bloch DA, Montgomery MA, Leiderman DB,
Elkashef A (2005). Efficacy screening trials of paroxetine,
pentoxifylline, riluzole, pramipexole and venlafaxine in
cocaine dependence. Addiction 100 (Suppl. 1), 12–22.
Collins SL, Levin FR, Foltin RW, Kleber HD, Evans SM
(2006). Response to cocaine, alone and in combination with
methylphenidate, in cocaine abusers with ADHD. Drug
and Alcohol Dependence 82, 158–167.
Dackis C (2004). Recent advances in the pharmacotherapy
of cocaine dependence. Current Psychiatry Reports 6,
323–331.
10 L. Karila et al.
Dackis CA, Kampman KM, Lynch KG, Pettinati HM,
O’Brien CP (2005). A double-blind, placebo-controlled
trial of modafinil for cocaine dependence.
Neuropsychopharmacology 30, 205–211.
Dackis CA, Lynch KG, Yu E, Samaha FF, Kampman KM,
Cornish JW, Rowan A, Poole S, White L, O’Brien CP
(2003). Modafinil and cocaine: a double-blind,
placebo-controlled drug interaction study. Drug and
Alcohol Dependence 70, 29–37.
Dackis CA, O’Brien CP (2001). Cocaine dependence: a
disease of the brain’s reward centers. Journal of Substance
Abuse Treatment 21, 111–117.
Deroche-Gamonet V, Darnaudery M, Bruins-Slot L,
Piat F, Le Moal M, Piazza PV (2002). Study of the
addictive potential of modafinil in naive and
cocaine-experienced rats. Psychopharmacology (Berlin) 161,
387–395.
Di Ciano P, Everitt BJ (2003). The GABA(B) receptor
agonist baclofen attenuates cocaine- and heroin-
seeking behavior by rats. Neuropsychopharmacology 28,
510–518.
Donovan JL, DeVane CL, Malcolm RJ, Mojsiak J, Chiang
CN, Elkashef A, Taylor RM (2005). Modafinil influences
the pharmacokinetics of intravenous cocaine in healthy
cocaine-dependent volunteers. Clinical Pharmacokinetics 44,
753–765.
Drake RG, Davis LL, Cates ME, Jewell ME, Ambrose SM,
Lowe JS (2003). Baclofen treatment for chronic
posttraumatic stress disorder. Annals of Pharmacotherapy 37,
1177–1181.
Dremencov E, Weizmann Y, Kinor N, Gispan-Herman I,
Yadid G (2006). Modulation of dopamine transmission by
5HT2C and 5HT3 receptors: a role in the antidepressant
response. Current Drug Targets 7, 165–175.
El-Sayeh HG, Morganti C, Adams CE (2006). Aripiprazole
for schizophrenia: systematic review. British Journal of
Psychiatry 189, 102–108.
Elkashef A, Vocci JF (2007). Promising medications for
the treatment of cocaine addiction. Presented at
American Psychiatric Association Annual Meeting, May
2007. San Diego, CA.
EMCDDA (2006). European Monitoring Center for Drugs
and Drug Abuse. Annual Report 2006: the state of the drug
problem in Europe (www.emcdda.europa.eu). Accessed 2
January 2007.
Erb S, Brown Z (2006). A role for corticotropin-releasing
factor in the long-term expression of behavioral
sensitization to cocaine. Behavioural Brain Research 25,
360–364.
Fadda P, Scherma M, Fresu A, Collu M, Fratta W (2003).
Baclofen antagonizes nicotine-, cocaine-, and
morphine-induced dopamine release in the nucleus
accumbens of rat. Synapse 50, 1–6.
Fechtner R, Khouri A, Figueroa E, Ramirez M, Federico M,
Dewey S, Brodie JD (2006). Short-term treatment of
cocaine and/or methamphetamine abuse with vigabatrin:
ocular safety pilot results. Archives of Ophthalmology 124,
1257–1262.
Feltenstein MW, Altar CA, See RE (2006). Aripiprazole
blocks reinstatement of cocaine seeking in an animal
model of relapse. Biological Psychiatry 61, 582–590.
Filip M, Frankowska M, Zaniewska M, Golda A,
Przegalinski E (2005). The serotonergic system and its role
in cocaine addiction. Pharmacological Reports 57, 685–700.
Fox BS, Kantak KM, Edwards MA, Black KM, Bollinger BK,
Botka AJ, French TL, Thompson TL, Schad VC,
Greenstein JL, et al. (1996). Efficacy of a therapeutic
cocaine vaccine in rodent models. Nature Medicine 2,
1129–1132.
Friedman H, Pross S, Klein T (2006). Addictive
drugs and their relationship with infectious
diseases. FEMS Immunology and Medical Microbiology
47, 330–342.
George TP, Chawarski MC, Pakes J, Carroll KM, Kosten TR,
Schottenfeld RS (2000). Disulfiram versus placebo for
cocaine dependence in buprenorphine-maintained
subjects: a preliminary trial. Biological Psychiatry 47,
1080–1086.
Gerasimov MR, Schiffer WK, Gardner EL, Marsteller DA,
Lennon IC, Taylor SJ, Brodie JD, Ashby Jr. CR, Dewey SL
(2001). GABAergic blockade of cocaine-associated
cue-induced increases in nucleus accumbens dopamine.
European Journal of Pharmacology 414, 205–209.
Goldstein RZ, Volkow ND (2002). Drug addiction and its
underlying neurobiological basis: neuroimaging evidence
for the involvement of the frontal cortex. American Journal
of Psychiatry 159, 1642–1652.
Gonzalez G, Desai R, Sofuoglu M, Poling J, Oliveto A,
Gonsai K, Kosten TR (2006). Clinical efficacy of
gabapentin versus tiagabine for reducing cocaine use
among cocaine dependent methadone-treated patients.
Drug and Alcohol Dependence 87, 1–9.
Gonzalez G, Sevarino K, Sofuoglu M, Poling J, Oliveto A,
Gonsai K, George TP, Kosten TR (2003). Tiagabine
increases cocaine-free urines in cocaine-dependent
methadone-treated patients: results of a randomized pilot
study. Addiction 98, 1625–1632.
Gorelick DA (1998). The rate hypothesis and agonist
substitution approaches to cocaine abuse treatment.
Advances in Pharmacology 42, 995–997.
Gorelick DA, Gardner E, Xi ZX (2004). Agents in
developments for the management of cocaine abuse.
Drugs 64, 1547–1573.
Gossop M, Carroll KM (2006). Disulfiram, cocaine, and
alcohol: two outcomes for the price of one? Alcohol and
Alcoholism 41, 119–120.
Grabowski J, Rhoades H, Schmitz J, Stotts A, Daruzska LA,
Creson D, Moeller FG (2001). Dextroamphetamine for
cocaine-dependence treatment: a double-blind
randomized clinical trial. Journal of Clinical
Psychopharmacology 21, 522–526.
Grabowski J, Rhoades H, Silverman P, Schmitz JM,
Stotts A, Creson D, Bailey R (2000). Risperidone for the
treatment of cocaine dependence: randomized,
double-blind trial. Journal of Clinical Psychopharmacology
20, 305–310.
New treatments for cocaine dependence 11
Grabowski J, Rhoades H, Stotts A, Cowan K, Kopecky C,
Dougherty A, Moeller FG, Hassan S, Schmitz J
(2004a). Agonist-like or antagonist-like treatment
for cocaine dependence with methadone for
heroin dependence: two double-blind randomized
clinical trials. Neuropsychopharmacology 29, 969–981.
Grabowski J, Roache JD, Schmitz JM, Rhoades H, Creson
D, Korszun A (1997). Replacement medication for cocaine
dependence: methylphenidate. Journal of Clinical
Psychopharmacology 17, 485–488.
Grabowski J, Shearer J, Merrill J, Negus SS (2004b).
Agonist-like, replacement pharmacotherapy for stimulant
abuse and dependence. Addictive Behaviors 29, 1439–1464.
Grassi MC, Cioce AM, Giudici FD, Antonilli L, Nencini P
(2007). Short-term efficacy of Disulfiram or Naltrexone in
reducing positive urinalysis for both cocaine and
cocaethylene in cocaine abusers: a pilot study.
Pharmacology Research 55, 117–121.
Green A (2005). Schizophrenia and comorbid substance use
disorder: effects of antipsychotics. Journal of Clinical
Psychiatry 66, 21–26.
Greenhill LL (2006). The science of stimulant abuse. Pediatric
Annals 35, 552–556.
Haney M, Hart CL, Foltin RW (2006). Effects of baclofen
on cocaine self-administration: opioid- and
nonopioid-dependent volunteers.
Neuropsychopharmacology 31, 1814–1821.
Hart C, Jatlow P, Sevarino K, Cance-Katz E (2000).
Comparison of intravenous cocaethylene and cocaine in
humans. Psychopharmacology ( Berlin) 149, 153–162.
Hart CL, Haney M, Vosburg SK, Rubin E, Foltin RW (2007).
Smoked cocaine self-administration is decreased by
modafinil. Neuropsychopharmacology. Published online: 13
June 2007. doi: 10.1038/sj.npp.1301472.
Heading C (2002). TA-CD. Xenova. IDrugs 5, 1070–1074.
Higgins ST, Budney AJ, Bickel WK, Hughes JR, Foerg F
(1993). Disulfiram therapy in patients abusing cocaine and
alcohol. American Journal of Psychiatry 150, 675–676.
Hoaken P, Stewart S (2003). Drugs of abuse and elicitation of
human aggressive behavior. Addictive Behaviors 28 ,
1533–1554.
Jasinski DR (2000). An evaluation of the abuse potential of
modafinil using methylphenidate as a reference. Journal of
Psychopharmacology 14, 53–60.
Jasinski DR, Kovacevic-Ristanovic R (2000). Evaluation of
the abuse liability of modafinil and other drugs for
excessive daytime sleepiness associated with narcolepsy.
Clinical Neuropharmacology 23, 149–156.
Johnson BA (2005). Recent advances in the development of
treatments for alcohol and cocaine dependence: focus on
topiramate and other modulators of GABA or glutamate
function. CNS Drugs 19, 873–896.
Johnson BA, Roache JD, Ait-Daoud N, Javors MA, Harrison
JM, Elkashef A, Mojsiak J, Li SH, Bloch DA (2006). A
preliminary randomized, double-blind, placebo-controlled
study of the safety and efficacy of ondansetron in the
treatment of cocaine dependence. Drug and Alcohol
Dependence 84, 256–263.
Kalivas PW (2004). Glutamate systems in cocaine addiction.
Current Opinion in Pharmacology 4, 23–29.
Kalivas PW, Volkow N, Seamans J (2005). Unmanageable
motivation in addiction: a pathology in
prefrontal-accumbens glutamate transmission. Neuron
45, 647–650.
Kampman KM, Pettinati H, Lynch KG, Dackis C,
Sparkman T, Weigley C, O’Brien CP (2004). A pilot trial
of topiramate for the treatment of cocaine dependence.
Drug and Alcohol Dependence 75, 233–240.
Kampman KM, Pettinati H, Lynch KG, Sparkman T,
O’Brien CP (2003). A pilot trial of olanzapine for the
treatment of cocaine dependence. Drug and Alcohol
Dependence 70, 265–273.
Kantak KM, Collins SL, Lipman EG, Bond J, Giovanoni K,
Fox BS (2000). Evaluation of anti-cocaine antibodies and a
cocaine vaccine in a rat self-administration model.
Psychopharmacology (Berlin) 148, 251–262.
Koob G (2000). Neurobiology of addiction. Toward the
development of new therapies. Annals of New York Academy
of Sciences 909, 170–185.
Koob G, Le Moal M (2001). Drug addiction, dysregulation of
reward, and allostasis. Neuropsychopharmacology 24, 97–129.
Kosten T, Owens SM (2005). Immunotherapy for the
treatment of drug abuse. Pharmacology and Therapeutics 108,
76–85.
Kosten T, Rosen M, Bond J, Settles M, Roberts J, Shields J,
Jack L, Fox BS (2002). Human therapeutic cocaine vaccine:
Safety and immunogenicity. Vaccine 20, 1196–1204.
Kosten TR, Biegel D (2002). Therapeutic vaccines for
substance dependence. Expert Review of Vaccines 1, 363–371.
Krupitsky EM, Burakov AM, Ivanov VB, Krandashova GF,
Lapin IP, Grinenko A, Borodkin YS (1993). Baclofen
administration for the treatment of affective disorders in
alcoholic patients. Drug and Alcohol Dependence 33, 157–163.
Kushner SA, Dewey SL, Kornetsky C (1999). The
irreversible gamma-aminobutyric acid (GABA)
transaminase inhibitor gamma-vinyl-GABA blocks cocaine
self-administration in rats. Journal of Pharmacology and
Experimental Therapeutics 290, 797–802.
Laffont F, Mayer G, Minz M (1994). Modafinil in diurnal
sleepiness. A study of 123 patients. Sleep 17, S113–115.
LaRowe SD, Mardikian P, Malcolm R, Myrick H, Kalivas P,
McFarland K, Saladin M, McRae A, Brady K
(2006). Safety and tolerability of N-acetylcysteine in
cocaine-dependent individuals. American Journal on
Addictions, 15, 105–110.
Lee B, Tiefenbacher S, Platt DM, Spealman RD (2003).
Role of the hypothalamic-pituitary-adrenal axis in
reinstatement of cocaine-seeking behavior in squirrel
monkeys. Psychopharmacology (Berlin) 168, 177–183.
Leiderman D, Shoptaw S, Montgomery A, Bloch D,
Elkashef A, LoCastro J, Vocci F (2005). Cocaine Rapid
Efficacy Screening Trial (CREST): a paradigm for the
controlled evaluation of candidate medications for cocaine
dependence. Addiction 100 (Suppl. 1), 1–11.
Levin FR, Evans SM, Brooks DJ, Garawi F (2007). Treatment
of cocaine dependent treatment seekers with adult ADHD:
12 L. Karila et al.
double-blind comparison of methylphenidate and placebo.
Drug and Alcohol Dependence 87, 20–29.
Lhuillier L, Mombereau C, Cryan JF, Kaupmann K (2007).
GABA(B) receptor-positive modulation decreases
selective molecular and behavioral effects of cocaine.
Neuropsychopharmacology 32, 388–398.
Ling W, Shoptaw S, Majewska D (1998). Baclofen as a
cocaine anti-craving medication: a preliminary clinical
study. Neuropsychopharmacology 18, 403–404.
Lingford-Hughes A, Nutt D (2003). Neurobiology of
addiction and implications for treatment. British Journal
of Psychiatry 182, 97–100.
Llosa T (1994). The standard low dose of oral cocaine: used
for treatment of cocaine dependence. Substance Abuse 15,
215–220.
Madras BK, Xie Z, Lin Z, Jassen A, Panas H, Lynch L,
Johnson R, Livni E, Spencer TJ, Bonab AA, Miller GM,
Fischman AJ (2006). Modafinil occupies dopamine and
norepinephrine transporters in vivo and modulates
the transporters and trace amine activity in vitro.
Journal of Pharmacology and Experimental Therapeutics
319, 561–569.
Malcolm R, Swayngim K, Donovan J, DeVane C, Elkashef
A, Chiang N, Khan R, Mojsiak J, Myrick D, Hedden SL,
Cochran K, Woolson R (2006). Modafinil and cocaine
interactions. American Journal of Drug and Alcohol Abuse 32,
577–587.
Maldonado R, Valverde O, Berrendero F (2006).
Involvement of the endocannabinoid system in drug
addiction. Trends in Neurosciences 29, 225–232.
Mardikian PN, Larowe SD, Hedden S, Kalivas PW,
Malcolm RJ (2007). An open-label trial of N-acetylcysteine
for the treatment of cocaine dependence: a pilot study.
Progress in Neuropsychopharmacology and Biological
Psychiatry 31, 389–394.
Margolin A, Kosten TR, Avants SK, Wilkins J, Ling W,
Beckson M, Arndt IO, Cornish J, Ascher JA, Li SH, et al.
(1995). A multicenter trial of bupropion for cocaine
dependence in methadone-maintained patients. Drug and
Alcohol Dependence 40, 125–131.
Martell BA, Mitchell E, Poling J, Gonsai K, Kosten TR
(2005). Vaccine pharmacotherapy for the treatment of
cocaine dependence. Biological Psychiatry 58, 158–164.
Martelle J, Claytor R, Ross J, Reboussin BA, Newman A,
Nader MA (2007). Effects of two novel D3-selective
compounds, NGB 2904 and CJB 090, on the reinforcing and
discriminative stimulus effects of cocaine in rhesus
monkeys. Journal of Pharmacology and Experimental
Therapeutics 321, 573–582.
Mello N, Negus SS, Rice KC, Mendelson JH (2006). Effects
of the CRF1 antagonist antalarmin on cocaine
self-administration and discrimination in rhesus monkeys.
Pharmacology, Biochemistry and Behavior 85, 744–751.
Mignot E, Nishino S, Guilleminault C, Dement WC (1994).
Modafinil binds to the dopamine uptake carrier site with
low affinity. Sleep 17, 436–437.
Mooney ME, Schmitz JM, Moeller FG, Grabowski J (2007).
Safety, tolerability and efficacy of levodopa-carbidopa
treatment for cocaine dependence: two double-blind,
randomized, clinical trials. Drug and Alcohol Dependence 88,
214–223.
Myrick H, Malcolm R, Taylor B, LaRowe S (2004).
Modafinil: preclinical, clinical, and post-marketing
surveillance – a review of abuse liability issues. Annals of
Clinical Psychiatry 16, 101–109.
Negus SS, Mello NK (2003). Effects of chronic
d-amphetamine treatment on cocaine- and
food-maintained responding under a progressive-ratio
schedule in rhesus monkeys. Psychopharmacology (Berlin)
167, 324–332.
Nestler E (2001). Molecular neurobiology of addiction.
American Journal on Addictions 10, 201–217.
Newton TF, Ling W, Kalechstein AD, Uslaner J, Tervo K
(2001). Risperidone pre-treatment reduces the euphoric
effects of experimentally administered cocaine. Psychiatry
Research 102, 227–233.
Ningaraj N, Chen W, Schloss J, Faiman M, Wu J-Y (2001).
S-Methyl-N,N-diethylthiocarbamate sulfoxide elicits
neuroprotective effect against N-methyl-D-aspartate
receptor-mediated neurotoxicity. Journal of Biomedical
Science 8, 104–113.
O’Brien CP, Dackis CA, Kampman K (2006). Does
modafinil produce euphoria? American Journal of
Psychiatry 163, 1109.
Petrakis IL, Carroll KM, Nich C, Gordon LT,
McCance-Katz EF, Frankforter T, Rounsaville BJ
(2000). Disulfiram treatment for cocaine dependence
in methadone-maintained opioid addicts. Addiction
95, 219–228.
Poling J, Oliveto A, Petry N, Sofuoglu M, Gonsai K,
Gonzalez G, Martell B, Kosten TR (2006). Six-month
trial of bupropion with contingency management
for cocaine dependence in a methadone-maintained
population. Archives of General Psychiatry 63, 219–228.
Przegalinski E, Filip M, Frankowska M, Zaniewska M,
Papla I (2005). Effects of CP 154,526, a CRF1 receptor
antagonist, on behavioral responses to cocaine in rats.
Neuropetides 39, 525–533.
Reid MS, Casadonte P, Baker S, Sanfilipo M, Braunstein D,
Hitzemann R, Montgomery A, Majewska D, Robinson J,
Rotrosen J (2005). A placebo-controlled screening trial of
olanzapine, valproate, and coenzyme Q10/L-carnitine for
the treatment of cocaine dependence. Addiction 100
(Suppl. 1), 43–57.
Roberts DC (2005). Preclinical evidence for GABAB agonists
as a pharmacotherapy for cocaine addiction. Physiology and
Behavior 86, 18–20.
Roberts DC, Brebner K (2000). GABA modulation of cocaine
self-administration. Annals of the New York Academy of
Sciences 909, 145–158.
Rothman RB, Blough BE, Baumann MH (2006). Dual
dopamine-5-HT releasers: potential treatment agents for
cocaine addiction. Trends in Pharmacological Sciences 27,
612–618.
Rothman RB, Blough BE, Woolverton WL, Anderson KG,
Negus SS, Mello NK, Roth BL, Baumann MH (2005).
New treatments for cocaine dependence 13
Development of a rationally designed, low abuse
potential, biogenic amine releaser that suppresses
cocaine self-administration. Journal of Pharmacology
and Experimental Therapeutics 313, 1361–1369.
Rush CR, Kelly TH, Hays LR, Baker RW, Wooten AF
(2002a). Acute behavioral and physiological effects of
modafinil in drug abusers. Behavioural Pharmacology 13,
105–115.
Rush CR, Kelly TH, Hays LR, Wooten AF (2002b).
Discriminative-stimulus effects of modafinil in cocaine-
trained humans. Drug and Alcohol Dependence 67, 311–322.
Schubiner H (2005). Substance abuse in patients with
attention-deficit hyperactivity disorder: therapeutic
implications. CNS Drugs 19, 643–655.
Schubiner H, Saules KK, Arfken CL, Johanson CE, Schuster
CR, Lockhart N, Edwards A, Donlin J, Pihlgren E (2002).
Double-blind placebo-controlled trial of methylphenidate
in the treatment of adult ADHD patients with comorbid
cocaine dependence. Experimental and Clinical
Psychopharmacology 10, 286–294.
Schwartz T, Nihalani N (2006). Tiagabine in anxiety
disorders. Expert Opinion in Pharmacotherapy 7, 1977–1987.
Shearer J, Wodak A, van Beek I, Mattick RP, Lewis J (2003).
Pilot randomized double blind placebo-controlled study of
dexamphetamine for cocaine dependence. Addiction 98,
1137–1141.
Shoptaw S, Watson DW, Reiber C, Rawson RA,
Montgomery MA, Majewska MD, Ling W (2005).
Randomized controlled pilot trial of cabergoline,
hydergine and levodopa/carbidopa: Los Angeles Cocaine
Rapid Efficacy Screening Trial (CREST). Addiction 100
(Suppl. 1), 78–90.
Shoptaw S, Yang X, Rotheram-Fuller EJ, Hsieh YC,
Kintaudi PC, Charuvastra VC, Ling W (2003).
Randomized placebo-controlled trial of baclofen for
cocaine dependence: preliminary effects for individuals
with chronic patterns of cocaine use. Journal of Clinical
Psychiatry 64, 1440–1448.
Siegel R, ElSohly M, Plowman T, Rury P, Jones R (1986).
Cocaine in herbal tea. Journal of the American Medical
Association 255, 40.
Sinha R, Garcia M, Paliwal P, Kreek MJ, Rounsaville BJ
(2006). Stress-induced cocaine craving and hypothalamic-
pituitary-adrenal responses are predictive of cocaine
relapse outcomes. Archives of General Psychiatry 63,
324–331.
Smelson DA, Losonczy MF, Davis CW, Kaune M,
Williams J, Ziedonis D (2002). Risperidone decreases
craving and relapses in individuals with schizophrenia
and cocaine dependence. Canadian Journal of Psychiatry
47, 671–675.
Smelson DA, Roy A, Roy M (1997). Risperidone diminishes
cue-elicited craving in withdrawn cocaine-dependent
patients. Canadian Journal of Psychiatry 42, 984.
Smelson DA, Williams J, Ziedonis D, Sussner BD,
Losonczy MF, Engelhart C, Kaune M (2004).
A double-blind placebo-controlled pilot study of
risperidone for decreasing cue-elicited craving in
recently withdrawn cocaine dependent patients. Journal
of Substance Abuse Treatment 27, 45–49.
Smelson DA, Ziedonis D, Williams J, Losonczy MF,
Williams J, Steinberg ML, Kaune M (2006). The efficacy
of olanzapine for decreasing cue-elicited craving in
individuals with schizophrenia and cocaine dependence:
a preliminary report. Journal of Clinical Psychopharmacology
26, 9–12.
Sofuoglu M, Kosten TR (2005). Novel approaches to the
treatment of cocaine addiction. CNS Drugs 19, 13–25.
Suh JJ, Pettinati HM, Kampman KM, O’Brien CP (2006).
The status of disulfiram: a half of a century later. Journal
of Clinical Psychopharmacology 26, 290–302.
Vocci FJ, Elkashef A (2005). Pharmacotherapy and other
treatments for cocaine abuse and dependence. Current
Opinion in Psychiatry 18, 265–270.
Volkow ND, Wang GJ, Telang F, Fowler JS, Logan J,
Childress AR, Jayne M, Ma Y, Wong C (2006). Cocaine
cues and dopamine in dorsal striatum: mechanism of
craving in cocaine addiction. Journal of Neuroscience 26,
6583–6588.
Walsh SL, Haberny KA, Bigelow GE (2000). Modulation
of intravenous cocaine effects by chronic oral cocaine in
humans. Psychopharmacology ( Berlin) 150, 361–373.
Warner A, Norman AB (2000). Mechanisms of cocaine
hydrolysis and metabolism in vitro and in vivo: a
clarification. Therapeutic Drug Monitoring 22, 266–270.
Wee S, Wang Z, He R, Zhou J, Kozikowski AP,
Woolverton WL (2006). Role of the increased
noradrenergic neurotransmission in drug self-
administration. Drug and Alcohol Dependence 82, 151–157.
Weil A (1978). Coca leaf as a therapeutic agent. American
Journal of Drug and Alcohol Abuse 5, 75–86.
White BP, Becker-Blease KA, Grace-Bishop K (2006).
Stimulant medication use, misuse, and abuse in an
undergraduate and graduate student sample. Journal of
American College Health 54, 261–268.
Winhusen T, Somoza E, Singal BM, Harrer J, Apparaju S,
Mezinskis J, Desai P, Elkashef A, Chiang CN, Horn P
(2006). Methylphenidate and cocaine: a placebo-controlled
drug interaction study. Pharmacology, Biochemistry and
Behavior 85, 29–38.
Winhusen TM, Somoza EC, Harrer JM, Mezinskis JP,
Montgomery MA, Goldsmith RJ, Coleman FS,
Bloch DA, Leiderman DB, Singal BM, Berger P,
Elkashef A (2005). A placebo-controlled screening
trial of tiagabine, sertraline and donepezil as
cocaine dependence treatments. Addiction 100
(Suppl. 1), 68–77.
Wise R (2002). Brain reward circuitry: insights from
unsensed incentives. Neuron 36, 229–240.
Xi ZX, Gilbert JG, Peng XQ, Pak AC, Li X, Gardner EL
(2006). Cannabinoid CB1 receptor antagonist AM251
inhibited cocaine-primed relapse in rats: role of eglutamate
in the nucleus accumbens. Journal of Neuroscience 26,
8531–8536.
14 L. Karila et al.
