New Treatment for Alcohol and Nicotine Dependence

We propose a novel pharmacological strategy for treating alcohol and nicotine dependence
concomitantly.

The reinforcing effects of both alcohol and nicotine are mediated through the
cortico-mesolimbic dopamine (CMDA) system, and the concomitant use of both drugs enhances
their pharmacological effects. We propose a better approach to control dopamine (DA) effects
by contemporaneous indirect modulation of DA release and its functional expression. Both DA
release from its cell bodies in the ventral tegmental area and the expression of its
reinforcing effects through the cortico-mesolimbic system are modulated by GABA efferents
under the tonic control of glutamate-mediated excitatory amino acid pathways. Thus, it is
reasonable to hypothesize that a medication that facilitates cortico-mesolimbic GABAergic
function and inhibits glutamate action should diminish both nicotine's and alcohol's
reinforcing effects by inhibiting the release of midbrain DA and its functional expression
through pathways projecting from the nucleus accumbens to the cortex. The promise of this
novel approach is exemplified by our recent proof-of-concept demonstration that topiramate
compared with placebo significantly improved smoking abstinence rates and decreased serum
cotinine levels among alcohol dependent smokers. An important clinical effect of topiramate
in alcohol-dependent individuals appears to be that its anti-withdrawal effects promote the
gradual tapering of drinking. Hence, due to this unique anti-withdrawal effect of
topiramate, we propose to adopt the same methodology for treating alcohol-dependent
individuals, as is common practice with smokers, of setting a target quit date (TQD) after
which relapse to either drug can be measured. We propose an 18-week, double-blind clinical
trial with follow-up visits at 1 month and 3 months, in which alcohol-dependent smokers will
receive brief behavioral compliance enhancement treatment (BBCET) plus a smoking self-help
manual as their psychosocial treatment, and will be randomized to receive placebo,high-dose
topiramate (up to 250 mg/day), or low-dose topiramate (up to 125 mg/day) to prevent relapse
to heavy drinking and smoking. Each of the 3 treatment arms shall contain 98 individuals,
with a total N of 294.

The TQD will occur at the beginning of the 6th week of treatment. Our primary objective is
to determine whether both low- and high-dose topiramate will be more efficacious than
placebo at reducing the percentage of heavy drinking days and increasing the continuous
abstinence rate for smoking determined by a combination of self-report and CO monitoring
after the TQD and in the last 4 weeks of treatment. We also will be able to determine
whether a lower dose of topiramate is as efficacious as the higher dose and, therefore, is
associated with a lower adverse profile. Our secondary objectives are to test whether
topiramate will be more efficacious than placebo at improving quality of life and reducing
craving after the TQD and in the last 4 weeks of treatment and whether this improvement will
be sustained in the follow-up phase.

Inclusion Criteria:

- Males and females who have given written informed consent

- Subjects must be above the age of 18

- Good physical health

- DSM-IV diagnosis of mild to severe alcohol use disorder

- Smoking ≥ 5 cigarettes/day

- Currently drinking at least 8 standard drink units (SDUs) per week for women and at
least 15 SDUs per week in the 30 days prior to randomization

- Subjects must provide evidence of stable residence

- The pregnancy test for females of child-bearing potential at screen and prior to
randomization must be negative. Additionally, women of child-bearing potential must
be using an acceptable form of contraception.

- Literate in English and able to read, understand, and complete the rating scales and
questionnaires accurately, follow instructions, and make use of the behavioral
treatments

- Willing to participate in a treatment program for alcohol and nicotine dependence

Exclusion Criteria:

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