Proof-of-Concept Clinical Trial of Lamotrigine as a Candidate Pharmacotherapy for Adolescent Alcohol Use Disorder
Phase: PHASE2
Conditions: Alcohol Use Disorder
Sponsor: Brown University

                                              
Enhancing the Effects of Alcohol Treatment with Lamotrigine 
 
Principal Investigator: 
Robert Miranda Jr., PhD, ABPP 
ClinicalTrials.gov ID: 
NCT04770493 
Date:  
 
 
February 02, 2021 
 
 
  
 
 
 
 

Rationale 
Alcohol use disorder (AUD) affects nearly one-third of adults in the United States during 
their lifetime. Excessive alcohol use causes myriad acute and long-term medical, 
psychological, and social problems. It carries an economic burden of $249 billion 
annually. Although advances in pharmacotherapy have improved treatment options for 
adults with AUD, treatment options for youth are limited.  
Adolescent and young adult alcohol use is a leading public health concern. The harmful 
effects of underage drinking are irrefutable and include premature death and possibly 
irreversible damage to the developing brain. In addition, adolescence is a critical period 
in the pathogenesis of AUD; an estimated 3 to 15% of youth develop AUD before age 
18. Clinical trials have tested psychosocial interventions with youth, including family 
treatments, cognitive behavior therapy (CBT), and motivational enhancement therapy 
(MET), that yield only modest short-term benefits. Our group has contributed 
substantially to this work.  
One potential way to improve treatments is to augment psychosocial interventions with 
pharmacotherapy. The National Institute on Alcohol Abuse and Alcoholism (NIAAA) has 
mounted a concerted effort to identify medications that reduce drinking for nearly three 
decades. Although this effort improved treatment for adults, no medication is indicated 
for adolescent use, and randomized controlled trials with teenagers are almost 
nonexistent. This gap raises key questions about if and how medications could benefit 
youth. The urgency of this issue is underscored by the fact that optimizing treatment 
options for youth requires closing this critical gap. 
Anticonvulsants are increasingly found to be efficacious for treating AUD. Many have 
intolerable side effects, however, that greatly limit their utility. Lamotrigine is a new 
generation mood-stabilizing anticonvulsant approved by the FDA to treat epilepsy in 
patients two and older and bipolar disorder in adults with fewer side effects than older 
anticonvulsants. We propose to study lamotrigine for three primary reasons.  
• First, lamotrigine is safe and well tolerated by youth. 
• Second, lamotrigine targets brain mechanisms implicated in the pathogenesis of 
AUD, namely the glutamatergic system, which mediates the acute and chronic 
effects of alcohol. 
• Third, mounting human research that shows lamotrigine reduces alcohol and 
other substance use as well as craving. 
On the whole, modulation of the glutamatergic system is a key pharmacological target 
for AUD treatment. Anticonvulsants reduce alcohol and other drug use in adults and 
adolescents but are not well tolerated. There is strong preclinical and emerging clinical 

evidence that lamotrigine also reduces alcohol and other drug use, and human studies 
show it is well tolerated. 
Objectives 
The primary objectives of this study are twofold. The first primary objective is to evaluate 
the feasibility, acceptability, and tolerability of lamotrigine (25 mg/day to 200 mg/day in 
two divided doses) as compared to placebo for 9 weeks plus a psychosocial platform 
comprised of motivational enhancement therapy and cognitive behavioral therapy (MET-
CBT; “Path 180”) among adolescents and young adults (ages 16 to 24 years) with AUD 
as confirmed by the Diagnostic and Statistical Manual of Mental Disorders – Fifth 
Edition (DSM-5™). 
The second primary objective is to leverage a human laboratory paradigm to evaluate 
the effects of lamotrigine on an intermediate phenotype associated with alcohol use and 
outcomes in clinical trials. Specifically, we hypothesize that lamotrigine, as compared to 
placebo, will decrease alcohol cue-elicited craving in the human laboratory during in 
vivo alcohol cue reactivity. 
Methodology 
This proof-of-concept study is a double-blind, randomized, placebo-controlled, parallel 
group, single-site clinical trial. After obtaining consent/parent permission/assent, 
potential subjects and, if younger than 18 years, their parent(s) will complete a medical 
history and psychiatric diagnosis interview (about the adolescent) to screen for eligibility. 
Youth will also complete a physical examination, vital signs, drinking history and an 
alcohol breathalyzer test. 
Forty-four eligible subjects will be randomized in an approximate 1:1 ratio to either 
lamotrigine or placebo for 9 weeks. 
Dose titration, maintenance and taper will occur as scheduled below. Lamotrigine will be 
self-administered by subjects once daily after eating and with a full glass of water 
beginning on Study Week 1, Day 1 and continuing through Study Week 11, Day 7. The 
first dose will be taken in the study clinic whenever possible. Subjects will be provided 
with water and a snack to take with first dose. Dose will be titrated, as tolerated, to a 
target dose of 200 mg in two divided doses per day of lamotrigine. Following the target 
dose period, participants will complete a 2-week medication taper period (see dosing 
schedule below).Capsules should be swallowed whole and should not be cut, crushed, 
or chewed. Capsules should be taken with food and water. 
 
 

 
Schedule of Administration of Investigational Product 
Study Period 
Time Period 
Daily Dose 
Dosing Schedule 
Titration 
Weeks 1-2 
25 mg  
Once daily 
 
Weeks 3-4 
50 mg 
Two divided doses 
 
Week 5 
100 mg 
Two divided doses 
 
Week 6 
150 mg 
Two divided doses 
Maintenance   
Week 7-9 
200 mg  
Two divided doses 
Taper 
Week 10 
100 mg 
Two divided doses 
 
Week 11 
50 mg 
Two divided doses 
 
At the randomization/baseline visit and after 7 weeks of investigational product 
administration (i.e., Study Week 8), subjects will undergo a human laboratory paradigm 
(i.e., alcohol cue reactivity assessment). 
Main Inclusion/Exclusion Criteria: Subjects will be male and female adolescents, ages 
16 to 24 years old, who meet DSM-5 criteria for AUD. They must be seeking to reduce 
their alcohol use.  
Investigational Product, Dosage and Mode of Administration: Lamotrigine (titrated for 6 
weeks; target dose [200 mg/day/BID] for 3 weeks) will be over encapsulated and 
supplied by a contracted pharmacy, along with identical matching placebo capsules.  
Reference Therapy, Dosage and Mode of Administration: Identically over encapsulated 
placebo tablets will be dispensed according to the same schedule as the lamotrigine 
capsules. 
 
Statistical Analysis Plan 
Primary Objectives 
• 
Feasibility of retention will be determined by the percentage of enrolled subjects 
who complete the protocol (target ≥ 70%) and treatment-specific retention rates. 
• 
Acceptability will be determined based on overall study withdrawal rates (≤ 20% 
considered acceptable), as well as treatment-specific withdrawal rates. Treatment 
satisfaction will be considered acceptable if ≥ 80% of responses on the CSQ-8 are rated 

either “satisfactory” or “highly satisfactory.” We will also examine reasons for termination 
qualitatively. 
Secondary Objectives 
• 
 We hypothesize that lamotrigine, as compared to placebo, will decrease alcohol 
craving during an alcohol cue-exposure paradigm in the human laboratory.