Conditions: Alcohol Dependence
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 50
Healthy volunteers: no

Brief summary:
Alcohol use disorders remain a significant public health problem. The pharmacological facilitation of behavioral treatment represents a promising strategy for addressing disordered drinking. Alcohol use disorders are recognized to be associated with various vulnerabilities that complicate the course of treatment and that may be amenable to glutamate modulators. The purpose of this randomized, double-blind, controlled trial is to test various glutamate modulators in conjunction with motivational enhancement therapy (MET) for alcohol use disorders.

Detailed description:
Individuals diagnosed with alcohol dependence will be randomized to receive a single infusion of glutamate modulators during week 2 while engaged in a 5-week course of MET. They will meet with staff twice weekly, except for week 2 during which they will present to the clinic three times. Clinic visits include MET sessions, psychiatric monitoring, assessments, and study procedures (e.g., medication administration).

Arms:
arm 1: Administration of CI-581a during wk 2 at 0.71 mg/kg in the context of a 5 wk course of MET arm 2: Administration of CI-581b during wk 2 at 0.025 mg/kg in the context of a 5 wk course of MET

Interventions: intervention 1: CI-581a intervention 2: CI-581b intervention 3: Motivational Enhancement Therapy (MET)
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

Protocol document:
Prot_000.pdf: 
Signed copy on file at IRB 
 
             v.9/2013 
New York State Psychiatric Institute 
Institutional Review Board 
 
 
September 5, 2017 
 
To: 
 
Dr. Elias Dakwar 
From:  
Dr. Edward Nunes, Chairman, IRB 
 
 
 
 
 
Subject: 
APPROVAL NOTICE: CONTINUATION APPROVAL 
 
 
 
 
 
         EXPEDITED PER 45CFR46.110(b)(1)(f)(8)(c) 
 
 
  
 
 
Your protocol #7014   entitled:    GLUTAMATERGIC MODULATION OF DISORDERED 
ALCOHOL USE: A RANDOMIZED CONTROLLED TRIAL  ACAR/PSF version date 8/30/17 
and consent forms (version) have been approved by the New York State Psychiatric Institute - 
Columbia University Department of Psychiatry Institutional Review Board from  
SEPTEMBER 8, 2017 TO SEPTEMBER 7, 2018.   
Consent requirements: 
     
    X Not applicable: (RECRUITMENT COMPLETED.  DATA BEING ANALYZED) 
 
     45CFR46.116(d) waiver or alteration of consent for the telephone screen.   
 
     Signature by the person(s) obtaining consent is required to document the consent process.          
 
     Documentation of an independent assessment of the participant’s capacity to consent is also 
required. 
 
Approved for recruitment of subjects who lack capacity to consent:   No  Yes    
 
 
Field Monitoring Requirements:    Routine  Special: ___________________  
 
 
  Only copies of consent documents that are currently approved by the IRB may be used to obtain 
consent for participation in this study. 
  A progress report and application for continuing review is required 2 months prior to the 
expiration date of IRB approval. 
  Changes to this research may not be initiated without the review and approval of the IRB except 
when necessary to eliminate immediate hazards to participants.  
  All serious and/or unanticipated problems or events involving risks to subjects or others must be 
reported immediately to the IRB.  Please refer to the PI-IRB website at http://irb.nyspi.org for 
Adverse Event Reporting Procedures and additional reporting requirements.    
 
CC:  RFMH (AA023010-01A1) 
        CU Grants & Contracts (DA029647-04) 
        CUMC-IRB (no number assigned) 
 
EN/ls 


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Protocol Title:
Glutamatergic Modulation of Disordered 
Alcohol Use: A Randomized, Controlled 
Trial
Protocol Number:
7014
First Approval:
09/19/2014
Expiration Date:
09/07/2017
Version Date:
09/05/2017
Contact Principal Investigator:
Elias Dakwar, MD
Email: elias.dakwar@nyspi.columbia.edu
Telephone: 646-774-8728
Co-Investigator(s):
Frances Levin, MD
Research Chief:
Herbert Kleber, MD
Cover Sheet
Choose ONE option from the following that is applicable to your study
If you are creating a new protocol, select "I am submitting a new protocol." As 5 Year Renewals are no 
longer required, this option remains for historical purposes.
I am submitting an annual continuation without modifications 
Division & Personnel
Division
What Division/Department does the PI belong to?
Psychiatry
Within the division/department, what Center or group are you affiliated with, if any? 
Substance Use
Unaffiliated Personnel
List investigators, if any, who will be participating in this protocol but are not affiliated with New York 
State Psychiatric Institute or Columbia University. Provide: Full Name, Degrees and Affiliation.


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There will be no unaffiliated personnel involved in this study.
Application for Continuation of Research
Status
Current Status of Study: 
All research interventions were completed. Only data analysis is ongoing.
Summary of Experiences to Date
Please provide a summary of scientific progress of the study and the experience of research participants, to 
date. This requirement is designed to allow for the investigator and the IRB to reassess the study’s risks and 
benefits in terms of developments in the field, changing practice patterns, and new IRB policies and 
procedures.
Study procedures have been well tolerated. There have been no adverse events. The most common effects
from the infusion are transient psychoactive effects (subsiding by 15 minutes post-infusion) and sedation
(resolving by 1 hr post-infusion). Participants have engaged with the psychotherapy appropriately and a
majority has reduced alcohol use substantially.
Funding
Have there been any changes in funding status since the prior approval? 
No
Have the principal investigator and other investigators made all required disclosures of financial interest in 
the study sponsor/product?
Yes
Summary
Have there been any study findings, recent literature, or untoward events occuring here or at other sites in 
the past year which might affect the analysis of the safety, risks or benefits of study participation? 
No
Have there been any serious adverse events (serious and/or unanticipated problems involving risks to 
subjects or others at this site which occured in the past year)? 
No
Have all study staff with a significant role in the design or implementation of the human subject components 
of this study received required training in human research subject protections?
Yes
Is the study covered by a certificate of confidentiality? 
Yes
Certificate expiration date (mm/dd/yyyy) 
09/31/2018


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Overall Progress
Approved sample size
50
Total number of participants enrolled to date
44
Number of participants who have completed the study to date 
40
Have there been any significant deviations from the anticipated study recruitment, retention or completion 
estimates? 
No
Comments / additional information 
Sample Demographics
Specify population
alcohol dependent individuals
Total number of participants enrolled from this population to date 
44
Gender, Racial and Ethnic Breakdown 
Race 
Ethnicity
Female 
Male 
White
Hispanic
2
1
 
Non-Hispanic
14
14
African American
Hispanic
1
0
 
Non-Hispanic
4
2
Other
Hispanic
0
2
 
Non-Hispanic
2
2
 
Total
23
21
Summary of Current Year's Enrollment and Drop-out 
Number of participants who signed consent in the past year
18
Did the investigator withdraw participants from the study? 
Yes
Circumstances of withdrawal:
1 participant stopped drinking during screening, and maintained abstinence after consent. Another 
participant decided she did not want to change her drinking. Both participants were not randomized and 
continued with MET, as per protocol.
Did participants decide to discontinue study involvement? 
No


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Procedures
To create the protocol summary form, first indicate if this research will include any of the following 
procedures
   Psychiatric Assessment
   Collection of Biological Specimens
   Medication Trial
   Use of Investigational Drug or Device
Population
Indicate which of the following populations will be included in this research
   Adults
   Adults over 50
   Substance Users
Research Support/Funding
Will an existing internal account be used to support the project?
No
Is the project externally funded or is external funding planned?
Yes
Select the number of external sources of funding that will be applicable to this study
2
Funding Source #1
Is the PI of the grant/contract the same as the PI of the IRB protocol? 
Yes
Select one of the following
The grant/contract application is a pending review or a funding decision
Source of Funding
Federal
Institute/Agency
NIAAA
Grant Name
R21
Grant Number
AA023010-01A1
Select one of the following


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Single Site
Business Office
RFMH
Does the grant/contract involve a subcontract? 
No
Funding Source #2
Is the PI of the grant/contract the same as the PI of the IRB protocol? 
No
Who is the PI of the grant/contract? 
Levin, Frances, MD
Select one of the following
The grant/contract is currently funded
Source of Funding
Federal
Institute/Agency
NIDA
Grant Name
K24
Grant Number
DA029647-04
Select one of the following
Single Site
Business Office
CU
Does the grant/contract involve a subcontract? 
No
Study Location
Indicate if the research is/will be conducted at any of the following
   NYSPI
This protocol describes research conducted by the PI at other facilities/locations
No
Lay Summary of Proposed Research 
Lay Summary of Proposed Research
Alcohol dependence is associated with many changes in the brain, including alterations in the 
functioning of molecules involved in neural communication (neurotransmitters). Glutamate is the 
most abundant excitatory neurotransmitter in the brain, and various lines of evidence indicate that 


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various problems associated with drug dependence involve alterations in the transmission of 
glutamate.  Modulation of glutamate is therefore an important medication strategy for alcohol 
dependence. Our investigations with ketamine, a potent glutamate modulator, in drug dependent 
individuals suggest that it may exert unique and helpful effects on problems associated with 
addiction, such as impaired motivation to quit, high sensitivity to stress, and reactivity to drug-
related cues. This project will evaluate the effect of a single dose of ketamine on alcohol use in 
treatment seeking, non-depressed, alcohol dependent individuals who complete a 5-week 
outpatient double-blind, randomized, controlled study. Participants will engage in Motivational 
Enhancement Therapy (MET), an evidence-based therapy aimed at shoring up motivation to effect 
positive changes. 
Background, Significance and Rationale
Background, Significance and Rationale
Modulation of N-methyl-D-aspartate (NMDA) receptor activity is recognized as an important treatment 
strategy for alcohol use disorders. As a high-affinity NMDA antagonist with potent modulatory and down-
stream effects, ketamine is a promising, if unconventional, candidate for uniquely targeting the NMDA 
alterations and related deficits associated with alcohol dependence.  
      In a recent study aimed at testing the anti-addiction benefits of ketamine, we investigated its effects (24 
h post-infusion) on dependence-related deficits that implicate glutamate-based neuroadaptations, 
specifically low motivation to quit and high cue reactivity. A single infusion significantly increased motivation 
to stop cocaine in active cocaine users (as assessed by the U. Rhode Island Change Assessment), as well 
as reduced cue-induced craving (by Visual Analogue Scale), when compared to the active control 
(lorazepam). The substantial effect of ketamine on motivation to quit extended to at least 72 h post-
infusion, and predicted abstinence during follow-up. 
      It is possible that ketamine may effectively address the problematic use of alcohol or other drugs, 
especially in the context of a treatment aimed at enhancing and sustaining ketamine-induced benefits (e.g., 
increased motivation to quit). To this end, we have feasibly integrated a single ketamine infusion into an 
ongoing  treatment for cocaine dependence. In the present trial, we propose to investigate the effect of a 
single sub-anesthetic dose of ketamine on problematic alcohol use in non-depressed alcohol dependent 
individuals receiving Motivational Enhancement Therapy (MET), an evidence-based treatment aimed at 
promoting motivation for changing problematic behaviors. We predict that ketamine will significantly reduce 
percentage of heavy drinking days (>4 drinks for men, >3 for women) as compared to the active control 
(midazolam). Other aims pertain to 1) abstinence following ketamine, and 2) effects of ketamine on deficits 
that implicate prefrontal dysfunction or NMDA hypersensitivity, such as craving and low self-efficacy. 
Specific Aims and Hypotheses
Specific Aims and Hypotheses


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Primary Aim: Test the hypothesis that ketamine will significantly reduce percentage of heavy drinking days 
(number of heavy drinking days divided by post-infusion study days) compared to the control. 
Secondary Aim 1: Test the hypothesis that ketamine, as compared to the control, will increase percentage 
of abstinence days (defined as number of abstinent days divided by post-infusion study days). 
Secondary Aim 2: Test the hypothesis that ketamine, as compared to the control, will significantly improve 
adaptations linked to disruptions in glutamate, including low mindfulness and self-efficacy, impulsivity, 
withdrawal phenomena, and perceived stress sensitivity. 
Description of Subject Population
Sample #1
Specify subject population
Alcohol Dependent Adults
Number of completers required to accomplish study aims
40
Projected number of subjects who will be enrolled to obtain required number of completers
55
Age range of subject population
21-60
Gender, Racial and Ethnic Breakdown
The study described in the present application seeks to include women and minorities; the study does not 
exclude any potential participants on the basis of race and gender. Based on previous studies conducted 
with treatment-seeking alcohol dependent individuals, the sample is expected to include approximately 
60% White, 35% African American, 20% Hispanic, 5% other racial groups. Approximately 35% will be 
women. This profile is representative of the areas from which our research facility draws participants in 
New York City and the greater metropolitan area.
Description of subject population
Applicants will be considered eligible if they meet baseline use criteria (e.g., at least 4 heavy drinking days 
per week), are medically healthy, have alcohol dependence, are interested in reducing or stopping use, 
and are between 21 and 60. Exclusion criteria include severe physiological dependence on alcohol or 
certain other substances, a history of abuse of or adverse reaction to ketamine or benzodiazepines, a 
history of psychotic or dissociative symptoms, a first-degree family history of psychosis, obesity (BMI > 35), 
or cardiovascular/pulmonary disease, and pregnancy, lactation, or active attempts to become pregnant.


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Recruitment Procedures
Describe settings where recruitment will occur
Adult male and non-pregnant female patients will be recruited in the New York City metropolitan area. This project will 
be carried out at the research clinic of the Biological Studies Unit (BSU) within the New York State Psychiatric 
Institute (NYSPI), where several studies for substance use disorders are currently being conducted. Infusions will 
take place at a dedicated site within the BSU. 
How and by whom will subjects be approached and/or recruited? 
At the first contact, a standardized telephone interview is conducted. Those who preliminarily meet entry 
criteria are scheduled for a first screening visit, during which they give informed consent, provide a urine 
sample for toxicology and urinalysis, complete the Hamilton Depression Scale (HAM-D) and Dissociative 
Experiences Scale (DES).
How will the study be advertised/publicized? 
We expect to randomize 40 participants recruited through word of mouth, advertising, and referral. 
Do you have ads/recruitment material requiring review at this time? 
Yes
Does this study involve a clinical trial?
Yes
Please provide the NCT Registration Number
NCT02539511
Concurrent Research Studies
Will subjects in this study participate in or be recruited from other studies? 
No
Inclusion/Exclusion Criteria
Name the subject group/sub sample
Alcoohl Dependent Adults
Create or insert table to describe the inclusion criteria and methods to ascertain them
Inclusion Criterion
Method of Ascertainment
 
 
Active alcohol dependence. In the case of the 
use of other drugs, alcohol is designated as the 
primary drug. At least four heavy drinking day 
over the past 7 days (>4 drinks a day for males, 
>3 drinks for females) OR minimum weekly use 
of 35 drinks for males and 28 for females
MINI, Psychiatric Interview, self-report, utox


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2. Physically healthy
Laboratory tests (urinalysis, blood chemistry, 12-
lead ECG in normal limits), physical examination, 
self-reported medical history
3. No adverse reactions to study medications
Subjects will be asked about previous exposure 
to ketamine and midazolam
4.21-69 years of age
Self-reported age, verification with legal identification
5. Capacity to consent and comply with study 
procedures, including sufficient proficiency in 
English
A short written test about study procedures, MINI, 
psychiatric interview
6. Seeking to reduce or stop alcohol use
Psychiatric Interview, self-report
Create or insert table to describe the exclusion criteria and methods to ascertain them
Exclusion Criterion
Method of Ascertainment
 
 
1. Meets DSM IV criteria for current 
major depression, bipolar disorder, 
schizophrenia, any psychotic illness, 
including substance induced 
psychosis, and current substance-
induced mood disorder with HAMD 
score > 12.
Psychiatric Interview, MINI, HAMD
2. Physiological dependence on 
another substance, such as opiods or 
benzodiazepines, excluding caffeine, 
nicotine, and cannabis
MINI, Psychiatric Interview
3. Delirium, Dementia, Amnesia, 
Cognitive Disorders, or 
Dissociative disorders. 
Significant dissociative 
symptoms (DES>30)  
MINI, Psychiatric Interview
4. Current suicide risk or a 
history of suicide attempt within 
the past year
MINI, Psychiatric Interview
5. Inability to safely initiate 24 
hours of abstinence from 
alcohol, as evidenced by CIWA 
> 10 during screening; repeated 
inability to initiate abstinence 
during the trial without 
Psychiatric Interview, CIWA


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incurring significant 
withdrawal (CIWA > 10); 
history of severe withdrawal 
phenomena over the past 6 
months (e.g.,  withdrawal-related 
seizure); or self-reported inability 
to maintain abstinence for 24 
hours without substantial 
distress. 
5. Pregnant or interested in 
becoming pregnant during the 
study period
Blood and urine pregnancy testing, 
self-report
6. Any of the following cardiac 
conditions: angina, clinically 
significant arrhythmia, or mitral 
valve prolapse
Laboratory tests (12-lead ECG in 
normal limits), physical examination, 
self-reported medical history
7. Unstable physical disorders 
which might make participation 
hazardous such as end-stage 
AIDS, hypertension (blood 
pressure elevated at >140/90), 
WBC < 3.5, active hepatitis or 
other liver disease with elevated 
transaminase levels (< 2-3 X 
upper limit of normal will be 
considered acceptable if PT/PTT 
is normal), renal failure (creat > 
2, BUN >40), epilepsy, or 
untreated diabetes
Physiological tests (urinalysis, blood 
chemistry, 12-lead ECG), physical 
examination, self-reported medical 
history
8. Previous history of ketamine 
or benzodiazepine misuse or 
abuse, and a history of an 
adverse reaction/experience 
with prior exposure to ketamine 
or benzodiazepine
Physical examination, self-reported 
medical history
9. Recent history of significant 
violence (past 2 years)
MINI, Psychiatric Interview
10. First degree relative with a 
psychotic disorder (bipolar 
disorder, schizophrenia, 
schizoaffective disorder, or 
psychosis NOS)
MINI, Psychiatric Interview


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11. BMI > 35
Physical examination
12. On psychotropic or other 
medications whose effect could 
be disrupted by participation in 
the study
Psychiatric interview, self-reported 
medical history
Waiver of Consent/Authorization
Indicate if you are requesting any of the following consent waivers
Waiver of consent for use of records that include protected health information (a HIPAA waiver of 
Authorization) 
No
Waiver or alteration of consent
No
Waiver of documentation of consent 
Yes
Waiver of parental consent 
No
Consent Procedures
Is eligibility screening for this study conducted under a different IRB protocol?
No
Describe procedures used to obtain consent during the screening process 
Participants will be provided a consent form (which also doubles as the primary study consent form) that 
outlines the screening procedures for the present protocol. Participants will be provided an opportunity to 
ask any questions. If they express understanding about what screening involves, they will be asked to 
document consent, and screening procedures will proceed appropriately. 
Describe Study Consent Procedures
Participants will have consented for screening, as above, and have completed screening . Eligible 
participants will then be provided the consent form for the present protocol, and after reading it and 
discussing it with the PI (E.D.), will undergo a brief quiz to ensure understanding.
Indicate which of the following are employed as a part of screening or main study consent procedures
   Consent Form
Waiver of Documentation of Consent


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Would the consent form signature be the only link between the subject’s identity and the research data?
Yes
Is breach of confidentiality the main study risk?
Yes
Describe the study component(s) for which waiver of documentation is requested
We request a waiver of documentation of consent for the phone screen only (due to verbal consent only, not 
written documentation of consent). The research presents no more than minimal risk of harm to subjects and 
involves no procedures for which written consent is normally required outside of the
research context.
Persons designated to discuss and document consent
Select the names of persons designated to obtain consent/assent
Dakwar, Elias, MD
Type in the name(s) not found in the above list
Study Procedures
Describe the procedures required for this study
Overview: Consenting participants meeting study criteria will be entered into the study and begin MET. In 
week 2, they will achieve abstinence for 24 hours, and be randomized (1:1) to receive either ketamine or 
active control (midazolam). We expect to randomize 40 participants.
 
Clinic Visits (5 weeks) Participants will present twice weekly to clinic for engagement in MET and to meet 
with a psychiatrist, except for week 2, when they will meet with staff on 3 occasions. Assessments are 
intended to investigate patterns of alcohol and other drug use by interview (Timeline Follow Back), and to 
ascertain craving (VAS), withdrawal (CIWA), self-efficacy (Drug Taking Confidence Questionnaire and 
Alcohol Abstinence Self Efficacy Scale), perceived stress (modified Perceived Stress Scale), mindfulness 
(Five Facet Mindfulness Questionnaire) and impulsivity (Barrett’s Impulsivity Scale). Follow-up by 
telephone occurs at 1 month and 3 months after study completion, and is intended to assess drinking 
behavior. Vital signs are obtained after measures are completed, and prior to the MET session and/or 
meeting with a psychiatrist. Participants who have consecutive BP readings of >160/110 between visits 
as they begin to taper or discontinue alcohol will be removed from the trial and provided referrals to 
other providers.  All participants meet with the PI or Co-I at every visit. The PI or Co-I is available at 
all times to meet with participants, and no participant undergoes procedures, including screening and 
therapy, without one of them being present or available on the floor. 
 
Motivational Enhancement Therapy (MET): MET is a psychotherapy found effective for various 
substance use disorders. The approach is patient-centered, with the therapist utilizing a variety of strategies 
to promote motivation and self-directed change by guiding the exploration and resolution of ambivalence. 
MET consists of an initial session, during which goals are explored and motivational statements elicited, 
and 2 to 4 subsequent sessions to achieve these goals. In this trial, a standard 5-week MET platform will be 


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provided, with an additional session after the infusion (6 sessions total). The short length of MET is 
appropriate for evaluating the efficacy of a single infusion, while still providing an effective treatment to 
participants. MET will be provided by individuals who will  have been trained in MET and the therapy 
procedures in this protocol will be nearly identical to what we have used in previous trials. Sessions may be 
taped if participants provide consent,  and will be overseen and supervised by Dr. Dakwar to ensure fidelity.
 
Abstinence Initiation: In week 1, participants will decide with their therapists on a day in week 2 in which 
they will initiate abstinence. They will also present to the clinic on that day for a session of MET and to 
receive assessments (CIWA, BAL, TLFB). Participants would have been screened prior to consent to ensure 
that the risks of alcohol cessation will be minimized (e.g., no history of severe withdrawal, no history of 
withdrawal-related seizures, self-reported ability to undergo alcohol cessation >24 hours). On the following 
day, 24 hours after abstinence initiation, they will return to the clinic, and be reassessed for intoxication and 
withdrawal. Participants who present intoxicated or in moderate withdrawal will be offered an 
opportunity to return at a different day within a week for a reassessment. 
 
Infusion Procedures: Assuming sobriety (BAC=0) and less than moderate withdrawal symptoms (CIWA < 
11), participants will be randomized to receive a single infusion of ketamine or midazolam. The infusion 
will take place at the BSU within the Division on Substance Abuse, during Week 2. So as to minimize risk, 
infusions will be given in a highly monitored setting. Further, our preliminary studies, as well as studies 
with depression, have suggested that a single dose of ketamine has efficacy. Thus, for the purposes of this 
study, a single infusion (0.11 mg/kg over 2 min bolus followed by 0.6 mg/kg over 50 minutes) may suffice 
to affect the outcome measures without exposing subjects to the added risk of multiple infusions. Patients 
will have not used alcohol in 24 hours to address the risk of adverse interactions with study medications. 
They will also be instructed to not eat since midnight prior to the infusion so as to reduce the risk of nausea 
and aspiration. Participants will be informed throughout the study that they may possibly receive any of a 
number of substances at each infusion, including amantadine, buspirone, d-cycloserine, ketamine, 
lorazepam, memantine, saline, or any combination of these. This IRB-approved procedure is consistent with 
blinding procedures at our institution and is intended to disguise what drug is specifically given so as to 
minimize expectancy effects (e.g., anticipating a certain set of psychoactive effects) and address the 
possibility of participants identifying which drug has been given.
 
Active control (midazolam 0.025 mg/kg in saline infused over 52 minutes) or ketamine hydrochloride (0.11 
mg/kg followed by 0.60 mg/kg in saline over 50 minutes) will be prepared and packaged for slow-drip 
infusion by the pharmacy at NYSPI, and administered between 10 am and 12 pm on day 2. This dose of 
ketamine was selected on the basis of published reports suggesting that it was well-tolerated. It was also the 
highest dose tolerated by participants in our preliminary studies, and may have added efficacy over the 
lower dose. Midazolam was chosen as the active control because it produces mild psychoactive effects, 
further obscuring the distinction between conditions so as to ensure blinding, and because of its short half-
life. Further, though midazolam might acutely reduce alcohol craving or withdrawal, it has no known 
persistent (> 8 hrs) effect on alcohol dependence. Blood pressure, heart rate, and blood oxygen saturation 
will be continuously monitored. Infusions will take place in the presence of an ACLS and BLS certified 
psychiatrist, who will be responsible for decisions pertaining to the discontinuation of the infusion in the 
case of an adverse event. The psychiatrist will remain available for up to three hours after the infusion is 
terminated and will provide a brief psychiatric evaluation and field sobriety test prior to discharge from the 
facility. After the infusion, a lunch will be provided to participants while they wait for medication effects to 


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fully subside and for assessments to be completed. The participant will also meet with a therapist for a 
session of MET prior to discharge. 
 
Prior experience with sub-anesthetic ketamine administration in research and clinical settings suggest that 
preparation and relaxation exercises reduce or prevent the anxiety that might develop during administration. 
In our preliminary study, we found relaxation and mindfulness-based exercises to be helpful when 
administered before and during the infusion if needed. These relaxation exercises will also be employed 
here. A Clinician Administered Dissociative States Scale (CADSS) and Hood Mysticism Scale (HMS) will 
be administered at the conclusion of the infusion by the research assistant. Participants will also complete 
various assessments pertaining to drug effect. Ketamine and norketamine (an active metabolite) levels will 
be obtained at 30 minutes into the infusion and at 70 minutes (18 minutes after the infusion is terminated), 
the results of which will remain unavailable to all staff for each participant until all assessments are 
complete. 
 
Blinding: Various other safeguards, in addition to making metabolite levels unavailable, will be placed to 
ensure that blinding is maintained. Staff who will be carrying out most of the assessments in this study will 
not participate in infusion procedures because of the possibility, given the expected psychoactive effects, 
that they will recognize which patients are randomized to ketamine. A blinded nurse will also collect serum 
for testing. 
 
Follow-up: Follow-up will occur by phone at 1 and 3 months after study completion, and will aim at 
assessing alcohol use patterns since discharge from the clinical trial. 
 
You can upload charts or diagrams if any
Criteria for Early Discontinuation  
Criteria for Early Discontinuation
Participants who experience two or more consecutive blood pressure readings of 160/110 
between visits over the course of study participation will be removed from the trial and 
referred to appropriate treatment. Participants who complain of new symptoms consistent 
with cardiovascular instability (chest pain, new onset dyspnea on exertion) will also be 
removed and provided appropriate referrals. Participants who experience a clinical worsening while 
involved in the study (e.g., development of psychiatric symptomatology, worsening drug use ) will be 
removed from the study, provided with acute psychiatric care if needed, and provided appropriate referrals. 
This will be ascertained by the close psychiatric and medical monitoring that participants receive throughout 
study participation. 
 
Participants who decide to discontinue will have their reasons for doing so documented, if these are 
available, and every effort will be made to ensure that their data are complete, including follow-up data for 
drop-outs. 


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Blood and other Biological Samples
Please create or insert a table describing the proposed collection of blood or other biological specimens
Blood will be collected during the screening process, during the study, and at the end of the study. Blood 
drawing will be conducted by personnel with the requisite training to carry these procedures out at minimal 
risk to participants. Urine will also be collected during screening to detect other drug use. Data will be 
coded with numbers assigned to each participant, and this data will be stored in password-protected 
computers. 
 
Two vials of blood will be drawn during the screening process amounting to 10 cc (¾ tbsp). During 
the study, blood will be drawn during infusions for ketamine and norketamine levels. These samples 
will require about 10 cc (1 tbsp).
Assessment Instruments
Create a table or give a brief description of the instruments that will be used for assessment
Interviews: Mini International Neuropsychiatric Interview (MINI): A semi-structured diagnostic interview 
designed to assist researchers in making reliable DSM-IV psychiatric diagnoses (45 min); Clinician 
Administered Dissociative States Scale (CADSS): A 23 item clinician administered instrument used to 
measure current dissociative symptoms (5 min); Dissociative Experiences Scale (DES): A 28 item 
questionnaire for assessing the extent of daily dissociative experience, modified to be administered by a 
clinician (5 min); Brief Psychiatric Rating Scale (BPRS) for positive symptoms: A 4 item subscale for 
assessing psychosis (1 min); Hood Mysticism Scale (HMS): a 32 item scale for assessing infusion-
dependent mystical experience, modified to be administered by study staff (5 min); Five Facet Mindfulness 
Questionnaire (FFMQ): A 39 item instrument modified to be clinician administered that assesses five 
mindfulness domains: observing, describing, acting with awareness, non-judging of inner experience, and 
non-reactivity (5 min); Clinical Institute Withdrawal Assessment (CIWA): a validated clinician-
administered assessment to ascertain severity of withdrawal symptoms (5 min); Timeline Follow-Back 
(TLFB): a retrospective method of quantifying daily consumption of alcohol and other drugs, assisted by the 
maintenance of a weekly use diary (5 min); Barratt Impulsiveness Scale (BIS): a 30 item questionnaire used 
to assess impulsivity, modified to be administered by a clinician (5 min).
 
Self-Reports: Drug-Taking Confidence Questionnaire (DCQ): A validated assessment of self-efficacy; 
Alcohol Abstinence Self-Efficacy Scale: a 40-item assessment that assesses confidence to stop using alcohol 
in various situations (5 min); Perceived Stress Scale (PSS): A 9 item scale that measures levels of subjective 


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stress, modified from a monthly assessment to one that evaluates stress between visits (5 min); VAS for 
alcohol craving (VAS-A): A 10 cm long line from “not at all” to “extremely” to assess craving intensity and 
frequency  (1 min). 
 
Physiological Measures: Breath alcohol concentration (BAC) will be assessed using the Alcohawk® ABI 
Digital Alcohol Breath Tester. This is a professional grade unit that meets the strict requirements for testing 
issued by the Food and Drug Administration (FDA) and the Department of Transportation (DOT). Gamma-
glutamayl-transferase (GGT) is a liver enzyme that is a widely accepted and validated laboratory measure of 
drinking. Plasma GGT can therefore provide an additional biological marker of drinking reduction.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
Please attach copies, unless standard instruments are 
used
Off label and investigational use of 
drugs/devices
Choose from the following that will be applicable to 
your study 
   Drug
Select the number of drugs used in this study
2
Drug #1
 
TABLE 1.
Assessments
(by week)
1
2A
2B
2C
3
4
5
 
AASE/DCQ
X
 
 
X
 
X
 
 
VAS-A
X
 
X
 
X
X
X
 
FFMQ
X
 
 
X
 
X
 
 
BAC/GGT
 
 
X
 
 
X
 
 
BPRS(+)
 
 
X
 
 
 
 
 
CADSS&HMS
 
 
X
 
 
 
 
 
(Nor)Ket
 
 
X
 
 
 
 
 
PSS
X
 
 
X
X
X
X
 
CIWA
X
 
X
X
X
X
X
BIS
X
 
 
X
 
X
 
 
DES
 
 
 
 
X
 
 
 
             
ASSESSMENT
TLFB
X
X
X
X
X
X
X
 
Assessments: AASE: Alcohol Abstinence Self Efficacy 
Scale;  DCQ: Drug Taking Confidence Questionnaire; 
(Nor)Ket: Ketamine and norketamine levels; BIS: Barratt 
Impulsiveness Scale; PSS: Perceived Stress Scale; VAS-A: 
Visual Analogue Scale for alcohol craving. FFMQ: Five Facet 
Mindfulness Questionnaire; CADSS:  Clinician Administered 
Dissociative Symptoms Scale; HMS: Hood Mysticism Scale; 
DES: Dissociative Experiences Scale; BAC: breath alcohol 
concentration by breathalyzer; GGT: serum levels of gamma-
glutamyl-transferase; BPRS (+): Brief Psychiatric Rating 
Scale for positive symptoms; CIWA: clinical institute 
withdrawal assessment; TLFB: Timeline Follow-back
Week 2 visits (A,B, and C)  occur consecutively, 3 days in a 
row 


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Name of the drug 
Ketamine Hydrochloride
Manufacturer and other information
The pharmacy at PI will be supplying the drug.
Approval Status
IND is approved
IND#
110,464
Who holds the IND/IND sponsor?
IND is held by PI/CU Investigator
Dakwar, Elias, MD
Drug #2
Name of the drug
Midazolam
Manufacturer and other information
The pharmacy at PI will be supplying the drug.
Approval Status
IND is approved
IND#
110,464
Who holds the IND/IND sponsor?
IND is held by PI/CU Investigator
Dakwar, Elias, MD
Research Related Delay to Treatment
Will research procedures result in a delay to treatment?
Yes
Maximum duration of delay to any treatment 
The screening process should take about a week, after which eligible participants will be consented and 
provided MET, an effective psychotherapy for alcohol use disorders. Ineligible participants will be referred 
to appropriate treatment. Thus, the maximum duration of delay to treatment is about a week.
Maximum duration of delay to standard care or treatment of known efficacy
 MET is an evidence-based, standard treatment for alcohol use disorders that is provided to all consenting 
participants after they complete the screening process. The maximum delay to standard treatment is 
therefore about a week.
Treatment to be provided at the end of the study
All participants will be referred to appropriate evidence-based treatment for substance use disorders, 
including 12-step groups, further psychotherapy, addiction psychiatry, or outpatient rehabilitation, 
depending on the individual's needs and preferences.


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Clinical Treatment Alternatives
Clinical treatment alternatives
Participants will be provided MET, an effective and standard approach to alcohol dependence. Other 
alternative include inpatient or outpatient rehabilitation; pharmacotherapy (such as topiramate, naltrexone, 
disulfiram, or acamprosate); 12-step groups; and other types of psychotherapy. Ineligible participants will 
be provided referrals to these services, as will study completers and those who opt to discontinue study 
participation in favor of other treatment.
Risks/Discomforts/Inconveniences 
Risks that could be encountered during the study period
Potential Risks:
 
Ketamine administration: A major risk of participating in this research project ensues from receiving 
ketamine hydrochloride. Ketamine is currently approved by the FDA as an anesthetic at doses significantly 
higher than the sub-anesthetic doses used in this study (2-3 mg/kg). Sub-anesthetic doses have been used in 
psychiatric research for nearly two decades in a variety of studies, including research exploring the 
glutamatergic system, studies employing a pharmacological model of schizophrenia, and more recently, 
clinical trials investigating the effect of ketamine on depression. The intravenous dose used in this study 
(0.71 mg/kg over 50 minutes) has been well studied in laboratory settings, and is comparable to the dose 
used in clinical trials for the treatment of depression. There has been no report of persistent problems or 
significant adverse effects, including hallucinations or other psychotic derangements, initiation of ketamine 
misuse, or behavioral disturbances. The short half-life of ketamine (2 to 3 hours) also ensures that the risk of 
interactions with alcohol will be minimized by the time that participants leave the facility post-infusion. Yet 
there remain various significant risks that are important to address, as well as various side effects that must 
be noted.
   
The following side effects are limited to the period of time during which ketamine is actively administered; 
due to ketamine's short half-life, they generally subside completely within 15 minutes of terminating the 
infusion. Ketamine infusions at the proposed dose can result in nausea, modest increases in blood pressure 
and heart rate, sedation, nystagmus, dissociative symptoms (depersonalization, derealization), anxiety, 
euphoria, perceptual changes (telescoping vision), behavioral alterations (including psychomotor 
retardation, slurred speech, and reduced hand-eye coordination), and diaphoresis. Transient ketamine-
induced psychotic symptoms have been reported as well, though these are rare. Though the above effects 
generally subside shortly after the infusion is terminated, they can be greatly distressing to certain 
participants and may cause lingering anxiety. In clinical practice, anesthesiologists have found that 
providing relaxation exercises while administering ketamine ameliorates the subjective distress that may 
accompany it. Mindfulness-based relaxation will be provided by a sitter for the duration of the infusion, and 
may reduce any subjective distress that ensues from the infusion. In addition to excluding patients who are 
likely to be medically or psychiatrically compromised by these acute effects, patients will be instructed to 
not eat since midnight preceding the infusion so as to minimize the risk of nausea and vomiting. In order to 


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ensure that adverse interactions do not occur between alcohol and study medications, participants will have 
ceased alcohol use for the 24 hours prior to the infusion. They will undergo assessments, including blood 
alcohol concentration (BAC) testing, a field sobriety test, and a CIWA evaluation, on that day to test for 
sobriety (BAC=0; no signs of intoxication by the sobriety test) and to ensure that participants are not 
experiencing moderate to severe withdrawal phenomena (CIWA < 11). 
   
Patients will be further instructed that they may request to stop the infusion at any time. Medical 
surveillance will ensure that any problematic changes in vital signs will be addressed.
 
Ketamine can also have cardiovascular effects due to its sympathomimetic properties. These effects 
include modest tachycardia and systolic blood pressure elevation. They tend to emerge in the latter 
half of the infusion session; on average, the heart rate elevation is by 15 bpm, and the blood pressure 
elevation is by 20 mmHg. In our experience to date with this dose of ketamine, we have found that 
these effects did not lead to any difficulties, were well tolerated, and subsided within 10 minutes of 
infusion discontinuation.  
   
Ketamine is also associated with some abuse liability. In the community, ketamine is generally insufflated, 
ingested, or injected intramuscularly, and is used in combination with other substances such as marijuana, 
alcohol, gamma-hydroxy-butyrate (GHB) and 3,4-methylenedioxymethamphetamine (ecstasy). There is a 
risk, therefore, that participants may seek out ketamine after becoming exposed to it, and develop 
problematic patterns of ketamine use during or after the study. This risk may be compounded by the fact 
that it is given in this study to individuals who may have an increased vulnerability to developing substance 
use problems in light of their problematic alcohol use. While this important risk cannot be removed entirely, 
various safeguards can be implemented to ensure that it is minimized, including:
  
1) using a blinding procedure and giving participants the impression that they may receive any of a number 
of medications during each infusion; this will protect participants from identifying ketamine following the 
infusion and seeking it out, even though our preliminary data indicate that cocaine users rated ketamine as a 
substance they would likely not seek out and did not in fact initiate ketamine misuse in the follow-up period 
in both laboratory and clinical settings. In order to protect informed consent, the side effects and risks of all 
possible medications, and particularly ketamine and midazolam, will be clearly conveyed
 
2) excluding participants with a history of ketamine misuse or abuse.
   
3) carefully monitoring drug use to ensure that any emergent patterns of misuse or abuse of ketamine, or any 
other substance, is properly addressed in a timely manner. Futhermore, ketamine is administered in this 
study in a way that is unrepresentative of how it is commonly used in the community (slow-drip IV 
infusion). In addition, this slow, sustained method of administration is unlikely to lead to the acute powerful 
effects generally associated with heightened reinforcing effects and abuse liability. See "Adequacy of 
protection against risks."
As mentioned above, ketamine may also precipitate psychosis in certain individuals. Recent evidence 
suggests that glutamate dysfunction is implicated in schizophrenia, and that NMDA antagonists can mimic 
the symptoms of schizophrenia.  Therefore, individuals who have a diathesis towards psychosis may be at 
greater vulnerability to developing a psychotic disorder after receiving NMDA antagonists. This risk is 


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addressed in the proposed study by 1) excluding individuals with a personal history of psychotic symptoms, 
2) excluding individuals with a first-degree family history of psychosis, and 3) closely monitoring patients 
for the emergence of psychotic symptoms.
 
Sedation following the administration constitutes another risk. Clinical and research experience suggest that 
mild sedation may persist for up to 8 hours following the infusion. Participants will be instructed to not 
drive following the infusion and to refrain from operating heavy machinery until the following day. They 
will also undergo a field sobriety test prior to discharge from the facility. 
Ketamine may interact adversely with opioids, sedatives, and alcohol. In order to minimize the risk of 
adverse interactions, participants will have initiated abstinence for at least 24 hours prior to the infusion, and 
will have remained in the facility for several hours post-infusion so that the acute effects of ketamine will 
have subsided by the time that they are discharged. A field sobriety test is also performed to ensure 
participants are not experiencing persistent psychoactive effects prior to discharge. 
 
Ketamine poses a risk to pregnancy; women who are pregnant or expecting to be pregnant will be excluded.
Ketamine may interact with psychotropics and other medications. During screening, the medication 
regimens of all participants will be rigorously investigated for medications that may lead to adverse 
interactions with ketamine, such as sedatives, opioids (including propoxyphene), tricyclic antidepressants, 
MAO inhibitors, and SNRIs such as duloxetine. Participants on medications whose effect may be disrupted 
by participation in the study will be excluded.
 
Midazolam infusion: A major risk of participating in this research ensues from receiving midazolam. 
Midazolam is a benzodiazepine that is FDA approved for the treatment of anxiety. Midazolam will be used 
in the study as an active placebo. The dose to be used in this study will be within the range of normal use, 
and is not normally associated with significant adverse events. The short half-life of midazolam (3 to 6 
hours) ensures that risk of adverse interactions with alcohol will be minimal. Yet there are important risks 
that need to be addressed in order to ensure the safety of participants.
 
The notable side effects of midazolam include sedation, euphoria, and respiratory depression. A small 
minority of individuals may also have an adverse reaction characterized by loss of behavioral control called 
"paradoxical disinhibition." Individuals with a history of any allergic or adverse reaction to midazolam will 
be excluded. Furthermore, patients with medical complications that may make participation hazardous, such 
as obstructive sleep apnea, obesity, or a propensity for respiratory depression, will be excluded as well.
 
Sedation following the administration constitutes another risk. Clinical experience suggest that sedation may 
persist for up to 6 hours following the infusion. Participants will be informed of this risk at that time and 
encouraged to abstain from operating heavy machinery or engaging in any activities that sedation may make 
hazardous. A field sobriety test will be performed prior to discharge from the facility on the infusion day. 
 
Midazolam also possesses some abuse liability. There is a risk, therefore, that participants may seek out 
midazolam after becoming exposed to it, and develop problematic patterns of midazolam use during or after 
the study. This risk may be compounded by the fact that it is given in this study to individuals who may 
have an increased vulnerability to developing substance use problems in light of their dependence on 
alcohol. While this important risk cannot be removed entirely, various safeguards can be implemented to 
ensure that it is minimized, including:


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1) exercising a blinding procedure and giving participants the impression that they may receive any of a 
number of medications during each infusion, while ensuring that the side effects and risks for each possible 
medication are clearly conveyed; this may prevent patients from identifying midazolam and subsequently 
seeking it out.
2) excluding participants with a history of midazolam misuse or abuse.
3) carefully monitoring drug use to ensure that any emergent patterns of misuse or abuse of midazolam, or 
any other substance, is properly addressed in a timely manner. 
Futhermore, midazolam is administered in this study in a way that is unrepresentative of how it is 
commonly used in the community (slow-drip IV infusion). In addition, this slow, sustained method of 
administration is unlikely to lead to the acute powerful effects generally associated with heightened abuse 
liability. See "Adequacy of protection against risks."
 
Midazolam may interact adversely with opioids, sedatives, and alcohol. In order to minimize the risk of 
adverse interactions, infusion procedures will be preceded by a 24-hour abstinent period. Participants who 
present intoxicated on the infusion day (by BAC and field sobriety test) will be scheduled for another 
attempt on the following week.
 
Midazolam poses a risk to pregnancy; women who are pregnant or expecting to be pregnant will be 
excluded.
 
Midazolam may interact with psychotropics and other medications. During screening, the medication 
regimens of all participants will be rigorously investigated for possible problematic interactions with 
midazolam, such as sedatives, opioids (including propoxyphene), and atypical antipsychotics (such as 
clozapine and olanzapine). Participants on medications whose effect may be disrupted by participation in 
the study will be excluded.
 
Pregnant and lactating women are especially at risk as the medications used can be harmful to a fetus or 
newborn child as well as the mother herself.
 
Abstinence Initiation: Another risk of research participation is related to abstinence initiation for a 24 hour 
period prior to the infusion. This abstinence period is intended to facilitate safe administration of 
medications in order to prevent adverse interactions with alcohol. It also serves to designate the date at 
which efforts at alcohol reduction or abstinence can begin in earnest (e.g., a “quit date”). The risk is that 
withdrawal phenomena might emerge during that 24-hour period that threaten participant safety. During 
screening, various measures and inclusion/exclusion criteria are intended to identify and exclude from 
enrollment individuals susceptible to developing problematic withdrawal phenomena. Furthermore, 
individuals are assessed with the CIWA on the day of infusion; those experiencing CIWA > 10 will be 
discharged from the study and provided appropriate medical management and/or referrals. 


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Structured interviews, rating scales, questionnaires: These should not pose any medical or physical risk. 
The major disadvantage is the time required to complete them, and possible discomfort at sharing the 
sensitive, personal information sought through them. Judging by our past experience with these measures, 
these are acceptable to most participants in our trials. Nonetheless, some participants may still object to how 
tiresome and time-consuming some of these assessments can be. All participants are informed that they may 
refuse to answer any questions, and that they may ask to stop at any time. Should participants become upset, 
uncomfortable, or exceedingly stressed while completing the interviews or assessments, assistance will be 
made available to them.
 
Blood drawing and intravenous placement: Blood drawing may cause slight and momentary discomfort 
at the puncture site, sometimes resulting in a small bruise. Intravenous placement can be associated with 
infection, clotting, pain, or bruising. Blood drawing and intravenous placement will be conducted by 
personnel with the requisite training to carry these procedures out at minimal risk to participants.
Blinding Procedure: Participants will be informed that they may receive any of a number of NMDA 
antagonists, any of a number of psychotropics, and/or saline at the infusion, even though they will only be 
receiving ketamine or midazolam, with saline. The ability to provide informed consent will be protected 
because patients will receive adequate information about the medications they may possibly receive, and 
particularly about ketamine and midazolam. However, participants may get frustrated at not knowing all the 
details of this study. We will do our best to reassure them that such blinding procedures have been designed 
to not add additional risk, and that they may refuse to participate or remove themselves from the study at 
any time.
Describe procedures for minimizing risks
Protection Against Risks
 
Screening:
The exclusion criteria are drafted to minimize the medical psychiatric risks to the participants.
To minimize the risk associated with the study, participants receive a thorough psychiatric and medical 
evaluation during the screening process. Close attention is paid to any evidence of a personal or family 
history of psychosis, as well as a history of ketamine or midazolam misuse or abuse; the most severe risks in 
this study are that participants will develop persistent psychosis after receiving ketamine, or that they will 
develop problematic patterns of use of midazolam or ketamine after being exposed to them. The above 
exclusion criteria ensure that participants with heightened vulnerability to these risks are excluded.
 
In order to minimize risk associated with the medications used, pregnancy, lactation, or failure to practice a 
reliable birth control method are exclusionary, and patients are instructed to inform their psychiatrist 
immediately if they suspect they may be pregnant. Urine HCG is done monthly during the trial. 
 
Participants with a history of an adverse reaction to any of the study medications are also excluded.
 
The screening process is also designed to detect chronic, unstable, and/or problematic medical or psychiatric 
conditions that may study participation hazardous. In addition, participants are asked about their medication 
history, and patients on medications whose effect may be disrupted by participation are excluded. The 


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screening evaluations include 1) complete physical examination, including assessment of blood pressure and 
heart rate, 2) serologic and biological analyses, including electrolytes, blood counts, pseudocholinsterase 
level, urinalysis, liver function tests (noting if there is an elevation > 3 X normal),, thyroid tests, urine 
toxicology, and urine pregnancy tests, and 3) an electrocardiogram (with consultation from a cardiologist, 
Dr. Angelo Biviano). This evaluation, with a concurrent medical history, is designed to detect any medical 
or other conditions that may make participation hazardous.
Infusion Administration Protections
We have provided over 60 infusions to cocaine and polysubstance users, as well as pathological gamblers, 
and have developed a safety protocol to minimize any associated risks, in addition to the screening 
procedures described above. These protections are incorporated into infusion procedures, as well as into 
follow-up assessments.
 
During the infusion, heart rate, blood oxygen saturation, and blood pressure will be continuously monitored. 
Greater than a 35% increase in baseline heart rate or blood pressure will lead to termination of the infusion 
or procedure. It is expected that blood pressure and heart rate should normalize within 15 minutes of 
terminating the infusion or procedure. Blood oxygen saturation lower than 90% will also result in the 
infusion being terminated. An ACLS and BLS certified staff psychiatrist will be available during all 
procedures and infusions. After the infusion, a psychiatric evaluation, including the administration of a 
BPRS, investigates for an adverse psychiatric reaction to the infusion. 
Participants will not be under the influence of alcohol, as well as other intoxicants, as assessed by BAC and 
a field sobriety test. This is to prevent adverse interactions between the study medications and other drugs, 
including alcohol. The approximately 24-hour pre-infusion abstinent period protects against interactions 
between alcohol, other intoxicants, and the study medications. Individuals who present in an acutely 
intoxicated state on the day of infusion will be provided another opportunity the following week to maintain 
abstinence before the infusion. Individuals who are unable to maintain abstinence on the second opportunity 
will be removed from the trail and provided referrals. The post-infusion period is modified accordingly 
(e.g., the infusion day is followed by a 7-week post-infusion period, whether the infusion occurs on the first 
or second opportunity). 
 
Participants will also be expected to not eat on the morning of to the infusions. These measures are intended 
to minimize the risk of nausea, vomiting, and aspiration during the infusion. Participants can elect to 
discontinue the infusion at any time. Nausea and vomiting, should it occur, will be treated supportively.
 
During infusions, participants may develop subjective distress at the psychoactive effects of ketamine or 
midazolam. Pre-infusion relaxation exercises have been found to reduce such distress in the setting of 
ketamine administration, and mindfulness-based relaxation exercises, drawn from the MBRP manual, will 
be provided before and during the infusion by a sitter. Psychological preparation has also been found helpful 
in such settings, and participants will be provided with information regarding what may occur at various 
points in the protocol: during the consent process, and prior to the infusion. These measures will minimize 
the risk of participants developing distress during the infusion. Additionally, participants may elect to 
discontinue the infusion at any time.
In order to address the potential cardiovascular effects of ketamine, vital signs (blood pressure and heart 


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rate) will be monitored every five minutes beginning five minutes before the infusion begins, and will be 
monitored after the infusion until baseline vital signs are restored. If the HR increases > [220-participant’s 
age]*, and if systolic blood pressure increases by > 60 mm or diastolic blood pressure increases by > 40 mm 
during the ketamine infusion relative to the blood pressure obtained during screening at baseline, the 
infusion will be permanently discontinued. The blood pressure will be monitored and if there is no decrease 
after 5 minutes, then nitroglycerin or clonidine will be administered. If high blood pressure is symptomatic, 
i.e., blurred vision, headache, chest pain, the subject will be transferred to the ER.
 
Persistent psychological effects may occur after receiving ketamine; rare but severe risks include persistent 
psychosis and dissociation. Participants will be monitored for 2 hours after receiving the infusion, and will 
be administered a BPRS, positive symptom subscale. They will also meet with a psychiatrist for medical 
and psychiatric clearance before discharge from the hospital. In addition, they will meet thrice a week with 
research staff for monitoring. Participants who develop psychosis will be removed from the study, and 
provided with the necessary level of care. Participants who develop persistent, clinically significant 
dissociative symptoms will also be removed from the study and provided with the necessary level of care. 
Participants will also educated, as mentioned above, on the potential persistent psychiatric risks of 
medication administration so that they can report problematic symptoms as soon as they emerge, without 
having to wait for an appointment. MDs are available 24 hours/day, 7 days/week for emergencies.
 
Prior to discharge from the facility on the day of infusion, participants will be monitored closely and 
provided various assessments, including a psychiatric evaluation and field sobriety test. These assessments 
are intended to identify persistent medication-related psychoactive effects, such as sedation or altered 
sensorium. Participants will remain in the facility under close psychiatric monitoring until they can pass the 
field sobriety test. 
 
Patients will be encouraged to contact the clinic should any problems arise. Patients will also be informed of 
the abuse liability of some of the substances that they believe they may receive by infusion; they will be 
encouraged to report any drug-liking effects from the infusion, or any desire to seek out similar effects. Our 
previous results suggest that these effects are not desired by participants, and that they do not go on to seek 
ketamine or benzodiazepines. 
 
Participants who experience a clinical worsening while involved in the study (e.g., development of 
psychiatry symptomatology, worsening drug use ) will be removed from the study, provided with acute 
psychiatric care if needed, and provided appropriate referrals.
 
Protections related to Abstinence-Precipitated Withdrawal:
In addition to the screening procedures mentioned above that are intended to identify individuals susceptible 
to problematic withdrawal during pre-infusion abstinence initiation, participants will be assessed for 
withdrawal on the day of the infusion (using CIWA). Individuals with problematic levels of withdrawal 
(CIWA > 10) will be discharged from the study and provided appropriate medical management and/or 
referrals. Participants who experience two or more consecutive blood pressure readings of 
160/110 between visits over the course of study participation will be removed from the trial 
and referred to appropriate treatment. Participants who complain of new symptoms 
consistent with cardiovascular instability (chest pain, new onset dyspnea on exertion) will 
also be removed and provided appropriate referrals.   


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Protections related to Pregnant Women and New Mothers
 
In order to safeguard against risks towards pregnant women, evaluation will be conducted on 
whether the risk of treatment is acceptable for women of childbearing potential. Staff will discuss 
with participants the risks associated with participation and the importance of adequate birth control 
practice.  In addition, staff will evaluate whether the participant is willing and reliable to practice 
effective birth control during the study. Urine pregnancy testing will be conducted at baseline 
evaluation and on a weekly basis throughout the course of the study. Staff will periodically discuss 
with patients to review importance of not becoming pregnant, and adequacy of birth control practices 
(all of which will be documented). As the testing methods used have limitations, participants will be 
encouraged to inform the research staff if they believe they have become pregnant so that the safety of 
the participant can be ensured.  As the risk towards pregnant women outweighs the benefits of 
participating in this study, if a participant becomes pregnant during the course of the study, they will 
be discontinued from their participation.
Methods to Protect Confidentiality
Describe methods to protect confidentiality
Protection of Confidentiality:
A certificate of confidentiality will be acquired for the study to offer added protection for the privacy of 
participants against forced disclosure by subpoena or court order. This certificate will allow investigators 
and others with access to research records to refuse to disclose information that could identify subjects in 
any civil, criminal, administrative, or legislative proceeding at the Federal, State, or Municipal level. The 
certificate of confidentiality is granted for studies that collect information that, if disclosed, could damage 
the participant's financial standing, reputation, employability, or insurability.
We use coded records (e.g., initials and numbers), and store signed consent forms in a locked file cabinet. 
Only coded records will be entered into the computer and the security of the electronic data is ensured at the 
level of the server, the user, and the database. Upon entry to the study, the participant is informed that it 
would be preferable if s/he divulges the contact information of someone s/he knows and trusts, and who 
knows of his or her participation in the study. This is used to aid in the case of emergency. Providing this 
information is not required for participation in the study. If s/he agrees to this, the participant will inform the 
designated individual that s/he may be contacted by study staff. Only after the participant has informed the 
designated individual about possible calls will the contact information be provided and the consent form 
addendum be signed. In the event that the study staff need to contact the participant's physician, a HIPPA 
form will be presented to the patient to authorize contact between the research psychiatrist and the 
participant's physician.
Will the study be conducted under a certificate of confidentiality?
Yes, we will apply for the Certificate of Confidentiality
Direct Benefits to Subjects  


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Direct Benefits to Subjects
Potential benefits of the proposed research to participants:
 
There are only a few effective pharmacotherapy treatments for alcohol dependence. This study may lead to 
greater understanding of how alcohol dependence might be treated using novel pharmacotherapy strategies. 
All participants will also receive a form of psychotherapy found effective for substance use problems. In 
light of the innovative aspects of this research proposal, we believe that we have put in place necessary and 
sufficient safeguards to protect the safety of participants, and detect early potential risks. We further believe 
that the risks of participation have been made manageable and reasonable, and outweigh the risks of alcohol 
use itself. Should our hypotheses concerning the use of ketamine be substantiated, we may also provide 
substantial therapeutic benefit to patients.
Compensation and/or Reimbursement 
Will compensation or reimbursement for expenses be offered to subjects?
Yes
Please describe and indicate total amount and schedule of payment(s). 
Include justification for compensation amounts and indicate if there are bonus payments.
Compensation: Participants will be given $10 at eacg screening visit and appointment day to defray the 
costs of travel and to compensate for time, as well as $25 for screening itself. Participants will also be 
compensated $25 for the infusion day, which is longer than a typical visit, to be received on the infusion 
day. Compensation is therefore a maximum of $170.
References
References
References are available upon request. 
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Form #PP2: HIPAA Authorization for Research 4.14.14 
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•
WƌŽǀŝĚĞƌƐŽĨƐĞƌǀŝĐĞƐĨŽƌƚŚĞZĞƐĞĂƌĐŚĂƚh͕Ez^W/ĂŶĚͬŽƌZ&D,͕ƐƵĐŚĂƐDZ/ŽƌWd͕ŽƌCentral Reference Laboratories 
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
NIAAA

Substance Use Research Center, New York State Psychiatric Institute 



Glutamatergic Modulation of Disordered Alcohol Use: A Randomized, Controlled Trial
Elias Dakwar, MD
7014


Form #PP2: HIPAA Authorization for Research 4.1.14 
Information has been disclosed to a third party which does not have to follow these laws (e.g., a drug company or the Sponsor 
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Elias Dakwar, MD, 1051 Riverside Drive, Unit 66, New York, NY 10032

SAP_001.pdf: 
 
 
 
 
 
 
 
 
 
 
 
Protocol #7014: Glutamatergic Modulation of Disordered 
Alcohol Use: A randomized, controlled trial 
 
NCT02539511 
 
September 5th, 2017 
 


II. RESEARCH STRATEGY. 
Overview: Alterations in glutamate neurotransmission are an important target of pharmacotherapy for alcohol 
dependence.1-4 Our investigations with ketamine, a potent glutamate modulator, in drug dependent individuals 
suggest that it may exert unique therapeutic effects on dependence-related vulnerabilities.47,48 This project will 
evaluate the effect of a single sub-anesthetic dose of ketamine on alcohol use in treatment seeking, non-
depressed, alcohol dependent individuals who complete a 5-week outpatient double-blind, randomized, 
controlled study. The R21 mechanism is appropriate for this project because we aim to evaluate a highly 
innovative but moderate-risk intervention in a manner that has the potential to make important contributions. 
Significance:The role of glutamate in alcohol dependence. Alcohol dependence remains a significant public 
health problem5 for which novel pharmacotherapy strategies are needed.6 As the field continues to elucidate 
the neural correlates of alcohol dependence, we have gained a greater understanding of alcohol-related 
neurobiological vulnerabilities that perpetuate problematic use, and that might be targeted by innovative 
medications development. One important target are alterations in glutamate neurotransmission, ranging from 
up-regulated glutamate receptors to prefrontal functional changes.1-4 Alterations in glutamate signaling have 
been implicated in several problematic adaptations to alcohol and drug use, including withdrawal, increased 
stress sensitivity, neurotoxicity, and cue reactivity.1-4,7,8 Perhaps best characterized are the changes in N-
methyl-D-asparate receptors (NMDARs), the predominant class of glutamate receptors involved in plasticity, 
memory, and learning.4 NMDARs have been found to be up-regulated with chronic alcohol exposure; and 
changes in NMDAR structure and functioning are thought to account for alcohol-associated neurotoxicity, 
prefrontal alterations, withdrawal, and stress sensitivity.1-4,7,20 The impact of adaptations such as stress 
sensitivity on alcohol use is well recognized. In rodents, stress, especially when uncontrollable, increases 
alcohol self-administration, and stressors, including cues, promote reinstatement of alcohol use.9,10 In humans, 
heightened cue and stress sensitivity demonstrably leads to cravings, alcohol use, and relapse.11,12 Alcohol-
induced stress sensitivity may thereby create a vicious circle of problematic and progressively uncontrollable 
alcohol use.1-4,11 The chronic stress brought on by compulsive drinking may further evolve into prefrontal 
pathology resembling “learned helplessness”: a glutamate-mediated adaptation typically associated with 
depression and prefrontal neural deficits,13,14 but which in substance users might manifest as demoralization, 
craving and stress sensitivity, and impaired self-efficacy.11,12,19 Thus, impaired motivation for changing drug 
use, as well as high sensitivity to stress or drug cues, may emerge from a cascade of adaptations in alcohol 
dependent individuals,3 with the early disruptions in glutamate signaling evolving into prefrontal abnormalities 
similar in pathophysiology to those associated with stress-related or affective conditions.15,16 Alcohol-related 
alterations in glutamate homeostasis have been observed to lead to prefrontal changes comparable to those 
observed with depressive and anxiety disorders;3,14-19  impaired prefrontal regulation of midbrain structures, 
such as the nucleus accumbens and amygdala, is a well-described correlate of not only affective and anxiety 
disorders, but also addictive disorders.3,14-19 Anterior cingulate cortex (ACC) alterations in particular have been 
implicated in stress sensitivity,17,18 as well as in high reactivity to cues and an increased risk of relapse.12,19  
Ketamine for Alcohol Dependence. Glutamate is therefore recognized as a promising target for alcohol 
treatment. Preclinical data suggest that NMDAR antagonists dampen withdrawal, reduce alcohol consumption, 
and address alcohol-related adaptations; 21-23 and in humans, mixed GABA agonists/NMDA antagonists such 
as topiramate and acamprosate have shown efficacy for some outcomes.50,51,72 As a high-affinity, 
noncompetitive NMDAR antagonist,24 ketamine hydrochloride is a possible, if unconventional, approach to 
effectively modulating this important class of receptors, as well as in addressing related prefrontal alterations. 
In a recent series of NIMH-funded trials, a single sub-anesthetic intravenous (IV) dose (0.5 mg/kg over 40 
minutes) of ketamine had beneficial effects on suicidality25, refractory unipolar depression26 and bipolar 
depression27 that persisted well beyond the acute perceptual and behavioral changes that accompany 
administration (in some cases, up to several weeks after a single dose).26 The mechanisms thought to account 
for its unique anti-depressant may also be relevant to alcohol treatment. These effects include regulating ACC 
activity29, which some evidence suggests might serve to reduce the risk of relapse12,19; and modulating default-
mode connectivity and excitability30, which have been shown to be altered in alcohol dependence.28 Emerging 
data further suggest that ketamine, alongside the possibly therapeutic effects emerging directly from its 
NMDAR antagonism and modulation of glutamate neurotransmission, promotes increased prefrontal synaptic 
remodeling and neural plasticity through various mechanisms, including alpha-amino-3-hydroxy-5-
methylisoxazole-4-proprionic acid (AMPA) receptor activation31, increased mammalian target of rapamycin 
(mTOR) signaling32, and mechanisms involving brain derived neurotrophic factor (BDNF) 33. This unique effect 
on plasticity may address alcohol dependence, as it does depression,32 by counteracting the synaptic deficits 
that develop with dependence,1-4 and restoring healthy prefrontal functioning through neural remodeling.31-33  
Ketamine: A Unique Modulator. These potent effects on prefrontal neural plasticity and connectivity/ activity are 
what primarily serve to distinguish ketamine from selective NMDAR antagonists with which it might be 
grouped, such as memantine, but which are ineffective for alcohol problems.34 Other important distinctions 
include ketamine’s high affinity for NMDA receptors and specific sub-receptor activity35-37, as well as its mode 


of administration (i.e., infused for discrete periods at sub-anesthetic doses).25-28  These differences indicate the 
ways in which ketamine may be uniquely helpful. Indeed, preclinical data suggest that ketamine’s downstream 
effect on plasticity, thought to primarily account for its anti-depressant efficacy, may also be crucial to its 
possible anti-addiction benefits. A recent rodent study found that ketamine-associated reductions in alcohol 
consumption were abolished with mTOR inhibition38; as mentioned, mTOR activation has been implicated in 
ketamine-related promotion of neural plasticity32.  The effects of ketamine on prefrontal plasticity might thereby 
address alcohol-related neuroadaptations in humans as well, particularly those associated with glutamate-
based prefrontal deficits such as impaired self-efficacy,13,14 impulsivity,39 and cue and stress sensitivity.12,16-19,40  
The Effect of Ketamine on Dependence Deficits. The neuroadaptations related to problematic alcohol intake 
are shared with other drugs, such as cocaine, and may represent pathology common to most substance use 
disorders.1-4,16,19 We therefore assessed the effect of ketamine on these dependence-related deficits,47,48  
specifically low motivation to quit and high reactivity to drug cues (see Preliminary Data). We found that sub-
anesthetic ketamine, when compared to an active control (lorazepam), significantly increased motivation to 
stop drug use (p<0.05) in active cocaine users, and reduced cue-induced craving (p<0.05). These effects were 
measured 24 hours post-infusion, but the enhanced motivation in particular persisted for at least 72 hours. 
Additionally, participants who experienced a robust improvement in motivation following ketamine (with a score 
corresponding to the “maintenance” stage of change) remained abstinent from cocaine, by urine toxicology, 
during the 4-week follow-up, even in the absence of treatment. It remains to be determined whether these 
apparently beneficial effects of ketamine extend to alcohol. Previous work with ketamine indicates that it can 
be safely and tolerably administered to detoxified alcohol dependent individuals.41,42,84 Further, ketamine has 
been found to facilitate abstinence initiation when administered intramuscularly (IM) in preliminary research.43 
Ketamine with Psychotherapy. The primary purpose of this trial is to investigate the efficacy of a sub-anesthetic 
dose of ketamine (0.71 mg/kg IV over 52 minutes) on problematic alcohol use in 40 non-depressed alcohol 
dependent individuals receiving Motivational Enhancement Therapy (MET), an effective psychotherapy for 
alcohol dependence44-46 that may serve to enhance and extend the benefits of ketamine in two ways. First, it 
provides a behavioral platform for harnessing the therapeutic potential of the above neurobiological effects. 
Second, we expect that MET might similarly synergize with ketamine’s psychoactive properties. We recently 
showed that a subset of psychoactive effects, as ascertained by the Hood Mysticism Scale,67 may mediate the 
robust effect of ketamine on motivation to quit:48  a finding consistent with reports of spontaneous mystical 
experiences motivating alcoholics towards sobriety.49 This profile distinguishes ketamine from agents with 
similar receptor activity but no psychoactive effects,36,37 and suggests a psychological mechanism by which 
ketamine may enhance motivation to quit.48  Thus, a psychotherapy aimed at optimizing this mechanism, as is 
the case with MET, may increase and sustain ketamine-induced motivational enhancement.42,48 Further, our 
experience (see below) suggests that integrating a ketamine infusion into addiction psychotherapy is feasible. 
Innovation: Though NMDAR antagonists have long held interest as potential treatments for alcohol use 
disorders, IV ketamine has not been investigated in non-depressed alcohol dependent individuals, ostensibly 
because of concerns about behavioral toxicity and abuse liability. These risks are important to address, but 
they should no longer be prohibitive, particularly in light of data from our group (see Preliminary Data) and 
others that under appropriate conditions ketamine can be administered without adverse effects, including 
psychotic symptoms, evidence of ketamine misuse, or behavioral disturbances.25-28,41,42,47 The proposed study 
would therefore represent the first attempt to study the effect of IV sub-anesthetic ketamine on alcohol 
dependence, without depressive comorbidity, in a clinical setting.  Another innovation pertains to combining 
ketamine with MET. Alongside the novelty of this pairing, the integration of pharmacotherapy with a therapeutic 
framework with which synergy is possible represents an innovative approach to addiction treatment.51 Even if 
our hypotheses are not confirmed, this proposal stands to contribute to the field because glutamate modulation 
with such potent prefrontal effects has yet to be investigated in this manner and with this population.  
Approach: 
Preliminary Data: The effects of subanesthetic doses of ketamine in cocaine users. In a lorazepam-
controlled double-blind trial,47 we assessed the effect of ketamine (0.11 mg/kg bolus over 2 minutes followed 
by 0.30 mg/kg IV) on motivation to stop use and cue-induced craving in non-depressed cocaine dependent 
individuals (n=8), as well as the effects of an additional ketamine dose on these outcomes (0.11 mg/kg 2-
minute bolus followed by 0.60 mg/kg IV, over 50 min) Assessments occurred 24 hours after each infusion; the 
three counter-balanced infusions were separated by 48 hours.  All infusions have been well tolerated, with no 
psychotic symptoms or behavioral disturbances reported. Ketamine (K1) increased reported motivation to stop 
use (University of Rhode Island Change Assessment) (p<0.05) (a), and reduced cue-induced craving by sum 
VAS scores  (p<0.05) (b), compared to the active control lorazepam (LZP). These changes in motivation to quit 
and cue-induced craving were robust and comparable to a 60% change from preceding values. A correlation 
was also found between post-K1 motivation scores and sustained abstinence in follow-up.  An additional 
ketamine dose (K2) led to further significant reductions in cue-induced craving.  All acute effects of ketamine 
resolved within 15 minutes post-infusion, with increased blood pressure and time-limited dissociative 
phenomena being the most common effect. Participants rated LZP, K1, and K2 as low and comparable in 
drug-liking scores (c), and there was no evidence of ketamine misuse or drug-seeking in the 1 month follow-up 


period. Post-hoc analyses indicated that participants rated the higher dose of ketamine (K2) as most helpful in 
regards to initiating cocaine abstinence or use reduction, but it was not associated with higher drug-liking 
scores. These promising preliminary data suggest that ketamine may have a beneficial effect on clinically 
relevant outcomes, and that it can be safely administered to drug dependent individuals.47,48   
              
 
FIGURE 1. K1 vs LZP on A) Motivation to quit, B) Cue-induced Craving, and C) Drug-liking Scores; *p=0.012, **p=0.012 
The Clinical Feasibility of Ketamine Combined with Psychotherapy. Expanding on the above data, we are 
conducting an ongoing trial for cocaine dependence that involves embedding a single ketamine infusion (vs. 
midazolam) in a mindfulness-based framework adapted to the individual setting. Our data thus far (n=26) 
suggest that this approach is feasible and well tolerated, with minimal adverse effects and a combined sample 
abstinence rate approaching 50%. Further, several of the patients with comorbid alcohol abuse or dependence 
(7 of 12 participants) maintained abstinence from alcohol by self-report. While we cannot yet determine 
whether ketamine is effective for substance problems because we remain blinded, our results so far suggest 
that psychoactive infusions can be feasibly combined with outpatient psychotherapy in clinical settings.   
Study participants, recruitment, screening: We expect to enroll 50 participants recruited through word of 
mouth, advertising, and referral. At the first contact, a standardized telephone interview is conducted. Those 
who preliminarily meet entry criteria are scheduled for a first screening visit, during which they give informed 
consent, provide a urine sample for toxicology and urinalysis, complete the Hamilton Depression Scale (HAM-
D)53 and Dissociative Experiences Scale (DES),54 and meet with a psychologist for a standardized diagnostic 
evaluation (MINI)52 and with a psychiatrist for a medical and psychiatric evaluation. If still eligible, they undergo 
serum collection (CBC, thyroid panel, Chem 20 panel including liver function tests) and other diagnostic tests 
(ECG). Applicants are eligible if they meet baseline use criteria (e.g., at least 4 heavy drinking days per week), 
are medically healthy, have alcohol dependence, are interested in reducing or stopping use, and are between 
21 and 60. Exclusion criteria include severe physiological dependence on alcohol or certain other substances, 
a history of abuse of or adverse reaction to ketamine or benzodiazepines, a history of psychotic or dissociative 
symptoms, a first-degree family history of psychosis, obesity (BMI > 35), or cardiovascular/pulmonary disease. 
Eligible participants are scheduled for another visit for informed consent and admission into the protocol.  
Setting and Personnel: This project will be carried out at our Substance Treatment and Research Site 
(STARS), an established outpatient facility in which several clinical trials for substance use disorders are 
currently being conducted. Infusions will take place at the Biological Studies Unit (BSU) within the New York 
State Psychiatric Institute (NYSPI). A multidisciplinary team of physicians, psychiatrists, and therapists will be 
involved in various capacities, including assessments, monitoring, and 
psychotherapy.    
Study Procedures: Consenting participants meeting study criteria will 
be entered into the study and begin MET. In week 2, they will achieve 
abstinence for 24 hours, and be randomized (1:1) to receive either 
ketamine or control. We expect to randomize at least 40 participants. 
TABLE 1. 
Procedures  
(by week) 
1 2
A 
2
B 
2
C 
3 4 5 
ACTIVITY
MET 
X X X  
X X X 
MD meet 
X  
 
X X X X 
Abstinence 
 
X  
 
 
 
 
Infusion 
 
 
X  
 
 
 
Study End 
 
 
 
 
 
 
X 
            ASSESSMENT 
AASE/DCQ 
X  
 
X  
X  
VAS-A 
X  
X  
X X X 
FFMQ 
X  
 
X  
X  
BAC/GGT 
 
 
X  
 
X  
BPRS(+) 
 
 
X  
 
 
 
CADSS&HMS 
 
 
X  
 
 
 
(Nor)Ket 
 
 
X  
 
 
 
PSS 
X  
 
X X X X 
CIWA 
X  
X X X X X 
BIS 
X  
 
X  
X  
DES 
 
 
 
 
X  
 
TLFB 
X X X X X X X 
Activities: MET: once weekly motivational enhancement therapy; MD meet: weekly 
meeting with a physician for measures and safety checks; Abstinence:  stop alcohol 
use for 24 hours; Infusion: randomized to ketamine or midazolam; Study end: end of 
study ratings 
Assessments: AASE: Alcohol Abstinence Self Efficacy Scale;  DCQ: Drug Taking 
Confidence Questionnaire; (Nor)Ket: Ketamine and norketamine levels; BIS: Barratt 
Impulsiveness Scale; PSS: Perceived Stress Scale; VAS-A: Visual Analogue Scale 
for alcohol craving. FFMQ: Five Facet Mindfulness Questionnaire; CADSS:  
Clinician Administered Dissociative Symptoms Scale; HMS: Hood Mysticism Scale; 
DES: Dissociative Experiences Scale; BAC: breath alcohol concentration by 
breathalyzer; GGT: serum levels of gamma-glutamyl-transferase; BPRS (+): Brief 
Psychiatric Rating Scale for positive symptoms; CIWA: clinical institute withdrawal 
assessment; TLFB: Timeline Follow-back 
aMD meet and MET occur on separate days each week, with most assessments 
occurring on the MD visit. TLFB occurs on both days.  
Week 2 visits (A,B, and C)  occur consecutively, 3 days in a row  


Clinic Visits (5 weeks) Participants will present twice weekly to clinic for engagement in MET and to meet with 
a psychiatrist, except for week 2, when they will meet with staff on 3 occasions. Assessments are intended to 
investigate patterns of alcohol and other drug use by interview (Timeline Follow Back) 55, and to ascertain 
craving (VAS), withdrawal (CIWA) 56, self-efficacy (Drug Taking Confidence Questionnaire and Alcohol 
Abstinence Self Efficacy Scale) 57,58, perceived stress (modified Perceived Stress Scale) 59, mindfulness (Five 
Facet Mindfulness Questionnaire) 60 and impulsivity (Barrett’s Impulsivity Scale)61. Follow-up by telephone 
occurs at 1 month and 3 months after study completion, and is intended to assess drinking behavior     
Motivational Enhancement Therapy (MET):  MET is a psychotherapy found effective for various substance 
use disorders.44-46 The approach is patient-centered, with the therapist utilizing a variety of strategies to 
promote motivation and self-directed change by guiding the exploration and resolution of ambivalence. MET 
consists of an initial session, during which goals are explored and motivational statements elicited, and 2 to 4 
subsequent sessions to achieve these goals. In this trial, a standard 5-week MET platform will be provided, 
with an additional session after the infusion (6 sessions total). The short length of MET is appropriate for 
evaluating the efficacy of a single infusion, while still providing an effective treatment to participants. Our 
therapists have been trained in MET and the therapy procedures in this protocol will be nearly identical to what 
we have used in previous trials. Sessions will be taped and overseen by a senior therapist to ensure fidelity.  
Abstinence Initiation: In week 1, participants will decide with their therapists on a day in week 2 in which they 
will initiate abstinence. They will also present to the clinic on that day for a session of MET and to receive 
assessments (CIWA, BAL, TLFB). Participants would have been screened prior to consent to ensure that the 
risks of alcohol cessation will be minimized (e.g., no history of severe withdrawal, no history of withdrawal-
related seizures, self-reported ability to undergo alcohol cessation >24 hours).  On the following day, 24 hours 
after abstinence initiation, they will return to the clinic, and be reassessed for intoxication and withdrawal.  
Infusion Procedures: Assuming sobriety (BAC=0) and less than moderate withdrawal symptoms (CIWA < 
11), participants will be randomized to receive a single infusion of ketamine or midazolam. The infusion will 
take place at the BSU within the Division on Substance Abuse, during Week 2. So as to minimize risk, 
infusions will be given in a highly monitored setting. Further, our preliminary studies, as well as studies with 
depression,25-28 have suggested that a single dose of ketamine has efficacy. Thus, for the purposes of this 
study, a single infusion (0.11 mg/kg over 2 min bolus followed by 0.6 mg/kg over 50 minutes) may suffice to 
affect the outcome measures without exposing subjects to the added risk of multiple infusions. Patients will 
have not used alcohol in 24 hours to address the risk of adverse interactions with study medications. They will 
also be instructed to not eat since midnight prior to the infusion so as to reduce the risk of nausea and 
aspiration. Participants will be informed throughout the study that they may possibly receive any of a number of 
substances at each infusion, including amantadine, buspirone, d-cycloserine, ketamine, lorazepam, 
memantine, saline, or any combination of these. This IRB-approved procedure is consistent with blinding 
procedures at our institution and is intended to disguise what drug is specifically given so as to minimize 
expectancy effects (e.g., anticipating a certain set of psychoactive effects) and address the possibility of 
participants identifying which drug has been given. 
  
Active control (midazolam 0.025 mg/kg in saline infused over 52 minutes) or ketamine hydrochloride (0.11 
mg/kg followed by 0.60 mg/kg in saline over 50 minutes) will be prepared and packaged for slow-drip infusion 
by the pharmacy at NYSPI, and administered between 10 am and 12 pm on day 2. This dose of ketamine was 
selected on the basis of published reports suggesting that it was well-tolerated.42,62,63 It was also the highest 
dose tolerated by participants in our preliminary studies, and may have added efficacy over the lower dose. 
Midazolam was chosen as the active control because it produces mild psychoactive effects, further obscuring 
the distinction between conditions so as to ensure blinding, and because of its short half-life. Further, though 
midazolam might acutely reduce alcohol craving or withdrawal, it has no known persistent (> 8 hrs) effect on 
alcohol dependence.64 Blood pressure, heart rate, and blood oxygen saturation will be continuously monitored. 
Infusions will take place in the presence of an ACLS and BLS certified psychiatrist, who will be responsible for 
decisions pertaining to the discontinuation of the infusion in the case of an adverse event. The psychiatrist will 
remain available for up to three hours after the infusion is terminated and will provide a brief psychiatric 
evaluation and field sobriety test prior to discharge from the facility. After the infusion, a lunch will be provided 
to participants while they wait for medication effects to fully subside and for assessments to be completed. The 
participant will also meet with a therapist for a session of MET prior to discharge.  
  
Prior experience with sub-anesthetic ketamine administration in research and clinical settings suggest that 
preparation and relaxation exercises reduce or prevent the anxiety that might develop during 
administration.65,47 In our preliminary study, we found relaxation and mindfulness-based exercises to be helpful 
when administered before and during the infusion if needed. These relaxation exercises will also be employed 
here. A Clinician Administered Dissociative States Scale (CADSS)66 and Hood Mysticism Scale (HMS) 67  will 
be administered at the conclusion of the infusion by the research assistant. Participants will also complete 
various assessments pertaining to drug effect. Ketamine and norketamine (an active metabolite) levels will be 
obtained at 30 minutes into the infusion and at 70 minutes (18 minutes after the infusion is terminated), the 
results of which will remain unavailable to all staff for each participant until all assessments are complete.  
Blinding: Various other safeguards, in addition to making metabolite levels unavailable, will be placed to 
ensure that blinding is maintained. Staff who will be carrying out most of the assessments in this study will not 
participate in infusion procedures because of the possibility, given the expected psychoactive effects, that they 
will recognize which patients are randomized to ketamine. A blinded nurse will also collect serum for testing.  


Compensation: Participants will be given $10 for each screening visit and appointment day to defray the costs 
of travel and to compensate for time, as well as $25 for screening itself. Participants will also be compensated 
$25 for the infusion day, which is longer than a typical visit. Compensation is therefore a maximum of $170.  
Interviews: Mini International Neuropsychiatric Interview (MINI): A semi-structured diagnostic interview 
designed to assist researchers in making reliable DSM-IV psychiatric diagnoses52; Clinician Administered 
Dissociative States Scale (CADSS): A 23 item clinician administered instrument used to measure current 
dissociative symptoms66; Dissociative Experiences Scale (DES):  A 28 item questionnaire for assessing the 
extent of daily dissociative experience, modified to be administered by a clinician54; Brief Psychiatric Rating 
Scale (BPRS) for positive symptoms: A 4 item subscale for assessing psychosis; Hood Mysticism Scale 
(HMS): a 32 item scale for assessing infusion-dependent mystical experience, modified to be administered by 
study staff; Five Facet Mindfulness Questionnaire (FFMQ): A 39 item instrument modified to be clinician 
administered that assess five mindfulness domains: observing, describing, acting with awareness, non-judging 
of inner experience, and non-reactivity60;  Clinical Institute Withdrawal Assessment (CIWA): a validated 
clinician-administered assessment to ascertain severity of withdrawal symptoms56; Timeline Follow-Back 
(TLFB): a retrospective method of quantifying daily consumption of alcohol and other drugs, assisted by the 
maintenance of a weekly use diary57; Barratt Impulsiveness Scale (BIS): a 30 item questionnaire used to 
assess impulsivity, modified to be administered by a clinician61. 
Self-Reports: Drug-Taking Confidence Questionnaire (DCQ): A validated assessment of self-efficacy58; 
Alcohol Abstinence Self-Efficacy Scale: a 40-item assessment that assesses confidence to stop using alcohol 
in various situations57; Perceived Stress Scale (PSS): A 9 item scale that measures levels of subjective stress, 
modified from a monthly assessment to one that evaluates stress between visits59; VAS for alcohol craving 
(VAS-A):  A 10 cm long line from “not at all” to “extremely” to assess craving intensity and frequency.  
Physiological Measures: Breath alcohol concentration (BAC) will be assessed using the Alcohawk® ABI 
Digital Alcohol Breath Tester. This is a professional grade unit that meets the strict requirements for testing 
issued by the Food and Drug Administration (FDA) and the Department of Transportation (DOT). Gamma-
glutamayl-transferase (GGT) is a liver enzyme that is a widely accepted and validated laboratory measure of 
drinking. Plasma GGT can therefore provide an additional biological marker of drinking reduction.83  
Data Analysis: 
Outcome measures and covariates: Primary outcome measures: The primary outcome will be self-reported 
abstinent days following the infusion. Secondary and exploratory outcome measures will be heavy drinking 
days post-infusion  (defined as the number of days with >4 drinks consumed for men and >3 women)68; time to 
first heavy drinking day; drinks per drinking day (number of drinks per week divided by number of drinking 
days); treatment retention; and measures of craving, GGT, withdrawal, mindfulness, impulsivity, motivation, 
and self-efficacy. Covariates: Covariates include baseline levels of alcohol use, and baseline levels of 
secondary outcomes. An exploratory covariate is serum ketamine levels.   
Overview of data analysis plan: Sample: The randomized trial will go on for 2 years. We expect at least 40 
participants to be randomized and receive medications. The main analyses in this study will be on all infused 
patients in an intent-to-treat (ITT) sample. Patients who decide to discontinue will have their reasons for doing 
so documented, if these are available, and every effort will be made to ensure that their data are complete, 
including follow-up data for drop-outs. Analytic Approach: Weekly assessments of percentage heavy drinking 
days will be modeled as a function of time and treatment (ketamine vs. midazolam) with mixed effects models. 
PROC GENMOD in SAS69 will be used to carry out analyses. Significance Testing: All tests will be two-sided 
and performed at significance level p = 0.05, except where noted. A primary outcome measure is specified in 
advance. Preliminary analysis: Before the primary analysis described in Hypotheses Testing is carried out, the 
data will be examined at all time points for outliers; distributions of continuous variables will be checked for 
normality; and transformations will be employed if necessary. The distribution of baseline demographic 
variables, and values will be examined in terms of means, standard deviations, and 95% confidence intervals. 
Power analysis:  Previous research suggests that a difference of 30% between active and control conditions 
in percent drinking days is clinically meaningful.68,70-72 With an n of at least 20 in each group, we will be able to 
detect a difference of 30% between ketamine vs. midazolam, with a medium effect size = 0.80, and two-tailed 
alpha = 0.05. Even if it fails to detect this large and meaningful difference, this preliminary trial will allow us to 
demonstrate feasibility, detect large effects on various outcomes, and estimate effect sizes for future studies.  
Testing the Primary Aim (ketamine promotes abstinence):  Percentage drinking days at each time point 
will be modeled using longitudinal mixed effects models. Participants will be modeled as random factors, with a 
temporal within-subject autoregressive (AR) correlation structure. The estimate of percentage reduction over 
time will be tested by examining the time-by-treatment interaction. Tests of difference will be performed over all 
time points separately and a test for trend will also be performed. 
Key Design Choices and Limitations Ketamine Safety Concerns. Ketamine administration carries certain 
risks, including increased blood pressure, perceptual changes, and abuse liability. However, the safety profile, 
pharmacokinetics, and range of tolerable sub-anesthetic doses of ketamine have been very well studied in 
diverse psychiatric populations, including alcohol dependent individuals.42 It has excellent, reliable 


bioavailability by the IV route, blood levels of active metabolites can be readily monitored, and due to its short 
half-life, its immediate cardiorespiratory effects tend to subside within fifteen minutes of stopping the 
infusion.62,63 Over the course of the past several years during which we have administered infusions to over 40 
drug-dependent participants, we have refined ketamine administration procedures and introduced several 
safeguards to ensure that its risks are minimized. Thus far, ketamine has been well tolerated, with the most 
common acute effect being dissociation and increased blood pressure (without symptoms), which resolve 
within 30 minutes of infusion termination. There were no instances of ketamine misuse, psychosis, or 
persistent dissociation over the course of study participation. We will institute the same precautions and 
procedures in the present study, and expect that infusions will be similarly well tolerated.  
Infusion administration procedures. We have aimed to address various limitations pertaining to infusion 
procedures, including the possibility of adverse interactions and unknown ketamine dose efficacy. The risk of 
interactions between intoxicants and ketamine is addressed by asking that participants maintain abstinence for 
24 hours prior to receiving the infusion and assessing sobriety prior to infusion initiation. The short half-lives of 
ketamine and midazolam (3 and 6 hours respectively) ensure that each study drug will be effectively cleared in 
case that participants resume drinking following discharge.62-64  The effect of IV subanesthetic ketamine on 
alcohol seeking has not yet been studied, so it is unclear whether the proposed dose will be effective on this 
outcome, despite our promising preliminary findings. A related concern is that alcohol use disorders are 
associated with a reduced response to ketamine,84 and that a therapeutic dose may need to be higher than in 
cocaine users. We have addressed these uncertainties by using the highest dose tolerated in our preliminary 
studies. Further, weekly assessments will elucidate the temporal course of ketamine’s effects. Thus, even 
short-lived effects should be apparent. Future studies can determine the optimal dose and frequency.   
Abstinence Initiation. There are risks associated with asking participants to maintain abstinence prior to 
receiving the infusion. One risk relates to the possibility that they will not do so, and will present to the BSU 
actively intoxicated. Obtaining BAC levels and performing a sobriety test prior to the infusion will identify 
intoxicated participants and defer the infusion until another day to prevent adverse interactions. Another risk 
relates to the precipitation of withdrawal phenomena. The current design expects that participants will 
experience some withdrawal, but that it will be mild enough (CIWA<11) to not constitute a risk. Despite 
screening procedures aimed at excluding individuals prone to severe withdrawal, some individuals may 
experience intolerable and/or severe withdrawal. Frequent administration of CIWA and close monitoring will 
ensure that these individuals will be identified quickly, discontinued, and provided appropriate management.  
Primary Outcome: The question of which addiction treatment outcome provides the most clinically relevant 
indication of efficacy is a matter of some debate. We have designated percent heavy drinking days as the 
primary outcome because it is widely used, clinically relevant, sensitive to changes in problematic use, and 
found to correlate with degree of functionality.68,70-72 Percent abstinent days, drinks per drinking day, and time 
to first heavy drinking will serve as secondary and exploratory outcomes to help clarify the temporal course and 
clinical relevance of ketamine efficacy. GGT and BAC will be obtained as biological markers of alcohol use. 83    
MET: A related problem is that the efficacy of the psychotherapy platform may disguise the efficacy of the 
medication. As an evidence-based intervention, MET provides treatment-seeking participants with feasible and 
effective care,44 but its efficacy is considered relatively modest85 and we do not expect it to obscure the efficacy 
of ketamine. Our assumption, moreover, is that MET may serve to heighten and extend the effects of ketamine 
on vulnerabilities that perpetuate problematic use, including low motivation to quit and impaired self-efficacy. If 
ketamine + MET leads to a significant effect on alcohol dependence, as compared to midazolam + MET, the 
hypothesis of synergy may be later investigated using the appropriate two by two study design. 
Possible Intensification of Alcohol-Cue Conditioning: Research with other glutamatergic agents that promote 
plasticity, such as D-cycloserine (DCS), suggests that receiving the medication while still using drugs may 
serve to enhance conditioning to drug-cues (thereby increasing cue reactivity).73,74 Efficacy in facilitating cue 
extinction may therefore require exposure to cues unpaired with acute drug effects,75 as in our inpatient 
preliminary study. Thus, in this proposed outpatient study with active alcohol users, it is possible that ketamine 
(though modulating glutamate and promoting plasticity through different mechanisms than does DCS)76 may 
have effects opposite to what is hypothesized. The pre-infusion 24-hour abstinent period and therapeutic 
setting makes this unlikely. Nonetheless, we will conduct an interim mid-point analysis to investigate this 
possibility, and will have precautions in place to identify, and exclude from further participation, individuals who 
experience clinical worsening. A ketamine-related intensification of cue reactivity or alcohol use in active users 
would provide important information about the role of glutamatergic modulation in alcohol dependence. As 
such, even if our primary hypothesis is contradicted, this study stands to contribute to the field. 
Future directions: The proposed study aims to investigate the effect of a single sub-anesthetic dose of 
ketamine on problematic alcohol use in individuals with alcohol dependence. Given the innovative and 
moderate-risk nature of this investigation, it is well suited to the R21 mechanism. The aims of this project would 
help push the field forward by clarifying the effect of potent glutamatergic modulation on alcohol use in 
individuals engaged in MET, and on various vulnerabilities associated with prefrontal deficits. Thus, it can 
possibly pave the way for future trials aimed at better understanding the utility of this unconventional 
intervention in clinical settings, in tandem with ongoing research aimed at addressing the same question in 
depression treatment. Future studies might also focus on clarifying the mechanisms by which ketamine-
induced glutamatergic modulation can improve prefrontal functioning and thus address alcohol dependence.