A Randomized, Placebo-Controlled, Double-Blind Study to Evaluate the Efficacy of Ketamine for the Treatment of Concurrent Opioid Use Disorder and Major Depressive Disorder
Phase: PHASE2
Conditions: Depression, Opioid-use Disorder, Opioid Abuse
Sponsor: Medical University of South Carolina

 
 
PROTOCOL TITLE: A Randomized, Placebo-Controlled, Double-Blind Study to Evaluate the Efficacy of 
Ketamine for the Treatment of Concurrent Opioid Use Disorder and Major Depressive Disorder 
 
PRINCIPAL INVESTIGATOR: Jennifer Jones, M.D. 
 
 
 
 

PROTOCOL TITLE: Ketamine for the Treatment of Opioid Use and Depression 
 
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TABLE OF CONTENTS 
1. OBJECTIVES/SPECIFIC AIMS ………………………………………………………………………. 4 
1.1. 
Introduction and Context 
1.2. 
Description of Current Standard of Care 
1.3. 
Purpose and Objectives of the Study 
1.4. 
Specific Aims 
2. BACKGROUND ………………………………………………………………………………………… 5 
2.1. 
Role of Depression in Maintaining Abstinence From Opioids 
2.2. 
Glutamatergic Dysregulation Contributes to Both Depression and Addiction Pathology 
2.3. 
Ketamine is a Glutamate Receptor Antagonist 
2.4. 
Previous Clinical Trials of Ketamine for Depression Treatment 
2.5. 
Previous Clinical Trials of Ketamine for Substance Use Disorder Treatment 
2.6. 
Novelty and Importance of the Current Study 
3. INTERVENTION TO BE STUDIED …………………………………………………………………... 6 
3.1. 
Overview of Study Medication 
3.2. 
Safety and Toxicity 
3.3. 
Study Drug, Dose, Mode of Administration and Justification 
3.4. 
Placebo Drug, Dose, and Mode of Administration 
4. STUDY ENDPOINTS …………………………………………………………………………………... 7 
4.1. 
Primary Outcomes 
4.2. 
Secondary Outcomes 
5. INCLUSION AND EXCLUSION CRITERIA/STUDY POPULATION ……………………………... 8 
5.1. 
Initial Screening Methodology 
5.2. 
Inclusion Criteria 
5.3. 
Exclusion Criteria 
5.4. 
Vulnerable Populations 
6. NUMBER OF SUBJECTS …………………………………………………………………………….. 9 
7. SETTING ………………………………………………………………………………………………… 9 
8. RECRUITMENT METHODS …………………………………………………………………………... 9 
8.1. 
Recruitment Sites 
8.2. 
Recruitment Methods 
8.3. 
Recruitment Materials 
9. CONSENT PROCESS ……………………………………………………………………………….. 9 
9.1. 
Qualifications of Study Personnel Obtaining Informed Consent and Capacity of 
Participants 
9.2. 
Location of Informed Consent 
9.3. 
Method of Obtaining Consent 
9.4. 
Capacity of Participants to Give Informed Consent 
10. STUDY DESIGN/METHODS ………………………………………………………………………… 10 
10.1. Overview of Study Design 
10.2. Duration of Treatment and Study 
10.3. Description of Assessments 
10.4. Schedule of Assessments 
10.5. Baseline Assessment Procedures 
10.6. Blinding and Method of Randomization 
10.7. Treatment Visit Procedures 

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11. SPECIMEN COLLECTION AND BANKING ………………………….…………………………… 13 
12. DATA MANAGEMENT ………………………………………………….…………………………… 13 
12.1. Data Analysis Plan 
12.1.1. Efficacy Analyses 
12.1.2. Handling of Missing Data 
12.2. Justification of Sample Size 
12.3. Data Confidentiality Procedures 
12.4. Data Quality Control Procedures 
12.5. Study Documentation and Data Handling 
12.6. Privacy Protection and Confidentiality Assurances  
12.7. Data Sharing 
13. PROVISIONS TO MONITOR THE DATA TO ENSURE THE SAFETY OF SUBJECTS …….. 16 
14. WITHDRAWAL OF SUBJECTS ……………….……………………………………………………. 17 
15. RISKS TO SUBJECTS…………………………. . .…………………………………………………. 17 
15.1. Overview 
15.2. Physical Risks 
15.3. Psychological Risks 
15.4. Abuse Liability  
15.5. Social Risks 
15.6. Legal Risks 
15.7. Economic Risks 
15.8. Unforeseeable Risks 
16. POTENTIAL BENEFITS TO SUBJECTS OR OTHERS ……………….………………………… 19 
16.1. Potential Benefits to Subjects 
16.2. Justification of Risks 
17. SHARING OF RESULTS WITH SUBJECTS ……………………….……………………………... 19 
18. DRUGS OR DEVICES ……………………………………..………….……………………………... 19 
18.1. Preparation, Handling and Storage of Study Medication 
18.2. Investigational New Drug (IND) Data 
19. REFERENCES ……………….……………………………………………………………………….. 19 
 
 

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1. OBJECTIVES/SPECIFIC AIMS 
1.1 Introduction and Context 
Opioid use disorder (OUD) has rapidly become a public health epidemic despite existing opioid 
substitution pharmacotherapies.  In 2016, an estimated 11.5 million Americans misused prescription 
opioids and 948,000 people used heroin, representing a 500% increase since 1999 (Centers for Disease 
Control, 2018).  This is highly concerning, as opioids are responsible for over 2/3 of all drug overdose 
deaths and in 2017, one person died approximately every 11 minutes of opioid overdose (Centers for 
Disease Control, 2018).  The high incidence of heroin use (there were 170,000 new heroin users in 2016) 
is also problematic given the risk of blood-borne infections including HIV and HCV (Health and Human 
Services, 2018).  The opioid epidemic is overall estimated to cost 504 billion dollars annually (Council of 
Economic Advisors, 2017).   
1.2 Description of Current Standard of Care 
All currently approved pharmacotherapies for OUD act as either agonists (i.e. methadone), antagonists 
(i.e. naltrexone), or partial agonists (i.e. buprenorphine) at the mu-opioid receptor.  Successful induction 
rates onto extended release opioid antagonist therapies such as monthly extended release naltrexone 
injection are low (40-46%, Bisaga et. al., 2018).  Furthermore, rates of relapse at 24 weeks (defined 7 
days of self-reported opioid use or 4 consecutive weeks of positive urine toxicology screens) are high for 
both monthly injections of extended release naltrexone (65%) and self-administered daily oral 
buprenorphine-naltrexone (57%, Lee et al., 2018).  Similarly, comparisons of daily methadone vs 
buprenorphine found mean opioid relapse rates after 13 weeks of treatment of approximately 40%, with 
no between-group differences (Mattick et al., 2003).  These findings suggest room for improvement using 
novel treatment approaches (Connery et al., 2015).  
1.3 Purpose and Objectives of the Study 
The primary objective of the proposed study is to directly address this critical need by preliminarily testing 
the efficacy of ketamine in reducing opioid use and depression symptoms among individuals (N=30) with 
concurrent OUD and MDD who have failed to maintain abstinence despite treatment with a standard of 
care pharmacotherapy for OUD (i.e. buprenorphine, methadone or naltrexone).  Effects on related 
symptoms and psychiatric conditions (e.g., cravings, motivation to quit, and anxiety symptoms) will also 
be explored.  To accomplish this, we will use an intent-to-treat, double-blind, randomized clinical trial to 
compare the efficacy of ketamine to placebo control over a twice-weekly treatment schedule for four 
weeks.  We will examine standardized, repeated dependent measures of clinical outcomes at baseline 
and multiple time points after the first treatment (48h to 8 weeks post initial treatment) with primary 
outcomes assessed at one month following the first treatment.  
1.4 Specific Aims 
To achieve these objectives, the following Specific Aims are proposed: 
Specific Aim 1: To demonstrate the feasibility of study recruitment and completion of the 
treatment protocol.  
Specific Aim 2: To preliminarily assess the efficacy of ketamine, as compared to placebo, 
in reducing OUD severity (i.e., percent days using opioids, abstinence rates) as measured 
by the Timeline Followback and urine drug screen tests.  
Specific Aim 3: To preliminarily assess the efficacy of ketamine, as compared to placebo, 
in reducing symptoms of depression using the Montgomery–Asberg Depression Rating 
Scale. 
 
 
 

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2.0 
BACKGROUND 
Role of Depression in Maintaining Abstinence From Opioids 
Negative affect has been found to be a key mediator in failure to achieve abstinence and depression is 
a frequent comorbidity in OUD. Nearly two out of three persons entering treatment for opioid detoxification 
screen positive for depression, however 48% of those meeting criteria for depression had not perceived 
a need for treatment (Brienza et al., 2000; Stein, 2017; Volkow, 2004). However, desire for improvement 
in mood is the most commonly cited reason for relapse in OUD following initial addictions treatment 
(Kadam et al., 2017; Huhn et al., 2018; Volkow et al., 2019). In addition to contributing to relapse and 
being a risk for unintentional overdose, OUD is an independent risk factor for completed suicide (Volkow 
et al., 2019). A national cohort study of veterans (n=4,863,086) found that after controlling for psychiatric 
and medical comorbidities, overall substance use was still associated with a 1.67 hazard ratio for suicide 
in men and 2.15 in women (Bohnert et al., 2017). Furthermore, in women, OUD was associated with the 
highest hazard ratio for suicide of any substance of abuse at 2.33 (Bohnert et al., 2017). 
 
Glutamatergic Dysregulation Contributes to Both Depression and Addiction Pathology 
Glutamatergic dysregulation in the prefrontal cortex and mesolimbic regions (including the amygdala and 
the nucleus accumbens) has been implicated in addiction pathology across multiple substances of abuse 
(Gass & Olive, 2008; Markou et al., 1998). Similarly, depression has been shown to have aberrant 
glutamate signaling (Abdallah et al., 2017; Murrough et al., 2017; Niciu et al., 2014). On a cellular level, 
astrocytes are responsible for maintaining glutamate homeostasis (Parpura and Verkhratsky, 2012) and 
both depression and addiction have been linked to impaired ability of astrocytes to upregulate glutamate 
(Rajkowska et al., 2013; Scofield et al., 2014).  Ketamine is a noncompetitive antagonist of NMDA 
glutamatergic receptors which has been widely used for pain control in conjunction with general 
anesthesia since it was FDA approved in 1970.  
 
Clinical Trials for Depression Treatment 
Results from several meta-analyses indicate that ketamine can induce ultra-rapid improvements in 
depression and suicidality (Han et. al., 2016; Wilkinson et. al., 2017). This remission is most enduring in 
individuals with a family history of substance use disorders (Niciu et al., 2014). It is widely accepted that 
all currently approved pharmacotherapy classes for depression (serotonin reuptake inhibitors, 
monoamine oxidase inhibitors, and tricyclic antidepressants) are associated with a delayed onset of anti-
depressant activity of 2-4 weeks. A meta-analysis of nine high-quality studies showed that ketamine was 
significantly more effective than placebo in reducing symptoms of major depressive disorder at 24 hours, 
72 hours, and 7 days post-infusion (Han et. al., 2016). Additionally, results from a recent meta-analysis 
of ten clinical trials showed accumulating evidence that ketamine can significantly reduce suicidal ideation 
within 24 hours with moderate to large effect sizes (Wilkinson et. al., 2017). The overall duration of anti-
depressant response was found to last between 3-12 days (Andrade, 2017). However, in a subgroup 
analysis, positive family history of alcoholism was found to be associated with a significantly longer 
duration of anti-depressant efficacy, averaging 17 days for the family history positive group and 3.6 days 
for the family history negative group (Niciu et. al., 2014). This suggests that the genetics underlying 
substance use confer a stronger response to the effects of ketamine. 
 
Clinical Trials for Substance Use Disorder Treatment 
Ketamine has shown early evidence of efficacy in the treatment of substance use disorders. One study 
evaluating the adjunctive use of ketamine in heroin use disorder showed that a single-session of high-
dose (2 mg/kg IM) ketamine demonstrated one-month abstinence rates of 85% compared to 55% 
abstinence in the low dose group (0.2 mg/kg IM), and one-year abstinence rates of 24% in the high dose 
group as compared to 6% in the low-dose control group (Krupitsky et al., 2002). In a follow-up study 
comparing three repeated sessions of ketamine infusions with concurrent psychotherapy to single-
session treatment, abstinence rates were increased to 50% in the 3 session group as compared to the 
single session rate of 22% (Krupitsky et al., 2007). Related studies found that ketamine is useful as an 
adjunct to psychotherapy in the treatment of alcohol use disorder (Krupitsky and Grinenko, 1997) with 

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one-year complete abstinence rates of 65.8% in the ketamine-assisted psychotherapy group compared 
to 24% in the control psychotherapy group. Intriguingly, the anti-depressant response to ketamine occurs 
primarily after the drug has been cleared from the body, suggesting that its primary effects are mediated 
through downstream processes. Ketamine has also been shown in a randomized controlled trial to 
facilitate rapid-opioid induction under general anesthesia, with significant improvements in clinical and 
subjective opioid withdrawal symptoms (Jovaisa et. al., 2006). More recently, ketamine has been studied 
in cocaine use disorder and found to improve levels of motivation to quit using and to reduce cocaine 
craving (Dakwar et al., 2014) and reduce rates of cocaine self-administration by 67% relative to baseline 
(Dakwar et al., 2017; Dakwar et al., 2018). Ketamine has been studied as an adjunct agent to 
benzodiazepines for acute alcohol withdrawal and has been found to reduce supplementary diazepam 
equivalent requirements by 40 mg at 12 hours post-ketamine initiation while maintaining equivalent levels 
of withdrawal symptoms between groups (Wong et al., 2015). 
 
Novelty and Importance of the Current Study 
While non-controlled trials for heroin and small pilot trials for other substance of abuse have shown 
evidence that ketamine improves abstinence rates and motivation to quit while reducing cravings, there 
are no completed randomized controlled trials evaluating the efficacy of ketamine in increasing 
abstinence in OUD.   
 
3.0 
INTERVENTION TO BE STUDIED    
3.1 Overview of Study Medication 
Ketamine was originally FDA approved in 1970 for pain control in conjunction with general anesthesia 
(Ketalar, 2018).  The drug has since been evaluated in academic settings for the treatment of pain and a 
multitude of psychiatric indications.  Ketamine has been increasingly studied in academic settings and 
used off-label in private practice settings over the past 10 years (Wilkinson et al., 2017).  Ketamine 
undergoes extensive hepatic first pass metabolism, with an oral bioavailability of approximately 16% 
(Mathew et al., 2012).  For induction of anesthesia, doses of 1 to 4.5 mg/kg IV or 6.5 to 13 mg/kg IM are 
recommended (Ketalar, 2018).   
3.2 Safety and Toxicity 
The acute toxicity of ketamine has been studied in multiple species.  In mature mice and rats, the 
intraperitoneal LD50 values have been shown to be approximately 100 times the average human 
intravenous dose (Ketalar, 2018).  Repeated, daily intravenous injections have been studied in rats, and 
dogs for as long as 6 weeks with excellent tolerability (Ketalar, 2018). Similarly, twice weekly treatments 
in monkeys over a four- to six-week period were well tolerated (Ketalar, 2018).  At sub-anesthestic doses 
in human clinical trials for depression, the most clinically significant physical adverse event from ketamine 
is a transient increase in blood pressure, which was experienced by 29.8% of participants with a mean 
systolic blood pressure increase of 19.6 mmHg (p<0.001) and a mean diastolic blood pressure increase 
of 13.4 mmHg (p<0.001, Wan et al., 2015).  Small, but statistically significant changes in perception 
(including derealization, depersonalization, distortion of time and space, and sense of illusion) were 
categorized as “feeling strange or unreal” and were experienced by 11.7% of participants (Wan et al., 
2015).  The average peak score of 4.5 on the Brief Psychotic Rating Scale is consistent with very mild 
symptom severity (Wan et al., 2015).   
3.3 Study Drug, Dose, Mode of Administration and Justification 
Ketamine is concentrated at a dose of 50mg/ml and will be administered by intramuscular administration 
in the amount of 60 mg (1.2 ml). This dose follows the FDA-dosing guidelines of a maximum dose of 60 
mg per treatment day, with a lifetime maximum of 8 treatments for psychiatric indications.  Each study 
drug administration will be directly observed by the PI.  For a 75 kg person, this dose will translate into an 
effective dose of 0.74 mg/kg based on an intramuscular bioavailability of 93%.  While formal dose 
response studies for depression are lacking, ketamine has been most widely studied for psychiatric 
indications at 0.5 to 1.0 mg/kg given intravenously.  Although there are only a few studies evaluating the 
use of ketamine in the treatment of substance use disorders, doses in these trials have ranged from 0.5 
to 0.8 mg/kg given intravenously or 2 mg/kg given intramuscularly (Jones et al., 2018).  

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3.4 Placebo Drug, Dose and Mode of Administration 
A visually identical sterile saline control injection of equal volume will be also administered intramuscularly.   
 
4.0 STUDY ENDPOINTS  
4.1 Primary Outcomes 
Primary outcomes will be 1) the percentage of individuals completing informed consent out of the number 
of individuals eligible on the initial screening and 2) the percentage of individuals that complete informed 
consent which complete the full protocol. 
4.2 Secondary Outcomes 
Secondary outcomes will include changes in depression severity (as measured on the Montgomery–
Asberg Depression Rating Scale), which will be calculated as a change from baseline to 4-week follow-
up.   
• 
Montgomery Asberg Depression Rating Scale (MADRS; Montgomery, 1979). The MADRS is a 
clinician administered, 10-item questionnaire of depression severity. The total score ranges from 
0-60, with scores of 0-6 considered normal (non-depressed), 7-19 indicative of mild depression, 
20-34 indicative of moderate depression, and 35-60 indicative of severe depression.  Individuals 
scoring 20 or higher on the MADRS will be included in the study. The MADRS evaluates the 
following symptoms of depression: 1) clinical appearance of sadness, 2) self-reported sadness, 
3) inner tension, 4) reduced sleep, 5) reduced appetite, 6) concentration difficulties, 7) lassitude, 
8) inability to feel, 9) pessimistic thought process, and 10) thoughts of suicide. The MADRS has 
a sensitivity of 94% and a specificity of 83%, has been shown to have high internal consistency, 
and correlates well with other measures of depression such as the Hamilton Depression Scale.    
4.3 Exploratory Outcomes 
Exploratory outcomes will include changes in characteristics related to opioid addiction including 
percentage of days using opioids and abstinence rates (Timeline Followback), motivation to quit 
(University of Rhode Island Change Assessment), craving for opioids (Visual Analog Scale), and related 
areas of psychiatric functioning. 
• Timeline Follow-Back (TLFB; Sobell & Sobell, 1992): The TLFB obtains retrospective self-
report of substance use by using a calendar and memory prompts to stimulate recall. 
Quantity and frequency assessments are made using this instrument (e.g., total amount of 
opioids used, percent of days using) as well as abstinence (yes/no). TLFB yields 
consistently high test-retest correlations and correlates well with other self-reports and 
collateral reports. The TLFB will assess consumption of opioids for 60 days prior to study 
entry, during the interventional phase and the follow-up phase. Use of nicotine and other 
drugs of abuse, including prescription drugs, will also be assessed using the TLFB.  
• Urine Drug Screen (UDS) tests: Urine samples will be tested with a Multi-Drug Panel Test, 
which allows for the detection of THC/Marijuana, Cocaine, Phencyclidine, Opioids, 
Methamphetamines, Amphetamines, Barbiturates, and Benzodiazepines.  
• Saliva Drug Screen tests: For follow-up visits conducted by telehealth, a Multi-Drug Panel 
saliva drug screen test may be optionally used in place of urine tests to facilitate ease of 
testing in a home setting. 
• University of Rhode Island Change Assessment Scale (URICA; DiClemente & Hughes, 
1999): This 32-item, self-reported questionnaire uses a five point Likert scale to assess 
levels of motivation to change according to the transtheoretical model (Precontemplation, 
Contemplation, Action, and Maintenance).  This will be measured as the level of motivation 
to make changes may be mechanistically related to improving in opioid use.  
• Visual Analog Craving Scale (VAS; McMillan & Gilmore-Thomas, 1996). At baseline, during 
the interventional visits, and at each follow-up visit, patients will be asked to report on the 
frequency, duration, and intensity of their opioid cravings on a 10 point (100 mm) VAS. This 
approach has been shown to yield a reliable and valid measure of craving in previous 
research.  

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• Generalized Anxiety Disorder Screener (GAD-7; Spitzer et al., 2006). The GAD-7 is a 7-
item self report instrument that will assess generalized anxiety symptomology.  
• Five Facets of Mindfulness Questionnaire (FFMQ; Baers et al., 2006): The FFMQ assesses 
five components of mindfulness including observation, non-judgement of experience, non-
reactivity to inner experience, acting with awareness, and description of experience.   
• PTSD Checklist (PCL-5; Weathers et al., 2013): The PCL-5 is a 20-item self-report measure. 
The PCL-5 is similar in form to the PTSD Checklist (PCL) based on the DSM-5 (Weathers 
et al., 1993), which has excellent psychometric characteristics for screening and as a 
secondary indicator of PTSD symptom severity (McDonald & Calhoun, 2010). 
• Insomnia Severity Index (ISI; Morin, 1993). The ISI is a 7-item, self-report measure that 
assesses perceived severity of insomnia.  The items sum to produce a total score (range 0–
28).  The ISI has an internal consistency alpha coefficient of 0.74, and has shown 
convergent validity with other measures such as the Pittsburgh Sleep Quality Index and 
sleep diaries). 
• Brief Pain Inventory (BPI; Cleeland, 1991). This 9-item questionnaire uses a 10-point Likert 
scale to assess the severity of pain and its interference on difference aspects of quality of 
life and function.  
   
5.0 
INCLUSION AND EXCLUSION CRITERIA/STUDY POPULATION 
5.1 Initial Screening Methodology 
Initial screening eligibility will be conducted by the PI or trained research personnel.  Patients with a self-
reported history of depression and opioid misuse or illicit opioid use for which they report being 
maintained on buprenorphine for at least thirty days will be eligible to complete informed consent and 
baseline evaluation. 
5.2 Inclusion Criteria 
A subject may be eligible for enrollment if all of the following inclusion criteria apply within the thirty days 
prior to randomization: 
1. 
Between the ages of 18 to 65 years old.  
2. 
Able to provide informed consent. 
3. 
Meet DSM-5 criteria for Major Depressive Disorder, without psychotic features. 
4. 
Score at least 20 on the Montgomery-Asberg Depression Rating Scale.  
5. 
Fulfill a minimum of 4 of 11 current opioid use disorder criteria by DSM-5.  
6. 
Have used opioids illicitly at least once in the past month. 
7. 
Subjects must be on a standard of care pharmacotherapy for OUD (buprenorphine, 
methadone or naltrexone) for at least one month.   
8. 
Subjects taking other psychotropic medications (e.g. anti-depressants or non-benzodiazepine 
anxiolytics) must be maintained on a stable dose for at least four weeks before study initiation.  
9. 
Must consent to random assignment to ketamine or placebo control. 
5.3 Exclusion Criteria 
Patients will be excluded from the study if any of the following criteria apply: 
1. 
They are considered an immediate suicide risk (by Columbia Suicide Severity Rating Scale of 
4 or greater, a history of a suicide attempt in the past year, or by clinician judgment) or felt to 
be likely to require hospitalization during the course of the study. 
2. 
They have a self-reported history of illicit ketamine use, or baseline urine drug testing positive 
for ketamine. 
3. 
They are in acute opioid withdrawal (as evidenced by a score of 5 or above on the Clinician 
Opioid Withdrawal Scale).  These subjects will be referred for clinical detoxification and 
pharmacotherapy induction.  Subjects may be re-assessed for study eligibility after one month 
of treatment with a standard of care OUD pharmacotherapy.    
4. 
Subjects who meet DSM-5 criteria for current bipolar disorder. 
5. 
Subjects who meet DSM-5 criteria for current or history of psychotic spectrum disorders.    

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6. 
Women who are pregnant or nursing, and women who do not consent to use methods of 
highly effective birth control during the interventional phase of the study. 
7. 
Subjects with current hypertension as defined by a systolic blood pressure (SBP) >140 mmHg 
or a diastolic blood pressure (DBP) >90 mmHg. 
8. 
Subjects with a self-reported history of delirium for any cause.   
9. 
A history of allergic or other adverse reaction to ketamine. 
10. Clinically significant abnormal laboratory values, physical exam findings or self-reported 
medical conditions for which a transient increase in blood pressure could be significantly 
detrimental (e.g. glaucoma, brain aneurysms, cardiovascular disease, or end-stage renal 
disease). 
11. Electrocardiogram (ECG) findings (obtained within thirty days prior to randomization) of 
tachycardia, prior myocardial infarction, myocardial ischemia, or aberrant conduction). 
 
6.0 
NUMBER OF SUBJECTS 
Approximately 30 patients are planned for enrollment in this study with no gender, race, or ethnicity 
exclusions.  
 
7.0 
SETTING 
All procedures will be conducted in private research study rooms on MUSC campus. 
 
8.0 
RECRUITMENT METHODS 
A chart review will be conducted for research purposes. Potentially eligible patients will be identified. The 
potentially eligible patients in the PIs practice will be informed about the study as the PI feels is 
appropriate. Then potential patients who have agreed to be contacted for future research by logging their 
MUSC Research Permissions preferences in MyChart will be contacted by phone and invited to 
participate. All other patients will be contacted through their providers to be informed of the study if the 
provider feels it is appropriate. 
 
Recruitment will also be conducted through online (i.e. Craigslist) and flyer advertisements throughout 
the hospital and outpatient clinics at MUSC and other local clinics providing OUD treatment.   
 
9.0 
CONSENT PROCESS 
9.1 Qualifications of Study Personnel Obtaining Informed Consent and Capacity of Participants 
The research team have completed (or will complete upon hiring) the Miami Collaborative IRB Training 
Initiative (CITI) course and its associated tests in research ethics.  Only the PIs, or Co-I’s will obtain 
informed consent.   
9.2 Location of Informed Consent 
Informed consent will be obtained at the study research offices, in a private and interruption-free 
environment.   
9.3 Method of Obtaining Consent 
Study personnel will ensure that the participant is given full and adequate written and verbal information 
about the nature, purpose, possible risks and benefits of the study.  There will be no mandatory waiting 
period prior to obtaining informed consent, however participants will not be required to make a decision 
at the time of initial contact.  Participants will also be allowed to discuss the study with family or other 
individuals prior to giving their informed consent.  After participants have reviewed the informed consent 
document, participants will be asked to relay their understanding of key elements related to the study 
procedures (i.e. voluntary nature of participation, basic study visit procedures, duration of study, 
anticipated risks and benefits) to ensure their understanding of the study prior to obtaining informed 
consent.  Consent content will be reviewed as necessary to ensure that subjects have an adequate 
understanding to provide initial and ongoing consent.  The participant’s signed and dated informed 
consent will be obtained before conducting any study tests or procedures that are not related to their 

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routine care.  The Investigator will maintain the original, signed informed consent document.  A copy of 
the signed informed consent document will be given to the participant. 
9.4 Capacity of Participants to Give Informed Consent 
No vulnerable populations (e.g. children, cognitively impaired individuals, incarcerated individuals, or 
pregnant women) will be included in the study, and informed consent must be obtained directly from the 
participants.   
 
10. 
STUDY DESIGN/METHODS 
10.1 Study Overview 
This is a double blind, placebo-controlled trial to assess the efficacy and safety of twice weekly 
intramuscular injections of ketamine in decreasing symptoms of OUD and MDD. Subjects will participate 
in a baseline visit to complete informed consent as well as complete assessments to evaluate study 
eligibility and collect baseline data. 
Eligible participants will return within 
one week for the initial ketamine 
intervention procedure.  Immediately 
prior to the interventional procedure, 
participants will be guided through a 
mindfulness-based 
exercise 
to 
facilitate relaxation and reduce anxiety 
during the intervention. Participants will 
be subsequently monitored for 120 
minutes, during which time they will 
complete measures assessing their 
perception 
of 
the 
interventional 
experience. 
 
Participants 
initially 
assigned to the placebo group may 
choose to optionally complete 8 
ketamine 
medication 
sessions 
beginning in Study WK #5. 
10.2 
Duration of Intervention and Study 
Participants will complete a total of 12-20 study visits (including baseline assessment) as shown in Figure 
1.  Intervention visits will occur over a 4-8 week period, with three follow-up visits completed over the 
subsequent four weeks.   
10.3 
Schedule of Assessments 
The instruments to be used are standardized, have good psychometric properties, and are widely used. 
The schedule of study assessments is provided in Table 2. 
 
 
 

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Table 2: Schedule of Assessments 
Instrument Name 
Purpose 
 
TIME POINT 
Wk
0 
Wk1 (Wk5) 
Wk2 (Wk6) 
Wk3 (Wk7) 
Wk4 (Wk8) 
Wk
5 
(9) 
Wk
6 
(10) 
Wk
8 
(12) 
BL 
Tx1 
Tx2 
Tx3 
Tx4 
Tx5 
Tx6 
Tx7 
Tx8 
1W 
F/U 
2W 
F/U 
4W 
F/U 
Self-Reports and Consent 
Informed Consent 
Obtain informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics Form 
Sample characterization 
X 
 
 
 
 
 
 
 
 
 
 
 
Concurrent Medications Form 
Monitor medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Treatment Services Tracking 
Form 
Assess treatment engagement 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
*Time Line Follow-Back 
(TLFB) 
Primary Outcome: opioid use 
(amt. and frequency) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Beck Depression Inventory-II  
Self-reported assessment of 
depression symptom severity  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Visual Analog Scale (VAS) 
Measure subjective levels of 
opioid craving 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
General Anxiety Disorder 
(GAD-7) 
Self report of anxiety symptom 
severity 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Mystical Experiences 
Questionnaire 
Measure of perceptual 
experiences 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Brief Pain Inventory 
Measure of pain and quality of 
life 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
University of Rhode Island 
Change 
Assessment (URICA) 
Measure of motivation for 
change 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
Insomnia Severity Index (ISI) 
Assess insomnia and sleep 
quality 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
Five Facets of Mindfulness 
(FFMQ) 
Assess aspects of mindfulness 
related 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
PTSD Checklist (PCL-5) 
Measure of PTSD symptoms 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
Fagerstrom Test of Nicotine 
Dependence (FTND) 
Measure of nicotine dependence 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
Assessment of the Blind 
Participant Perception of 
Randomization 
 
 
 
 
 
 
 
 
X 
 
 
 
Study goals 
To characterize goals for 
treatment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Clinician Assessments 
History and Physical Exam 
Eligibility assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs Measurement 
Obtain readings of blood 
pressure, pulse, temperature, 
respirations and pulse oximetry 
X 
X* 
X* 
X* 
X* 
X* 
X* 
X* 
X* 
X 
X 
X 
Modified Observer 
Alertness/Sedation Scale 
(MOASS) 
Measure of sedation 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Clinical Opioid Withdrawal 
Scale (COWS) 
Clinician assessment of opioid 
withdrawal symptoms 
X 
 
 
 
 
 
 
 
 
 
 
 
 
*Montgomery-Asberg 
Depression Rating Scale 
(MADRS) 
Primary Outcome: Clinician 
assessed measure of depression 
symptom severity 
X 
 
X 
 
X 
 
X 
 
X 
X  
X 
X 
Columbia Suicide Severity 
Rating Scale 
Assess for presence and severity 
of suicidal ideation 
X 
 
 
 
 
 
 
 
 
 
 
 
Mini International 
Neuropsychiatric Interview 
Assess for psychotic spectrum 
and bipolar disorder, presence 
and severity of OUD 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pre-screening Questionnaire 
To assess for basic eligibility 
criteria before completing a full 
baseline visit. 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Laboratory and Procedural Tests 
Pregnancy Test (female 
participants only) 
Eligibility assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Drug Screen 
Eligibility assessment (benzos), 
secondary outcome measure 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum blood tests  
(CBC, CMP) 
Assessment of hemodynamic, 
hepatic, and renal function 
X** 
 
 
 
 
 
 
 
 
 
 
 
Electrocardiogram (ECG) 
Assessment of cardiac function 
X** 
 
 
 
 
 
 
 
 
 
 
 

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* Vital signs (blood pressure, pulse, and respiratory rate) will be obtained prior to treatment sessions, and at 45 and 90 minutes post-treatment.  Pulse 
oximetry will be monitored immediately prior to treatment, and for 90 minutes after treatment.  If there is an increase in systolic or diastolic blood pressure 
>30 mm Hg from baseline, or an increase in pulse rate >30 bpm from baseline, the measurements should be repeated after the patient has been in a 
resting position for 10 minutes.  ** Will be performed for individuals with significant prior cardiac, renal or liver diseases.   
 
10.4 
Baseline Assessment Procedures 
After completing study informed consent, participants will undergo a comprehensive evaluation to assess 
for inclusion and exclusion criteria.  This will include self-reports, clinician assessments, and laboratory 
tests as shown in Table 1.  This will include assessment of depression severity, and participants at highest 
risk for suicidality will be excluded. The comprehensive exam will also include a history and physical 
exam by the study PI (pulse oximetry measurements will be a component of the respiratory evaluation), 
baseline medication evaluation for potential harmful interactions, laboratory panels (including 
assessment of renal and hepatic function), and electrocardiogram to ensure safe study participation.  
Baseline assessments may be conducted by telehealth with vital signs to be provided by participant’s 
home or pharmacy measurement. 
10.5 
Method and Administration of Randomization 
Randomized permuted blocks will be employed to obtain balanced randomization sequences for the two 
groups. The PI will be blinded to the randomization sequence and communicated to a designated 
pharmacist who not involved in clinical management of participants in order to preserve the double-blind 
design.  The randomization assignment of participants will be carried out by this pharmacist   
10.6 
Intervention Visit Procedures 
Prior to administration of the study compounds, participants will complete self-report questionnaires, urine 
testing, and clinical assessments. They will subsequently complete a 10-minute mindfulness-based 
psychological relaxation exercise and fill out a questionnaire regarding their study goals.  Participant will 
be asked to disinfect their shoulder using an alcohol wipe, and the study physician will then administer 
the medication by intramuscular administration into the participant’s deltoid muscle.  Vital signs will be 
monitored prior to treatment, and at 45 and 90 minutes post-treatment, and blood oxygen levels will be 
continuously monitored using pulse oximetry.  If during the post-administration observation period, 
ketamine administration causes an increase in systolic or diastolic blood pressure >30 mm Hg from 
baseline, or an increase in pulse rate >30 bpm from baseline, the measurements should be repeated 
after the patient has been in a resting position for 10 minutes. If the criterion is still met, then that patient 
will not receive further administration of ketamine and will be withdrawn from the study.  After completion 
of the injection, participants will be monitored for 120 minutes, during which time they will undergo 
debriefing and complete assessments of their perceptual experience of the intervention.  We will evaluate 
the effects of a twice weekly interventions for 4 weeks, and monitor outcomes over an additional 4-week 
follow-up period to inform pharmacotherapy frequency in future clinical trials. Follow-up visits may be 
conducted by telehealth. 
 
11.0 
SPECIMEN COLLECTION AND BANKING 
Data will be in the form of self-reported questionnaires, medical record review (including labs and 
pertinent medical history for the purpose of eligibility clarification), urine and breath samples, physical 
exam and electrocardiogram and structured clinical interviews conducted by the PI.  This data will be 
obtained specifically for research purposes.  No biologic specimens will be stored for future use.  Serum 
based laboratory tests (complete blood counts, complete metabolic panels) and electrocardiograms will 
be conducted using MUSC’s clinical laboratories with test results entered into the participant’s electronic 
medical record.   
 
12.0 
DATA MANAGEMENT 
12.1 Data Analysis Plan 
Baseline demographic characteristics will be collected and descriptive statistics will be used to 
characterize participants. Data will be collected and managed using the secure REDCap (Research 
Electronic Data Capture) database.  Descriptive statistics for primary outcomes will include 1) the 
percentage of individuals completing informed consent out of the number of individuals eligible on the 

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initial screening and 2) the percentage of individuals that complete informed consent which complete the 
full protocol.  Other descriptive statistics for the sample population will be analyzed, and baseline 
characteristics that are found to be significantly associated with other outcome measures will be included 
as covariates. Spaghetti plots will be produced to guide modeling outcomes as a function of time. All 
analyses will be conducted based on intention to treat.  Subjects assigned to Group B (placebo) who 
complete Study Wk4 (at which time main outcomes are assessed), may choose to receive 8 ketamine 
treatments before completing follow-up visits.  To preserve study blinding, subjects who are among the 
final 6 subjects being enrolled will not be unblinded until primary outcomes are assessed for all 30 
subjects. 
12.2 Hypotheses for Analyses 
Feasibility Hypothesis: From the cohort of individuals completing the initial prescreening 
assessment, a 75% study enrollment rate will be deemed feasible.  Therefore, we 
anticipate that 40 individuals will be needed to complete prescreening so that 30 
participants will enroll in the study.  Of the individuals enrolling in the study, we anticipate 
60% of participants will complete the study protocol.   Completion is defined for the study 
purposes as completing at least 75% of the study visits. 
Hypothesis 1: Ketamine will result in significantly greater reduction in depression 
symptoms as compared to placebo at one-month.  To test this hypothesis, we will employ 
repeated measures ANOVA using linear mixed models approach to assess reduction on 
the total score of the MADRS.  
Hypothesis 2: Ketamine will result in significantly greater reduction in frequency of opioid 
use as compared to placebo at one-month. To test this hypothesis, we will treat the percent 
days using opioids (TLFB) as a continuous variable and analyze using linear mixed 
models approach. Abstinence at one-week (on UDS) will be compared by intervention 
groups using logistical regression analyses.  An arcsine square root or logit transformation 
may be considered to stabilize variance of the proportions. 
Hypothesis 3: Response to ketamine will be influenced by changes in motivation to quit 
(URICA) and qualities of psychoactive perceptual experience (HMS).  To test this 
hypothesis, we will employ repeated measures ANOVA using linear mixed models 
approach. 
 
Alternate Approaches: Diagnostics of the residuals will be performed to test the 
assumptions of the analysis.  If the assumptions are found to be inadequate, alternative 
methods of analysis (e.g. ordinal logistic regression or Poisson regression) will be 
considered.   
 
The primary dependent variables in all three analyses will be intervention group (ketamine or placebo), 
time (number of days), and the interaction between the two.  Main hypothesis of interest will be the 
interaction and the post-hoc comparison at the one month after the first intervention.  We anticipate the 
study population to include participants that are currently on antidepressants as well as those that are not.  
We considered stratifiying randomization by this variable, however since the proporption of participants 
on antidepressants at baseline is expected to be small, this will be considered as an independent variable 
in the statistical analysis.  To account for within subject correlations, several structures, such as spatial 
autocorrelation (to accommodate unequal time points), and AR(1) symmetry, will be examined.  
Diagnostics will be performed to test the assumptions of normality and if found inadequate, appropriate 
transformations will be considered.  An arcsine square root transformation may be considered to stabilize 
variance of the proportions.  In all of the analyses, covariates will be considered to examine mediations.   
In a secondary analysis based on the spaghetti plots, we will consider linear and non-linear models of 
outcomes as a function of time.  Specifically, over the 8-week follow-up period, we will examine if there 
exists a threshold point in time where the effect of ketamine plateaus.  To achieve this, treating the joint-
point as unknown, we will fit segmented regression models using non-linear mixed models.   
12.3 Justification of Sample Size 

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For a 75% anticipated enrollment rate from the initial prescreened sample of 40 individuals, feasibility can 
be estimated within a margin of error of 14% with 95% confidence.  Similarly, assuming a 60% rate of 
study enrollment of eligible participants, with a sample size of 30 we can estimate feasibility within a 17% 
margin of error with a 95% confidence interval.  This study is powered to estimate the effects of ketamine 
on significant reduction in MADRS symptoms at the end of one month (see Hypothesis 1).  Over the 
course of a two-year study, we estimate that we will be able to recruit 15 patients in each of the two 
intervention arms (2/month over 15 months).  At 80% power, this sample size will allow us to detect a 
minimum difference in MADRS scores of 14.4 at one month between the ketamine and the placebo groups 
in a study design with 7 repeated measurements having a AR(1) correlation of 0.9, and a standard 
deviation of 15.8, with a significance level of 0.050 (Singh et al., 2016; Niciu et al., 2014).  While we will 
examine changes in depression severity as a continuous variable, we will also examine other clinically 
accepted changes in depression severity such as response (defined as a 50% reduction in symptom 
severity from baseline) and remission (defined as below the threshold for mild depression which is a score 
of 6 on the MADRS).  Baseline averages for the MADRS scores for this population will be assumed to be 
34 (Niciu et al., 2014; Han et al., 2016; Singh et al., 2016).  The minimum difference in MADRS of 14.4 is 
anticipated to be approximately 50% of the baseline measurements.  Although there is limited information 
on the effectiveness of ketamine in the treatment of addiction, a sample of 30 subjects (15 in each arm) 
will provide adequate power to detect an 22% difference between the two groups in the percent of days 
abstinent from opioid use using the same longitudinal design as described above with 7 time points 
(Hypothesis 2).  For this calculation, we assumed an AR(1) correlation of 0.9 and a standard deviation of 
25% at a significance level of 0.05; an arcsine transformation was used for variance stabilization.  Over 
the 8-week follow-up period, we will examine if there exists a threshold point in time where the effect of 
ketamine plateaus.  To achieve this, we will use a segmented regression analysis using non-linear mixed 
models.  We will take all efforts to keep dropouts to a minimum. However, our past experience suggests 
the rates of dropout are up to 20%. This could reduce the sample size per group to 12 and 12. The 
corresponding differences we could detect would be a minimum MADRS score difference of 16.1 and a 
26% difference between groups in terms of the percent of days abstinent from opioid use.  No interim 
analyses are planned. 
12.4 Data Confidentiality Procedures 
We will take rigorous precautions to maintain confidentiality for all participants, using procedures that the 
PI and her mentors have successfully employed in similar previous, as well as ongoing related studies.  
All study data related to mental health outcomes (i.e., the participant responses to questionnaires) and 
demographics will not have any unique identifying data attached.  There will be only one master list of 
participants (not linked to participant responses).  This list will be kept locked separate from other data 
and will be available only to the PI, her mentors, and approved study personnel.  All data will be 
confidentially stored (i.e., in locked files or on encrypted servers) so as to protect the confidentiality of 
participant information. Access to research records (paper and computerized) will be restricted to the 
project staff, and to sponsor audit personnel and MUSC IRB auditors when indicated.  All study personnel 
have completed (or will complete upon hiring) a certified program of instruction in the protection of human 
subjects in research, such as the University of Miami CITI course.  These courses in the responsible 
conduct of research and the protection of human subjects will be completed on an annual basis, in 
compliance with MUSC regulations. 
12.5 Data Quality Control Procedures 
Data quality will be monitored by random inspection of the completed forms by the study team and any 
irregularities or problems detected will be discussed with the PI. At its discretion, the Sponsor or its 
designee may conduct a quality assurance audit of this study. Auditing procedures of the Sponsor and/or 
its designee will be followed in order to comply with GCP guidelines and ensure acceptability of the study 
data for registration purposes. If such an audit occurs, the Investigator will give the auditor direct access 
to all relevant documents, and will allocate his/her time and the time of his/her staff to the auditor as may 
be required to discuss findings and any relevant issues. 
12.6 Study Documentation and Data Handling 

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Any clinical study event that is judged to be an AE will be recorded on the AE form during the course of 
the study. The PI and/or trained Research Assistant will ensure this information is captured during every 
study visit.  Whenever a study participant has reported an AE, the study coordinator will discuss the event 
immediately with the PI (if possible while the study participant is there) who will evaluate the event.  If the 
AE is not serious, the information will be recorded, managed medically as appropriate, and the event will 
be followed until resolution. SAEs will also be recorded on the AE Form, managed medically as 
appropriate, and the event is followed until resolution.  In addition, the PI will review all completed AE 
forms for determination of SAE that require reports to the Sponsor. The PI will inform the Sponsor 
immediately of knowledge of a SAE.  All information available on the event (hospital records, lab tests, 
discharge summaries, etc.) will be forwarded to the Sponsor so they can determine whether the SAE is 
unexpected or associated and the reporting outcome of the SAE.  As additional information becomes 
available on the SAE, it will be forwarded to the Sponsor.  All SAE reports will be sent to the MUSC IRB 
within 24 hours of learning of event occurrence. 
 
AEs/SAEs will be documented and reported as per IRB requirements. Research staff will identify AEs and 
obtain all available information to assess severity, seriousness, study relatedness, expectedness, 
outcome and the need for change or discontinuation in the study intervention.  Adverse events will be 
documented on AE Logs and additional relevant AE information, if available, will be documented in a 
progress note in the research record as appropriate to allow monitoring and evaluating of the AE. If the 
AE meets the definition for Serious, appropriate SAE protocol specific reporting forms will be completed 
and disseminated to the appropriate persons and within the designated timeframes as indicated above. 
For each AE/SAE recorded, the research staff will follow the AE/SAE until resolution, stabilization or until 
the participant is no longer in the study.  When a reportable SAE is identified, the research assistant will 
initiate an SAE form, and the following individuals will be notified within 24 hours of the site’s initial 
notification of the SAE:   
1. 
The PI (Dr. Jones) will provide oversight, consultation, assessment and 
documentation as appropriate of the SAE.    
2. 
The research staff will notify the MUSC IRB, and complete the AE report form in 
conjunction with the PI.  Both committees meet monthly.  Communication with the MUSC 
IRB is through email, memos, official IRB forms, and online reporting. 
3. 
The data safety monitoring board members. 
 
 
If complete information is not available when the initial 24-hour SAE report is disseminated, follow-
up information will be gathered to enable a complete assessment and outcome of the event.  This 
information may include hospital discharge records, autopsy reports, clinic records, etc.  The research 
staff will attach copies of source documents to the SAE report for the PI and for forwarding to the sponsor 
as appropriate.  All deaths that occur during the study or 30 days post termination from the study are 
required to be reported as adverse events even if they are expected or unrelated.  Other adverse events 
are reportable to the MUSC IRB if the AE is unexpected AND related or possibly related AND serious or 
more prevalent than expected.  All three criteria must be met for an AE to be reported to the MUSC IRB.  
The IRB definition of unexpected is that the AE is not identified in nature, severity or frequency in the 
current protocol, informed consent, investigator brochure or with other current risk information.  The 
definition of related is that there is a reasonable possibility that the adverse event may have been caused 
by the drug, device or intervention.   
12.7 Privacy Protection and Confidentiality Assurances 
While absolute confidentiality cannot be guaranteed, every possible effort will be made to protect the 
privacy of study participants, and all of the investigators have an excellent history of maintaining patient 
privacy and data security.  Participants will be provided with a written informed consent document which 
specifies the risks and confidentiality protections and limits of study procedures.  Subject names will 
remain confidential and all study data related to outcomes (i.e., the participant responses to 
questionnaires) and demographics will not have any unique identifying data attached in any way. There 
will be only one master list of participants (again, not linked to any participant responses) which will be 

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kept locked separate from all data and will be available only to the PI, Co-Is and approved study personnel.  
All data will be stored in a confidential manner (i.e., in locked files or on encrypted computers) so as to 
protect the confidentiality of participant information. Access to research records (paper and computerized) 
will be restricted to the project staff.  Access to de-identified study data will be limited to named project 
investigators, sponsor audit personnel, and MUSC IRB auditors. 
12.8 Data Sharing 
The data collected from study participants, including PHI, will be entered into and securely stored in the 
database on a secure server by a member of the research study team.  Electronic data will be stored, 
managed, and analyzed by the study PI and her statistical advisor.  
 
13.0 
PROVISIONS TO MONITOR THE DATA TO ENSURE THE SAFETY OF SUBJECTS  
Ongoing Clinical Monitoring: The research team will closely monitor for any increase in substance use or 
psychiatric distress at every study intervention visit.  Subjects with clinically significant worsening of 
depression (i.e. development of suicidal ideation) or worsening of opioid use will be immediately referred 
for a higher level of treatment, and the DSMB will alerted within 48 hours to review trial safety.  Mental 
health symptoms will be monitored using standardized measures at each visit in order to detect any 
worsening symptoms.  Additionally, participants will be advised to observe any signs of worsening 
substance use or depression symptoms, and to discuss these with the research team.  All participants will 
be informed at the initial visit that they may terminate participation at any point.  If a participant experiences 
distress or other problems between visits, he or she will be encouraged to Dr. Jones or his/her outpatient 
mental health provider.  If a participant needs or desires immediate attention, arrangements will be made 
for an appointment with an experienced mental health provider.  The informed consent document will 
provide direction to contact the study staff during office hours and/or go to the Emergency Room at any 
time for worsening of symptoms.  In addition, participants will have access to urgent care services at 
MUSC.  If any of the research personnel believes that a participant is medically or psychiatrically 
compromised by participation, the PI will be notified and will contact the participant immediately to assess 
concerns and assure participant safety.  The PI will attempt to address all participant concerns and will 
set up an alternate referral for counseling for those who desire it from outside the project.  All participants 
will review, at the initiation of participation, an informed consent document which specifically reviews 
potential psychological distress as a potential outcome of participation.  If necessary, the participant will 
be asked to complete a safety plan and to call the project staff, a national hotline, or 911.  The Mobile 
Crisis unit of Charleston County, which involves a team of police and psychiatric workers, or the EMS unit 
may be dispatched to the participant’s home to assure safety.  The investigative team has a long history 
of ensuring participant safety using similar methods in these populations. 
 
Pre-Intervention Assessment: A comprehensive exam will be conducted as part of the baseline 
assessment to minimize risks from study participation.  This will include assessment of depression 
severity, and participants at highest risk for suicidality will be excluded.  Participants will also be required 
to be in buprenorphine treatment for at least a one month period prior to study participation.  The 
comprehensive exam will also include a history and physical exam by the study PI (pulse oximetry 
measurements will be a component of the respiratory evaluation), baseline medication evaluation for 
potential harmful interactions, and electrocardiogram to ensure safe study participation.   
 
Peri-Intervention Monitoring: Subjects will be continuously medically and psychiatrically monitored 
throughout the course of the intervention and for a minimum of two hours after (or until any distress or 
dissociative symptoms reach clinically insignificant levels, and blood pressure returns to within 20% of 
their baseline values).  Subjects will be instructed not to eat for at least 2 hours before taking the 
intervention sessions and not drink liquids at least 30 minutes after the intervention sessions to reduce 
the risk of nausea and vomiting.  Emergency services will be immediately and continuously available on 
MUSC premises in the event of any medical complications.  Subjects will not be allowed to drive 
themselves after the interventional visits, and alternative transportation will be arranged if needed. 
 
14.0 
WITHDRAWAL OF SUBJECTS 

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All potential participants will be thoroughly screened for eligibility after completing informed consent.  The 
PI may withdraw subjects from participation at any time if the participant demonstrates or reports 
significant distress, is felt to be at risk of harm to themselves or to others, or is otherwise unable to 
complete the study protocol.  Referrals to university and community resources will be made as indicated 
for all participants withdrawn from the study.  The trial will be stopped under any of the following conditions: 
1) there is clear evidence of harm; 2) there is no likelihood of the intervention demonstrating benefit, or 3) 
there is overwhelming evidence of the benefit of the intervention. 
 
15.0 
RISKS TO SUBJECTS 
15.1 Overview 
All medications have potential side effects. Ketamine has been well studied since its FDA approvals in 
1970.  Based on extensive prior research with intravenous ketamine in the treatment of depression, the 
prevalence of the most commonly observed adverse reactions are estimated below by category.  
Participants will be informed of all potential side effects associated with ketamine before study 
participation, and will be closely monitored both during the treatment and at each follow-up visit.   
15.2 Physical Risks 
The most clinically significant physical adverse event from ketamine is a transient increase in blood 
pressure, which in previous studies was experienced by 29.8% of participants with a mean systolic blood 
pressure increase of 19.6 mmHg +/- 12.8 mmHg (p<0.001) and a mean diastolic blood pressure increase 
of 13.4 mmHg +/-  9.8 mmHg (p<0.001) with peak levels reached on average at 40 minutes post-
treatment and resolving by 240 minutes post-treatment (Wan et al., 2015). Participants experiencing 
clinically significant hypertension (greater than 180 mmHg SBP or greater than 105 mmHg DBP) will be 
treated with standard of care hypertensives (e.g. clonidine) and monitored until symptom resolution.    
 
The most prevalent physical adverse effect was an increase in sedation (level of alertness) and is 
estimated based on previous studies to occur in approximately 16% of patients receiving ketamine.  
Sedation will be monitored using the Modified Observer Alertness/Sedation Scale (MOAA/S) at baseline, 
40 minutes and 1.5 hours post medication administration.  While ketamine is not associated with 
respiratory depression, continuous pulse oximetry will be monitored for a minimum of 1.5 hours post 
medication administration, or until resolution of sedation.  A medical emergency team will be called for 
participants that are unable to be aroused with painful trapezius squeeze (MOAA/S score of 0) or that 
experience hypoxia (i.e. a pulse oximeter reading of 92% or less).  Due to cognitive impairment 
associated with this transient increase in sedation, participants will not be allowed to drive themselves 
following the interventions, and will be advised not to operate heavy machinery for at least 24 hours after 
the interventions.  
 
There are also the standard risks associated with intramuscular injections.  These include temporary local 
pain, irritation, or redness at the site of the injection.  There is a very small (<1%) risk of infection, muscle 
fibrosis, or persistent muscle or nerve damage at the site of injection.   
15.3 Psychological Risks 
The most clinically significant risks of ketamine in previous clinical trials include dissociation (including 
derealization and depersonalization) and perceptual changes (e.g. distortion of time and space, sense of 
illusions).  These effects are estimated based on prior studies to occur in 42% of subjects receiving 
ketamine.  Anxiety is estimated to occur in 15% of subjects receiving ketamine.  Psychological distress 
will be minimized with pre-treatment relaxation exercises and psychological reassurance as needed.  
Psychological distress will be minimized with pre-intervention relaxation exercises and psychological 
reassurance as needed.  In prior trials with ketamine for depression, these measures are sufficient to 
manage dissociation and anxiety in the overwhelming majority of participants.  However, standard of care 
medications for agitation associated with delirium or psychotic symptoms (e.g. lorazepam) will be 
available in the event that participants develop severe anxiety psychological distress lasting longer than 
thirty minutes.  Psychiatric hospitalization will be arranged if needed, in the unlikely event of severe or 
prolonged psychiatric symptoms (e.g. lasting greater than four hours or the business day).  Participants 

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may also have emotional distress from answering the questionnaires, although this is mild in the 
investigators’ experience with these instruments.   
15.4 Abuse Liability 
Ketamine is a psychoactive substance, and consequently has abuse liability.  Ketamine is classified as 
Schedule III controlled substances (CIII).  While there have been no randomized controlled trials 
evaluating the risk of subsequent illicit or recreational use of ketamine following medical administration 
(either for induction of sedation in conjunction with general anesthesia or in monitored off-label use for 
depression or pain management), in the extensive sub-anesthetic trials of ketamine for depression, there 
have been no published reports of illicit use developing after initial medical treatment with ketamine.  
None of the previous studies using ketamine in the treatment of substance use disorders reported illicit 
ketamine use following the ketamine interventions (Jones et al., 2018).  While national statistics on 
ketamine are not collected, overall use prevalence rates for the entire hallucinogen classification (which 
includes ketamine) are estimated at 0.3% (Center for Behavioral Health Statistics and Quality, 2018).  
Animal models using intracranial self-stimulation have demonstrated that ketamine fails to progress to 
self-administration, also suggesting a lack of abuse liability (Hillhouse et. al., 2014).  Globally, the World 
Health Organization (WHO) evaluates the overall risks and abuse liability of ketamine; in their most recent 
report, the WHO affirmed that ketamine does not pose a global health risk, and again recommended its 
continued use (WHO, 2015).  Substance use will be assessed at each visit throughout the study, and 
participants will be referred for ongoing care if they develop worsening substance use.  If participants 
report illicit use of ketamine between intervention sessions, they will be withdrawn and referred for 
substance abuse treatment.   
15.5 Social Risks: Adverse social consequences may arise if the participants’ medical history or 
psychiatric history (including substance use history as well as psychiatric comorbidities) are inadvertently 
communicated to others.   
15.6 Legal Risks: Legal risks may arise if individuals are homicidal or suicidal and make these intentions 
known to the PI project staff, who may then be required to notify authorities and the target of homicidal 
intent.  There is also a legal and physical risk if participants were to drive or operate heavy machinery 
while cognitively impaired (which may occur if they use opioids or as a result of the intervention). 
15.7 Economic Risks: Subjects will be compensated for study participation as well as for any medical 
care related to study-related injuries. 
15.8 Other Risks: While every possible effort will be made to protect the privacy of study participants, 
there is a risk of loss of confidentiality.  There is also a risk of being randomized to the placebo 
intervention as opposed to the ketamine.  There may also be unknown risks associated with the study 
procedure or intervention. 
 
 
16.0 
POTENTIAL BENEFITS TO SUBJECTS OR OTHERS 
16.1 Potential Benefits to Subjects 
Potential benefits of participation in this study may include a reduction in OUD and depression symptoms.  
Participants may also gain diagnostic information about their medical or psychiatric comorbidities, 
although this is not guaranteed.  Overall, there is no guarantee or promise that participants will receive 
any benefit from participation in this study.   
16.2 Justification of Risks 
The potential benefits of the knowledge to be gained from the proposed study are considerable. This study 
proposes to test intamuscular ketamine in the treatment of co-occurring OUD and MDD among 
participants. The plans for monitoring risk as described above warrant the conduct of this study for the 
knowledge that may reasonably be expected to result.  
 
17.0 
SHARING OF RESULTS WITH SUBJECTS 
The data collected from study participants, including PHI, will be entered into and securely stored in the 
database on a secure server by a member of the research study team.  Electronic data will be stored, 

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managed, and analyzed by the study PI and a statistical mentor advisor.  Individual baseline data may 
be released to participants on request for their subsequent medical use or disclosure.  
18.0 
DRUGS OR DEVICES  
The IND application for ketamine’s use in this study will be submitted by Dr. Jones for FDA review.   
Medication and placebo will be stored in lock boxes on the MUSC campus and be administered by the 
participant under the direct supervision of the PI.   
 
19.0 
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