Ketamine-assisted Psychotherapy for the Treatment of Persistent Depression in Abstinent Opioid Users
Phase: PHASE2
Conditions: Opioid Use Disorder, Severe, in Sustained Remission, Opioid Use Disorder, Severe, in Early Remission, Major Depressive Disorder
Sponsor: Medical University of South Carolina

PROTOCOL TITLE: Ketamine-assisted psychotherapy for the treatment of persistent depression in 
abstinent opioid users 
 
NCT Number: Pro00115696 
 
Document date: August 18, 2022 
 
PRINCIPAL INVESTIGATOR:  
Eric T. Dobson, M.D. 
 
 
 
 
 

PROTOCOL TITLE: Ketamine-assisted psychotherapy for the treatment of persistent depression 
in abstinent opioid users 
 
Version Date: August 18, 2022 
 
Page 2 of 23 
 
 
 
 
 
TABLE OF CONTENTS 
1. OBJECTIVES/SPECIFIC AIMS ………………………………………………………………………. 4 
1.1. 
Introduction and Context 
1.2. 
Current Treatment 
1.3. 
Purpose and Objectives of the Study 
1.4. 
Specific Aims 
2. BACKGROUND ………………………………………………………………………………………… 6 
2.1. 
Role of Depression in Maintaining Abstinence From Opioids 
2.2. 
Glutamatergic Dysregulation Contributes to Both Depression and Addiction Pathology 
2.3. 
Clinical Trials for Depression Treatment 
2.4. 
Clinical Trials for Substance Use Disorder Treatment 
2.5. 
Novelty and Importance of the Current Study 
3. INTERVENTION TO BE STUDIED …………………………………………………………………... 7 
3.1. 
Overview of Study Medication 
3.2. 
Safety and Toxicity 
3.3. 
Study Drug, Dose, Mode of Administration and Justification 
4. STUDY ENDPOINTS …………………………………………………………………………………... 8 
4.1. 
Primary Outcomes 
4.2. 
Secondary Outcomes 
5. INCLUSION AND EXCLUSION CRITERIA/STUDY POPULATION ……………………………... 9 
5.1. 
Initial Screening Methodology 
5.2. 
Inclusion Criteria 
5.3. 
Exclusion Criteria 
5.4. 
Number of Subjects 
5.5. 
Setting 
5.6. 
Recruitment Methods 
6. CONSENT PROCESS ……………………………………………………………………………….   10 
6.1. 
Qualifications of Study Personnel Obtaining Informed Consent and Capacity of 
Participants 
6.2. 
Location of Informed Consent 
6.3. 
Method of Obtaining Consent 
6.4. 
Capacity of Participants to Give Informed Consent 
7. STUDY DESIGN/METHODS ………………………………………………………………………… 11 
7.1. 
Study Overview 
7.2. 
Duration of Treatment and Study 
7.3. 
Description of Assessments 
7.4. 
Schedule of Assessments 
7.5. 
Baseline Assessment Procedures 
7.6. 
Treatment Visit Procedures 
8. DATA MANAGEMENT ………………………………………………….…………………………… 13 
8.1. 
Data Analysis Plan 
8.2. 
Data Confidentiality Procedures 
8.3. 
Data Quality Control Procedures 
8.4. 
Study Documentation and Data Handling 
8.5. 
Privacy Protection and Confidentiality Assurances  
8.6. 
Data Sharing 

PROTOCOL TITLE: Ketamine-assisted psychotherapy for the treatment of persistent depression 
in abstinent opioid users 
 
Version Date: August 18, 2022 
 
Page 3 of 23 
 
 
 
 
 
9. PROVISIONS TO MONITOR THE DATA TO ENSURE THE SAFETY OF SUBJECTS …….. 15 
10. WITHDRAWAL OF SUBJECTS ……………….……………………………………………………. 15 
11. RISKS TO SUBJECTS…………………………. . .…………………………………………………. 16 
11.1. Overview 
11.2. Physical Risks 
11.3. Psychological Risks 
11.4. Abuse Liability  
11.5. Social Risks 
11.6. Legal Risks 
11.7. Economic Risks 
11.8. Unforeseeable Risks 
12. POTENTIAL BENEFITS TO SUBJECTS OR OTHERS ……………….………………………… 17 
16.1. Potential Benefits to Subjects 
16.2. Justification of Risks 
13. SHARING OF RESULTS WITH SUBJECTS ……………………….……………………………... 17 
14. DRUGS OR DEVICES ……………………………………..………….……………………………... 17 
14.1. Preparation, Handling and Storage of Study Medication 
14.2. Investigational New Drug (IND) Data 
15. REFERENCES ……………….……………………………………………………………………….. 17 
 
 

PROTOCOL TITLE: Ketamine-assisted psychotherapy for the treatment of persistent depression 
in abstinent opioid users 
 
Version Date: August 18, 2022 
 
Page 4 of 23 
 
 
 
 
 
1.0 OBJECTIVES/SPECIFIC AIMS 
1.1 Introduction and Context 
 
Depression is common in patients with opioid use disorder (OUD). In patients seeking buprenorphine-
naloxone treatment for OUD, about 1 in 4 have concurrent major depressive disorder (MDD) (Savant et 
al., 2013). Similarly, about one third to one half of patients enrolled in methadone maintenance treatment 
(MMT) are depressed (Peles, Schreiber, Naumovsky, & Adelson, 2007; Zhang et al., 2016). 
Unfortunately, depression occurs independent of MMT treatment duration suggesting that stabilization of 
OUD alone is not sufficient to improve mood symptoms (Peles et al., 2007). 
 
The relationship between OUD and depression is complex and bidirectional. Depressed patients who 
initiate opioid therapy are more likely to transition to long-term high-dose therapy and are at higher risk 
of opioid abuse or non-medical use (Sullivan, 2018). Conversely, chronic opioid use can cause 
neurobiological changes increasing negative affective states leading to higher suicide risk and continued 
opioid use (Rizk, Herzog, Dugad, & Stanley, 2021). Given this interdependence, concurrent treatment of 
both mood and opioid use disorder symptoms is paramount to prevent destabilization of either disorder 
(Vekaria et al., 2021).  
 
1.2 Current Treatment 
 
Current literature is limited regarding the treatment of depressed patients with OUD despite desire for 
positive mood being the most commonly cited reason for relapse in patients with OUD (Kadam, Sinha, 
Nimkar, Matcheswalla, & De Sousa, 2017; Unnithan, Gossop, & Strang, 1992).  A large, randomized 
placebo-controlled trial of imipramine in depressed patients receiving MMT showed promising results 
with 57% of imipramine-treated patients considered “responders” per clinical global impression compared 
with 7% of placebo-treated patients. Unfortunately, drop-out was common with only 84 of 137 patients 
completing an adequate 6 week trial (Nunes et al., 1998). Contrastingly, an RCT involving buprenorphine 
+ desipramine vs buprenorphine + placebo vs methadone + desipramine vs methadone + placebo failed 
to show efficacy of desipramine over placebo in 164 opioid- and cocaine-dependent patients. 
Concerningly, patients receiving buprenorphine + desipramine more frequently had urine drug screens 
positive for opioids than those receiving buprenorphine + placebo (Kosten, Falcioni, Oliveto, & Feingold, 
2004).  
 
Selective serotonin reuptake inhibitors (SSRIs), the first line treatment in patients with moderate-to-
severe MDD have a mixed-to-negative evidence base in co-occurring MDD and OUD (Carpenter, Brooks, 
Vosburg, & Nunes, 2004; Petrakis et al., 1998). Regarding the treatment of depression in patients on 
opioid agonist therapy, a 2010 Cochrane review found there is “low evidence supporting the clinical use 
of antidepressants to treat depression in opioid dependence”, while also noting that current literature is 
limited  (Pani, Vacca, Trogu, Amato, & Davoli, 2010). This finding was further supported by a subsequent 
meta-analysis examining antidepressant use in patients engaged with MMT (Pedrelli et al., 2011). Given 
the prevalence of depression in patient with OUD regardless of stage of recovery and ineffectiveness of 
current interventions, more effective treatments for depression in OUD are critically needed. 
1.3 Purpose and Objectives of the Study 
The primary objective of the proposed study is to preliminarily explore the feasibility, efficacy, and 
tolerability of ketamine-assisted psychotherapy in treatment of MDD in patient with OUD currently in early 
or sustained remission by DSM-V criteria. We seek to enroll 10 individuals with current moderate-to-
severe major depression despite ongoing abstinence from opioids.  
1.4 Specific Aims 
To achieve these objectives, the following Specific Aims are proposed: 

PROTOCOL TITLE: Ketamine-assisted psychotherapy for the treatment of persistent depression 
in abstinent opioid users 
 
Version Date: August 18, 2022 
 
Page 5 of 23 
 
 
 
 
 
Specific Aim 1: To preliminarily explore the efficacy of ketamine-assisted psychotherapy 
in reducing symptoms of depression using the Montgomery Asberg Depression Rating 
Scale (MADRS). 
Specific Aim 2: To preliminarily explore the tolerability of ketamine-assisted 
psychotherapy in treatment of depression including adverse effects, cravings and relapse 
 
 
 

PROTOCOL TITLE: Ketamine-assisted psychotherapy for the treatment of persistent depression 
in abstinent opioid users 
 
Version Date: August 18, 2022 
 
Page 6 of 23 
 
 
 
 
 
2.0 BACKGROUND 
 
2.1 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 frequently seen comorbidity in OUD in all stages of treatment and recovery. Nearly two out of three 
persons entering treatment for opioid detoxification screen positive for depression (Brienza et al., 2000; 
Stein, Santiago Rivera, Anderson, & Bailey, 2017; Volkow, 2004). In patients seeking buprenorphine-
naloxone treatment for OUD, about 1 in 4 have concurrent major depressive disorder (MDD) (Savant et 
al., 2013). Similarly, about one third to one half of patients enrolled in methadone maintenance treatment 
(MMT) are depressed (Peles et al., 2007; Zhang et al., 2016). Unfortunately, depression occurs 
independent of MMT duration suggesting that stabilization of OUD alone is not sufficient to improve mood 
symptoms (Peles et al., 2007) and desire for improvement in mood is the most commonly cited reason 
for relapse in OUD following initial addictions treatment (Huhn et al., 2019; Kadam et al., 2017; Volkow, 
Jones, Einstein, & Wargo, 2019). In addition to contributing to relapse and being a risk for unintentional 
overdose, OUD is an independent risk factor for completed suicide. 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. Furthermore, in 
women, OUD was associated with the highest hazard ratio for suicide of any substance of abuse at 2.33 
(Bohnert, Ilgen, Louzon, McCarthy, & Katz, 2017). 
 
2.2 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). Similarly, depression has been shown to have aberrant glutamate signaling 
(Murrough, Abdallah, & Mathew, 2017; Niciu et al., 2014). On a cellular level, astrocytes are responsible 
for maintaining glutamate homeostasis (Parpura & Verkhratsky, 2012) and both depression and addiction 
have been linked to impaired ability of astrocytes to upregulate glutamate (Rajkowska & Stockmeier, 
2013; Scofield & Kalivas, 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.  
 
2.3 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. 
 
2.4 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-

PROTOCOL TITLE: Ketamine-assisted psychotherapy for the treatment of persistent depression 
in abstinent opioid users 
 
Version Date: August 18, 2022 
 
Page 7 of 23 
 
 
 
 
 
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 (E. 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% (Evgeny M Krupitsky et al., 2007). Related studies found that ketamine is 
useful as an adjunct to psychotherapy in the treatment of alcohol use disorder (E M Krupitsky & Grinenko, 
1997) with 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. 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 
(Elias Dakwar, Levin, Foltin, Nunes, & Hart, 2014) and reduce rates of cocaine self-administration by 
67% relative to baseline (E Dakwar, Hart, Levin, Nunes, & Foltin, 2017; E Dakwar et al., 2018). 
Additionally, a single dose of ketamine combined with motivational enhancement therapy has been 
shown to increase abstinence and increase time to relapse in subjects with alcohol use disorder (Elias 
Dakwar et al., 2020) while a single dose of ketamine combined with mindfulness-based relapse 
prevention has yielded similar results in subjects with cocaine dependence (Elias Dakwar et al., 2019). 
Finally, ketamine combined with motivational enhancement therapy and mindfulness-based relapse 
prevention has shown promising open-label evidence for the treatment of cannabis use disorder (Azhari 
et al., 2021). 
 
2.5 Novelty and Importance of the Current Study 
Past  studies have shown promising results for ketamine in the rapid treatment of MDD (Han et al., 2016) 
particularly in those with a family history of substance use (Niciu et al., 2014), however no prior studies 
have investigated the efficacy of ketamine-assisted psychotherapy in the treatment of depressed 
participants with OUD currently in early or sustained remission. 
  
 
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, 2021).  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, 2021).   
 
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, 2021).  Repeated, daily intravenous injections have been studied in rats, and 
dogs for as long as 6 weeks with excellent tolerability (Ketalar, 2021). Similarly, twice weekly treatments 
in monkeys over a four- to six-week period were well tolerated (Ketalar, 2021).  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. The average 

PROTOCOL TITLE: Ketamine-assisted psychotherapy for the treatment of persistent depression 
in abstinent opioid users 
 
Version Date: August 18, 2022 
 
Page 8 of 23 
 
 
 
 
 
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 100 mg/ ml and will be administered by intramuscular administration 
in the amount of 0.5 mg/kg with plan to flexibly titrate by 0.25 mg/kg each session based on tolerability to 
a maximum weight-based dose of 1.5 mg/kg. Total dose on a given day will be limited to 60 mg regardless 
of subject’s weight. 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.  Recent studies 
have shown that intramuscular ketamine may be as effective as intravenous ketamine for depression and 
may be more practical clinically (Chilukuri et al., 2014; Xu et al., 2016). 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, Mateus, 
Malcolm, Brady, & Back, 2018). When given intramuscularly, ketamine has a peak time of 5-30 minutes 
following injection and a bioavailability of 86-97% (Grant, Nimmo, & Clements, 1981). Of note, ketamine 
elimination clearance is high with a half-life of 2-3 hours and clearance in women that is up to 20% higher 
than men (Mion & Villevieille, 2013). 
 
4.0 STUDY ENDPOINTS  
 
4.1 Primary Outcome 
 
Montgomery Asberg Depression Rating Scale (MADRS; (Montgomery & Asberg, 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 craving 
for opioids (Visual Analog Scale) and related areas of psychiatric functioning. 
 
• Beck Depression Inventory (BDI-II; Beck, Steer, & Brown, 1996). A widely used 21-item self-
report measure of depressive symptoms. 
• Visual Analog Craving Scale (VAS; McMillan & Gilmore-Thomas, 1996). At baseline, during 
the interventional visits, and at each follow-up visit, subjects 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.  
• Timeline Follow-Back (TLFB; Linda C. 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 

PROTOCOL TITLE: Ketamine-assisted psychotherapy for the treatment of persistent depression 
in abstinent opioid users 
 
Version Date: August 18, 2022 
 
Page 9 of 23 
 
 
 
 
 
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.   
• Generalized Anxiety Disorder Screener (GAD-7; Spitzer, Kroenke, Williams, & Löwe, 
2006)). The GAD-7 is a 7-item self report instrument that will assess generalized anxiety 
symptomology.  
• Five Facets of Mindfulness Questionnaire (FFMQ; Baer, Smith, Hopkins, Krietemeyer, & 
Toney, 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; Blevins, Weathers, Davis, Witte, & Domino, 2015): 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, Belleville, Bélanger, & Ivers, 2011). 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 & Ryan, 1994). 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.  
• Mystical Experience Questionnaire (MEQ). This 30-item self-report questionnaire was 
developed and validated through factor analysis of retrospective accounts of profound 
experience with psilocybin-containing mushrooms. It includes four factors: transcendence 
of time and space, ineffability, positive mood and mystical (internal unity, external unity, 
noetic quality, and sacredness)  (Barrett, Johnson, & Griffiths, 2015; Maclean, Leoutsakos, 
Johnson, & Griffiths, 2012). 
   
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.  Subjects with a self-
reported history of depression and opioid misuse or illicit opioid use for which they report being abstinent 
for at least 3 months (early remission) will be eligible to complete informed consent and baseline 
evaluation. 
 
5.2 Inclusion Criteria 
A subject may be eligible for enrollment if all the following inclusion criteria apply within the thirty days 
prior to first experimental session: 
1. 
Between the ages of 18 to 64 years old.  
2. 
Able to provide informed consent.  
3. 
Meet DSM-5 criteria for Major Depressive Disorder, without psychotic features based on 
clinical interview. 
4. 
Score at least 20 on the Montgomery-Asberg Depression Rating Scale (MADRS, moderate 
or severe depression).  
5. 
Must meet criteria for opioid use disorder in early or sustained remission (3 months or great) 
by DSM-5 based on clinical interview. 
6. 
Subjects taking other psychotropic medications (e.g. anti-depressants, anxiolytics, 
methadone, buprenorphine, naltrexone) must be maintained on a stable dose for at least four 
weeks before study initiation.  
 

PROTOCOL TITLE: Ketamine-assisted psychotherapy for the treatment of persistent depression 
in abstinent opioid users 
 
Version Date: August 18, 2022 
 
Page 10 of 23 
 
 
 
 
 
5.3 Exclusion Criteria 
Subjects will be excluded from the study if any of the following criteria apply: 
1. 
They are considered an immediate suicide risk by clinician assessment, self-report a suicide 
attempt within the past year or felt to be likely to require hospitalization during the study. 
2. 
Subjects who meet DSM-5 criteria for current bipolar disorder based on clinical interview. 
3. 
Subjects who meet DSM-5 criteria for current or history of psychotic spectrum disorders based 
on clinical interview.   
4. 
Subjects meeting DSM-5 criteria for current substance use disorder (i.e., not in early or 
sustained remission) other than tobacco use disorder. 
5. 
Subjects who report use of ketamine >20 times in the past or who meet DSM-5 criteria for 
Other Hallucinogen Use Disorder due to ketamine use including subjects who are currently in 
early or sustained remission. 
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 hypertension as defined by a baseline visit systolic blood pressure (SBP) >140 
mmHg or a diastolic blood pressure (DBP) >90 mmHg. 
8. 
A history of allergic or other adverse reaction to ketamine (or its excipients). 
9. 
Clinically significant physical exam findings or self-reported medical conditions for which a 
transient increase in blood pressure could be significantly detrimental (e.g. glaucoma, 
aneurysmal disease, cardiovascular disease, or end-stage renal disease). 
10. QTc will be measured in subjects currently taking methadone and those with QTc 450ms or 
longer will be excluded. 
11. Subjects who live greater than 20 miles from the study site and cannot arrange their own 
transportation will be excluded from the study.   
12. Subjects with clinically significant kidney or liver impairment.   
 
 
5.4 
NUMBER OF SUBJECTS 
Approximately 10 subjects are planned for enrollment in this study with no gender, race, or ethnicity 
exclusions.  
 
5.5 
SETTING 
All procedures will be conducted in private research study rooms on MUSC campus. 
 
5.6 
RECRUITMENT METHODS 
Recruitment will 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.   
 
Initial screening eligibility will be conducted by the PI or trained research personnel.  Subjects with a self-
reported history of depression and opioid misuse or illicit opioid use for which they report being abstinent 
for at least 3 months (early remission) will be eligible to complete informed consent and baseline 
evaluation. 
 
6.0 
CONSENT PROCESS 
6.1 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.   
 
6.2 Location of Informed Consent 

PROTOCOL TITLE: Ketamine-assisted psychotherapy for the treatment of persistent depression 
in abstinent opioid users 
 
Version Date: August 18, 2022 
 
Page 11 of 23 
 
 
 
 
 
Informed consent will be obtained at the study research offices, in a private and interruption-free 
environment. 
 
6.3 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 
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. 
 
6.4 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.   
 
7.0 STUDY DESIGN/METHODS 
7.1 Study Overview 
This is an open label trial of ketamine-assisted psychotherapy to assess the efficacy and safety of weekly 
intramuscular injections of ketamine along with multimodal psychotherapy, including supportive, non-
directive and insight-oriented components, for decreasing symptoms of MDD in subjects with OUD in early 
or sustained remission. Psychotherapy will include setting goals for treatment of subject’s depression as 
well as setting an intention or focus for each medication session. After medication administration, therapy 
will include supportive talk and guidance during acute medication effects. At the end of each session, the 
subject will be encouraged to reflect on his or her experience as it relates to their intention and broader 
goals. Finally, the subject will be encouraged to build insight into their depression and develop behavioral 
goals to enact their insights and reach their goals. 
 
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 for the initial ketamine 
intervention procedure.  Participants will be subsequently monitored until they have returned to baseline 
based on clinical assessment during which time they will complete measures assessing their perception 
of the interventional experience 
 
7.2 Duration of Intervention and Study 
Participants will complete a total of 12 study visits (including baseline assessment and follow-up 
assessments) as shown in Figure 1.  Medication sessions with intramuscular ketamine will occur weekly 
for eight weeks. Participants will meet virtually or in person for follow-up 1, 2, 4, and 8 weeks following 
final medication session. 
 
7.3 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 1. 
 

PROTOCOL TITLE: Ketamine-assisted psychotherapy for the treatment of persistent depression 
in abstinent opioid users 
 
Version Date: August 18, 2022 
 
Page 12 of 23 
 
 
 
 
 
 
 

PROTOCOL TITLE: Ketamine-assisted psychotherapy for the treatment of persistent depression 
in abstinent opioid users 
 
Version Date: August 18, 2022 
 
Page 13 of 23 
 
 
 
 
 
Table 1: Schedule of Assessments 
 
Instrument Name 
Purpose 
 
TIME 
POINT 
 
BL 
(Wk 0) 
Tx 1-8 
(Wk 1-8) 
Follow-up 
(Wk 9, 10, 12, 16) 
Self-Reports and Consents 
 
Informed Consent 
Obtain informed consent 
X 
 
 
Demographics Form 
Sample characterization 
X 
 
 
Beck Depression Inventory-II 
Self-reported assessment of 
depression symptom severity 
X 
X 
X 
Visual Analog Scale (VAS) 
Measure subjective levels of 
opioid craving 
X 
X 
X 
General Anxiety Disorder 
(GAD-7) 
Self-report of anxiety symptom 
severity 
X 
X 
X 
Mystical Experiences 
Questionnaire (MEQ) 
Measure of perceptual 
experiences 
 
X 
 
Brief Pain Inventory 
Measure of pain and quality of 
life 
X 
X 
X 
Insomnia Severity Index (ISI) 
Assess insomnia and sleep 
quality 
X 
X 
X 
Five Facets of Mindfulness 
(FFMQ) 
Assess aspects of mindfulness 
related 
X 
X 
X 
PTSD Checklist (PCL-5) 
Measure of PTSD symptoms 
X 
X 
X 
Fagerstrom Test of Nicotine 
Dependence (FTND) 
Measure of nicotine dependence 
X 
X 
X 
Timeline Follow-Back (TLFB) 
Measure of substance use 
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* 
 
Montgomery-Asberg 
Depression Rating Scale 
(MADRS) 
Primary Outcome: Clinician 
assessed measure of depression 
symptom severity 
X 
X 
X 
Pre-screening Questionnaire 
To assess for basic eligibility 
criteria before completing a full 
baseline visit. 
X 
 
 
 
Laboratory and Procedural Tests 
Urine Pregnancy Test (female 
subjects only) 
Eligibility assessment 
X 
X 
 
Urine Drug Screen 
Assessment of illicit drug use 
X 
X 
 
Electrocardiogram (ECG; 
subjects on methadone only) 
Assessment of cardiac function 
X 
 
 
* Vital signs (blood pressure, pulse, respiratory rate, and pulse oximetry) will be obtained prior to treatment sessions and at 60 minutes post-treatment.  
Temperature will be monitored immediately prior to 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, subjects will be treated with standard of care antihypertensive medications (i.e. clonidine) and the 
measurements will be repeated every 20 minutes until BP and pulse are within 30 points of the baseline values.   
 
7.4 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 and clinician assessments as shown in 
Table 1.  This will also include assessment of depression severity and participants at highest risk for 
suicidality based on clinician assessment, those with a self-reported suicide attempt within the past year, 
and those felt likely to require hospitalization during the course of the study 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) and baseline medication evaluation for 
potential harmful interactions.  Urine pregnancy tests will be completed for every woman of childbearing 
potential. Urine drug screening will be collected at baseline and prior to each ketamine session to monitor 

PROTOCOL TITLE: Ketamine-assisted psychotherapy for the treatment of persistent depression 
in abstinent opioid users 
 
Version Date: August 18, 2022 
 
Page 14 of 23 
 
 
 
 
 
for opioid and other illicit substance use. For patients currently taking methadone, ECG will be performed 
to assess for cardiac function with QTc interval of 450ms or longer being exclusionary. Assessments may 
be conducted by telehealth with vital signs to be provided by participant’s home or pharmacy 
measurement. 
 
 
7.5 Intervention Visit Procedures 
Prior to administration of the study compounds, participants will complete self-report questionnaires and 
clinical assessments.  The study physician will disinfect the subject’s 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 60 minutes post-
treatment.  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 subject will be treated with standard of care antihypertensives (i.e. 
clonidine), and repeat vital sign measurements will be taken approximately every 20 minutes until blood 
pressure and pulse are within 30 points of baseline values. Standard of care antihypertensive 
medications will be procured via intrainstitutional transfer from MUSC investigational drug services 
pharmacy distribution center. They will be stored in a DHEC compliant locked box within a locked room 
accessible only to study team members. If the subject experiences symptoms of hypertensive 
emergency, the subject will not receive further administration of ketamine and will be withdrawn from the 
study.  After completion of the injection, participants until returned to baseline per clinical assessment 
which time they will undergo debriefing and complete assessments of their perceptual experience of the 
intervention.  We will evaluate the effects of a weekly interventions for 8 sessions. Participants will return 
for follow-up assessment 1, 2, 4 and 8 weeks following final medication session. Follow-up visits may be 
conducted by telehealth. 
 
8.0 
DATA MANAGEMENT 
8.1 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. 
 
8.2 Data Confidentiality Procedures 
We will take rigorous precautions to maintain confidentiality for all participants, using procedures that the 
PI and his 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, his 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. 
 
8.3 Data Quality Control Procedures 

PROTOCOL TITLE: Ketamine-assisted psychotherapy for the treatment of persistent depression 
in abstinent opioid users 
 
Version Date: August 18, 2022 
 
Page 15 of 23 
 
 
 
 
 
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. 
 
8.4 Study Documentation and Data Handling 
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. 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. Dobson) 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. Communication with the MUSC IRB is through email, memos, official IRB forms, and online 
reporting. 
 
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.   
 
8.5 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 subject 
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 

PROTOCOL TITLE: Ketamine-assisted psychotherapy for the treatment of persistent depression 
in abstinent opioid users 
 
Version Date: August 18, 2022 
 
Page 16 of 23 
 
 
 
 
 
will be only one master list of participants (again, not linked to any participant responses) which will be 
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 PI, co-Is 
and MUSC IRB auditors. 
 
8.6 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 his statistical advisor. 
 
9.0 
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 PI will review trial safety.  The PI will be responsible for assessing 
potential participants for inclusion and exclusion criteria, and for assessing for adverse effects (AE's) 
throughout the trial. AE's will collected, documented, and reported. 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. All SAE reports 
will be sent to the MUSC IRB within 24 hours of learning of event occurrence. The PI will be responsible 
for withdrawal of a study participant if they become pregnant or feel that participation is no longer in a 
subject's best interests. 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 contact 
Dr. Dobson 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. 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.   

PROTOCOL TITLE: Ketamine-assisted psychotherapy for the treatment of persistent depression 
in abstinent opioid users 
 
Version Date: August 18, 2022 
 
Page 17 of 23 
 
 
 
 
 
 
Peri-Intervention Monitoring: Subjects will be continuously medically and psychiatrically monitored 
throughout the course of the intervention and until return to medical and psychiatric baseline.  Subjects 
will be instructed not to eat for at least 2 hours before taking the intervention sessions to reduce the risk 
of nausea and vomiting.  Emergency services will be contacted 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. 
 
10.0 
WITHDRAWAL OF SUBJECTS 
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. 
 
11.0 
RISKS TO SUBJECTS 
11.1 Overview 
All medications have potential side effects. Ketamine has been well studied since its FDA approval 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 potential side effects associated with ketamine before study participation, 
and will be closely monitored both during the treatment and at each follow-up visit.   
11.2 Physical Risks 
The most significant physical adverse event from ketamine is a transient increase in blood pressure, 
which in previous studies was experienced by 29.8% of subjects with a mean systolic blood pressure 
increase of 19.6 mmHg +/- 12.8 mmHg and a mean diastolic blood pressure increase of 13.4 mmHg +/-  
9.8 mmHg. Peak levels are reached on average 40 minutes post-treatment and resolve 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, or greater than 30 mmHg SBP or DBP from 
baseline values) will be treated with standard of care hypertensives (e.g. clonidine) and monitored until 
symptom resolution.    
 
The most prevalent physical adverse effect was transient sedation and occurs in approximately 16% of 
patients receiving ketamine.  Sedation will be monitored via continuous clinical observation during 
interventional sessions.  A medical emergency team will be called for participants that are unable to be 
aroused with painful trapezius squeeze or that experience hypoxia (i.e. a pulse oximeter reading of 92% 
or less), although in the investigative team’s extensive experience using ketamine clinically for depression 
at these doses, such serious events have never occurred.  Vital signs will be routinely monitored during 
treatment and emergency airway equipment will be immediately available. Subjects will be monitored for 
2 hours post-dose by trained healthcare professionals (eg PI, co-I, or study nurse). Due to transient 
cognitive impairment associated with sedation, participants will not be allowed to drive themselves 
following the interventions. Subjects who do not have transportation and live within 20 miles will receive 
compensation for taxi, Uber or Lyft transportation to and from medication sessions up to $100 each way. 
Subjects who live greater than 20 miles from the study site and cannot arrange their own transportation 
will be excluded from the study. Participants 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 including 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.   

PROTOCOL TITLE: Ketamine-assisted psychotherapy for the treatment of persistent depression 
in abstinent opioid users 
 
Version Date: August 18, 2022 
 
Page 18 of 23 
 
 
 
 
 
11.3 Psychological Risks 
Ketamine commonly causes transient dissociation (including derealization and depersonalization) and 
perceptual changes (e.g. distortion of time and space, sense of illusions).  Based on prior studies these 
effects occur in 42% of subjects receiving ketamine.  Anxiety occurs 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 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 (e.g. benzodiazepines) will be available in the event 
that participants develop severe anxiety psychological distress unmitigated by reassurance and 
relaxation exercises.  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 
may also have emotional distress from answering the questionnaires, although this is mild in the 
investigators’ experience with these instruments.   
11.4 Abuse Liability 
Ketamine is a psychoactive substance and is considered to have 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).  Animal models using intracranial 
self-stimulation have demonstrated that ketamine fails to progress to self-administration, also suggesting 
a lack of abuse liability.  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, 2016). Substance use will be 
assessed at each visit throughout the study, and participants will be referred for ongoing care if they 
develop new or worsening substance use.  If participants report illicit use of ketamine between 
intervention sessions, they will be withdrawn and referred for substance abuse treatment.   
11.5 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.   
11.6 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. Subject will be advised against operating heavy machinery following 
treatment. 
11.7 Economic Risks: Subjects will be reimbursed for travel expenses including taxi, Uber or Lyft fare 
within 20 miles of study site as well as for any medical care related to study-related injuries. Subjects will 
not be compensated for medications sessions but will receive $15 for each follow-up session completed. 
11.8 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 may also be unknown risks associated with the study 
procedure or intervention. 
 
 
12.0 
POTENTIAL BENEFITS TO SUBJECTS OR OTHERS 
12.1 Potential Benefits to Subjects 
Potential benefits of participation in this study may include a reduction in depression symptoms.  
Participants may also gain diagnostic information about their medical or psychiatric comorbidities, 

PROTOCOL TITLE: Ketamine-assisted psychotherapy for the treatment of persistent depression 
in abstinent opioid users 
 
Version Date: August 18, 2022 
 
Page 19 of 23 
 
 
 
 
 
although this is not guaranteed.  Overall, there is no guarantee or promise that participants will receive 
any benefit from participation in this study.   
12.2 Justification of Risks 
The potential benefits of the knowledge to be gained from the proposed study are considerable. This study 
proposes to test intramuscular ketamine in the treatment of co-occurring OUD in early or sustained 
remission 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.  
 
13.0 
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, 
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.  
14.0 
DRUGS OR DEVICES  
The IND application for ketamine’s use in this study has been submitted by PI for FDA review.   IND 
number 159117 has been issued by the FDA. Study will not begin until a Study May Proceed letter is 
received from the FDA. Medication and placebo will be stored in lock boxes on the MUSC campus and 
be administered by the PI or   co-I. 
 
15.0 
REFERENCES 
 
Andrade, C. (2017). Ketamine for Depression, 4: In What Dose, at What Rate, by What Route, for How 
Long,  and at What Frequency? The Journal of Clinical Psychiatry, 78(7), e852–e857. 
https://doi.org/10.4088/JCP.17f11738 
Azhari, N., Hu, H., O’Malley, K. Y., Blocker, M. E., Levin, F. R., & Dakwar, E. (2021). Ketamine-
facilitated behavioral treatment for cannabis use disorder: A proof of  concept study. The American 
Journal of Drug and Alcohol Abuse, 47(1), 92–97. https://doi.org/10.1080/00952990.2020.1808982 
Baer, R. A., Smith, G. T., Hopkins, J., Krietemeyer, J., & Toney, L. (2006). Using self-report assessment 
methods to explore facets of mindfulness. Assessment, 13(1), 27–45. 
https://doi.org/10.1177/1073191105283504 
Barrett, F. S., Johnson, M. W., & Griffiths, R. R. (2015). Validation of the revised Mystical Experience 
Questionnaire in experimental sessions  with psilocybin. Journal of Psychopharmacology (Oxford, 
England), 29(11), 1182–1190. https://doi.org/10.1177/0269881115609019 
Beck, A. T., Steer, R. A., & Brown, G. K. (1996). Manual for the Beck Depression Inventory-II. San 
Antonio, TX: Psychological Corporation. 
Blevins, C. A., Weathers, F. W., Davis, M. T., Witte, T. K., & Domino, J. L. (2015). The Posttraumatic 
Stress Disorder Checklist for DSM-5 (PCL-5): Development and  Initial Psychometric Evaluation. 
Journal of Traumatic Stress, 28(6), 489–498. https://doi.org/10.1002/jts.22059 
Bohnert, K. M., Ilgen, M. A., Louzon, S., McCarthy, J. F., & Katz, I. R. (2017). Substance use disorders 
and the risk of suicide mortality among men and women in the  US Veterans Health Administration. 
Addiction (Abingdon, England), 112(7), 1193–1201. https://doi.org/10.1111/add.13774 
Brienza, R. S., Stein, M. D., Chen, M., Gogineni, A., Sobota, M., Maksad, J., … Clarke, J. (2000). 
Depression among needle exchange program and methadone maintenance clients. Journal of 
Substance Abuse Treatment, 18(4), 331–337. https://doi.org/10.1016/s0740-5472(99)00084-7 
Carpenter, K. M., Brooks, A. C., Vosburg, S. K., & Nunes, E. V. (2004). The effect of sertraline and 
environmental context on treating depression and  illicit substance use among methadone 
maintained opiate dependent patients: a controlled clinical trial. Drug and Alcohol Dependence, 
74(2), 123–134. https://doi.org/10.1016/j.drugalcdep.2003.11.015 
Chilukuri, H., Reddy, N. P., Pathapati, R. M., Manu, A. N., Jollu, S., & Shaik, A. B. (2014). Acute 
antidepressant effects of intramuscular versus intravenous ketamine. Indian Journal of 
Psychological Medicine, 36(1), 71–76. https://doi.org/10.4103/0253-7176.127258 

PROTOCOL TITLE: Ketamine-assisted psychotherapy for the treatment of persistent depression 
in abstinent opioid users 
 
Version Date: August 18, 2022 
 
Page 20 of 23 
 
 
 
 
 
Cleeland, C. S., & Ryan, K. M. (1994). Pain assessment: global use of the Brief Pain Inventory. Annals 
of the Academy of Medicine, Singapore, 23(2), 129–138. 
Dakwar, E, Hart, C. L., Levin, F. R., Nunes, E. V, & Foltin, R. W. (2017). Cocaine self-administration 
disrupted by the N-methyl-D-aspartate receptor  antagonist ketamine: a randomized, crossover 
trial. Molecular Psychiatry, 22(1), 76–81. https://doi.org/10.1038/mp.2016.39 
Dakwar, E, Nunes, E. V, Hart, C. L., Hu, M. C., Foltin, R. W., & Levin, F. R. (2018). A sub-set of 
psychoactive effects may be critical to the behavioral impact of  ketamine on cocaine use disorder: 
Results from a randomized, controlled laboratory study. Neuropharmacology, 142, 270–276. 
https://doi.org/10.1016/j.neuropharm.2018.01.005 
Dakwar, Elias, Levin, F., Foltin, R. W., Nunes, E. V, & Hart, C. L. (2014). The effects of subanesthetic 
ketamine infusions on motivation to quit and  cue-induced craving in cocaine-dependent research 
volunteers. Biological Psychiatry, 76(1), 40–46. https://doi.org/10.1016/j.biopsych.2013.08.009 
Dakwar, Elias, Levin, F., Hart, C. L., Basaraba, C., Choi, J., Pavlicova, M., & Nunes, E. V. (2020). A 
Single Ketamine Infusion Combined With Motivational Enhancement Therapy for  Alcohol Use 
Disorder: A Randomized Midazolam-Controlled Pilot Trial. The American Journal of Psychiatry, 
177(2), 125–133. https://doi.org/10.1176/appi.ajp.2019.19070684 
Dakwar, Elias, Nunes, E. V, Hart, C. L., Foltin, R. W., Mathew, S. J., Carpenter, K. M., … Levin, F. R. 
(2019). A Single Ketamine Infusion Combined With Mindfulness-Based Behavioral Modification  to 
Treat Cocaine Dependence: A Randomized Clinical Trial. The American Journal of Psychiatry, 
176(11), 923–930. https://doi.org/10.1176/appi.ajp.2019.18101123 
Gass, J. T., & Olive, M. F. (2008). Glutamatergic substrates of drug addiction and alcoholism. 
Biochemical Pharmacology, 75(1), 218–265. https://doi.org/10.1016/j.bcp.2007.06.039 
Grant, I. S., Nimmo, W. S., & Clements, J. A. (1981). Pharmacokinetics and analgesic effects of i.m. and 
oral ketamine. British Journal of Anaesthesia, 53(8), 805–810. https://doi.org/10.1093/bja/53.8.805 
Han, Y., Chen, J., Zou, D., Zheng, P., Li, Q., Wang, H., … Xie, P. (2016). Efficacy of ketamine in the 
rapid treatment of major depressive disorder: a  meta-analysis of randomized, double-blind, 
placebo-controlled studies. Neuropsychiatric Disease and Treatment, 12, 2859–2867. 
https://doi.org/10.2147/NDT.S117146 
Huhn, A. S., Sweeney, M. M., Brooner, R. K., Kidorf, M. S., Tompkins, D. A., Ayaz, H., & Dunn, K. E. 
(2019). Prefrontal cortex response to drug cues, craving, and current depressive symptoms  are 
associated with treatment outcomes in methadone-maintained patients. 
Neuropsychopharmacology : Official Publication of the American College of  
Neuropsychopharmacology, 44(4), 826–833. https://doi.org/10.1038/s41386-018-0252-0 
Jones, J. L., Mateus, C. F., Malcolm, R. J., Brady, K. T., & Back, S. E. (2018). Efficacy of Ketamine in 
the Treatment of Substance Use Disorders: A Systematic  Review. Frontiers in Psychiatry, 9, 277. 
https://doi.org/10.3389/fpsyt.2018.00277 
Kadam, M., Sinha, A., Nimkar, S., Matcheswalla, Y., & De Sousa, A. (2017). A Comparative Study of 
Factors Associated with Relapse in Alcohol Dependence and  Opioid Dependence. Indian Journal 
of Psychological Medicine, 39(5), 627–633. https://doi.org/10.4103/IJPSYM.IJPSYM_356_17 
Ketalar (ketamine hydrochloride) [prescribing information]. Chestnut Ridge, NY: Par Pharmaceutical; 
September 2021. (n.d.). 
Kosten, T., Falcioni, J., Oliveto, A., & Feingold, A. (2004). Depression predicts higher rates of heroin use 
on desipramine with buprenorphine  than with methadone. The American Journal on Addictions, 
13(2), 191–201. https://doi.org/10.1080/10550490490435966 
Krupitsky, E., Burakov, A., Romanova, T., Dunaevsky, I., Strassman, R., & Grinenko, A. (2002). 
Ketamine psychotherapy for heroin addiction: immediate effects and two-year  follow-up. Journal of 
Substance Abuse Treatment, 23(4), 273–283. https://doi.org/10.1016/s0740-5472(02)00275-1 
Krupitsky, E M, & Grinenko, A. Y. (1997). Ketamine psychedelic therapy (KPT): a review of the results of 
ten years of  research. Journal of Psychoactive Drugs, 29(2), 165–183. 
https://doi.org/10.1080/02791072.1997.10400185 
Krupitsky, Evgeny M, Burakov, A. M., Dunaevsky, I. V, Romanova, T. N., Slavina, T. Y., & Grinenko, A. 

PROTOCOL TITLE: Ketamine-assisted psychotherapy for the treatment of persistent depression 
in abstinent opioid users 
 
Version Date: August 18, 2022 
 
Page 21 of 23 
 
 
 
 
 
Y. (2007). Single versus repeated sessions of ketamine-assisted psychotherapy for people with  
heroin dependence. Journal of Psychoactive Drugs, 39(1), 13–19. 
https://doi.org/10.1080/02791072.2007.10399860 
Linda C. Sobell, M. B. S. (1992). Timeline Followback. In R. . Litten & J. . Allen (Eds.), Measuring 
Alcohol Consumption (pp. 41–72). Totowa, N.J.: Humana Press. 
Maclean, K. A., Leoutsakos, J.-M. S., Johnson, M. W., & Griffiths, R. R. (2012). Factor Analysis of the 
Mystical Experience Questionnaire: A Study of Experiences  Occasioned by the Hallucinogen 
Psilocybin. Journal for the Scientific Study of Religion, 51(4), 721–737. 
https://doi.org/10.1111/j.1468-5906.2012.01685.x 
Mathew, S. J., Shah, A., Lapidus, K., Clark, C., Jarun, N., Ostermeyer, B., & Murrough, J. W. (2012). 
Ketamine for treatment-resistant unipolar depression: current evidence. CNS Drugs, 26(3), 189–
204. https://doi.org/10.2165/11599770-000000000-00000 
McDonald, S. D., & Calhoun, P. S. (2010). The diagnostic accuracy of the PTSD checklist: a critical 
review. Clinical Psychology Review, 30(8), 976–987. https://doi.org/10.1016/j.cpr.2010.06.012 
McMillan, D. E., & Gilmore-Thomas, K. (1996). Stability of opioid craving over time as measured by 
visual analog scales. Drug and Alcohol Dependence, 40(3), 235–239. https://doi.org/10.1016/0376-
8716(96)01218-5 
Mion, G., & Villevieille, T. (2013). Ketamine pharmacology: an update (pharmacodynamics and 
molecular aspects, recent  findings). CNS Neuroscience & Therapeutics, 19(6), 370–380. 
https://doi.org/10.1111/cns.12099 
Montgomery, S. A., & Asberg, M. (1979). A new depression scale designed to be sensitive to change. 
The British Journal of Psychiatry : The Journal of Mental Science, 134, 382–389. 
https://doi.org/10.1192/bjp.134.4.382 
Morin, C. M., Belleville, G., Bélanger, L., & Ivers, H. (2011). The Insomnia Severity Index: psychometric 
indicators to detect insomnia cases and  evaluate treatment response. Sleep, 34(5), 601–608. 
https://doi.org/10.1093/sleep/34.5.601 
Murrough, J. W., Abdallah, C. G., & Mathew, S. J. (2017). Targeting glutamate signalling in depression: 
progress and prospects. Nature Reviews. Drug Discovery, 16(7), 472–486. 
https://doi.org/10.1038/nrd.2017.16 
Niciu, M. J., Luckenbaugh, D. A., Ionescu, D. F., Richards, E. M., Vande Voort, J. L., Ballard, E. D., … 
Zarate, C. A. J. (2014). Ketamine’s antidepressant efficacy is extended for at least four weeks in 
subjects  with a family history of an alcohol use disorder. The International Journal of 
Neuropsychopharmacology, 18(1). https://doi.org/10.1093/ijnp/pyu039 
Nunes, E. V, Quitkin, F. M., Donovan, S. J., Deliyannides, D., Ocepek-Welikson, K., Koenig, T., … 
Woody, G. (1998). Imipramine treatment of opiate-dependent patients with depressive disorders. A  
placebo-controlled trial. Archives of General Psychiatry, 55(2), 153–160. 
https://doi.org/10.1001/archpsyc.55.2.153 
Pani, P. P., Vacca, R., Trogu, E., Amato, L., & Davoli, M. (2010). Pharmacological treatment for 
depression during opioid agonist treatment for opioid dependence. Cochrane Database of 
Systematic Reviews, (9). https://doi.org/10.1002/14651858.CD008373.pub2 
Parpura, V., & Verkhratsky, A. (2012). Astrocytes revisited: concise historic outlook on glutamate 
homeostasis and  signaling. Croatian Medical Journal, 53(6), 518–528. 
https://doi.org/10.3325/cmj.2012.53.518 
Pedrelli, P., Iovieno, N., Vitali, M., Tedeschini, E., Bentley, K. H., & Papakostas, G. I. (2011). Treatment 
of major depressive disorder and dysthymic disorder with antidepressants  in patients with 
comorbid opiate use disorders enrolled in methadone maintenance therapy: a meta-analysis. 
Journal of Clinical Psychopharmacology, 31(5), 582–586. 
https://doi.org/10.1097/JCP.0b013e31822c0adf 
Peles, E., Schreiber, S., Naumovsky, Y., & Adelson, M. (2007). Depression in methadone maintenance 
treatment patients: rate and risk factors. Journal of Affective Disorders, 99(1–3), 213–220. 
https://doi.org/10.1016/j.jad.2006.09.017 

PROTOCOL TITLE: Ketamine-assisted psychotherapy for the treatment of persistent depression 
in abstinent opioid users 
 
Version Date: August 18, 2022 
 
Page 22 of 23 
 
 
 
 
 
Petrakis, I., Carroll, K. M., Nich, C., Gordon, L., Kosten, T., & Rounsaville, B. (1998). Fluoxetine 
treatment of depressive disorders in methadone-maintained opioid addicts. Drug and Alcohol 
Dependence, 50(3), 221–226. https://doi.org/10.1016/s0376-8716(98)00032-5 
Rajkowska, G., & Stockmeier, C. A. (2013). Astrocyte pathology in major depressive disorder: insights 
from human postmortem  brain tissue. Current Drug Targets, 14(11), 1225–1236. 
https://doi.org/10.2174/13894501113149990156 
Rizk, M. M., Herzog, S., Dugad, S., & Stanley, B. (2021). Suicide Risk and Addiction: The Impact of 
Alcohol and Opioid Use Disorders. Current Addiction Reports, 1–14. 
https://doi.org/10.1007/s40429-021-00361-z 
Savant, J. D., Barry, D. T., Cutter, C. J., Joy, M. T., Dinh, A., Schottenfeld, R. S., & Fiellin, D. A. (2013). 
Prevalence of mood and substance use disorders among patients seeking primary care office-
based buprenorphine/naloxone treatment. Drug 
Anfile:///Users/Ericdobson/Downloads/PMC5266602.Nbibd Alcohol Dependence, 127(1–3), 243–
247. https://doi.org/10.1016/j.drugalcdep.2012.06.020 
Scofield, M. D., & Kalivas, P. W. (2014). Astrocytic dysfunction and addiction: consequences of impaired 
glutamate  homeostasis. The Neuroscientist : A Review Journal Bringing Neurobiology, Neurology 
and  Psychiatry, 20(6), 610–622. https://doi.org/10.1177/1073858413520347 
Spitzer, R. L., Kroenke, K., Williams, J. B. W., & Löwe, B. (2006). A brief measure for assessing 
generalized anxiety disorder: the GAD-7. Archives of Internal Medicine, 166(10), 1092–1097. 
https://doi.org/10.1001/archinte.166.10.1092 
Stein, M. D., Santiago Rivera, O. J., Anderson, B. J., & Bailey, G. L. (2017). Perceived need for 
depression treatment among persons entering inpatient opioid  detoxification. The American 
Journal on Addictions, 26(4), 395–399. https://doi.org/10.1111/ajad.12554 
Sullivan, M. D. (2018). Depression Effects on Long-term Prescription Opioid Use, Abuse, and Addiction. 
The Clinical Journal of Pain, 34(9), 878–884. https://doi.org/10.1097/AJP.0000000000000603 
Unnithan, S., Gossop, M., & Strang, J. (1992). Factors associated with relapse among opiate addicts in 
an out-patient  detoxification programme. The British Journal of Psychiatry : The Journal of Mental 
Science, 161, 654–657. https://doi.org/10.1192/bjp.161.5.654 
Vekaria, V., Bose, B., Murphy, S. M., Avery, J., Alexopoulos, G., & Pathak, J. (2021). Association of co-
occurring opioid or other substance use disorders with increased healthcare utilization in patients 
with depression. Translational Psychiatry, 11(1), 265. https://doi.org/10.1038/s41398-021-01372-0 
Volkow, N. D. (2004). The reality of comorbidity: depression and drug abuse. Biological Psychiatry, 
56(10), 714–717. https://doi.org/10.1016/j.biopsych.2004.07.007 
Volkow, N. D., Jones, E. B., Einstein, E. B., & Wargo, E. M. (2019). Prevention and Treatment of Opioid 
Misuse and Addiction: A Review. JAMA Psychiatry, 76(2), 208–216. 
https://doi.org/10.1001/jamapsychiatry.2018.3126 
Wan, L.-B., Levitch, C. F., Perez, A. M., Brallier, J. W., Iosifescu, D. V, Chang, L. C., … Murrough, J. W. 
(2015). Ketamine safety and tolerability in clinical trials for treatment-resistant  depression. The 
Journal of Clinical Psychiatry, 76(3), 247–252. https://doi.org/10.4088/JCP.13m08852 
WHO Expert Committee on Drug Dependence. (2016). World Health Organization Technical Report 
Series, (998), 1–34. 
Wilkinson, S. T., Toprak, M., Turner, M. S., Levine, S. P., Katz, R. B., & Sanacora, G. (2017). A Survey 
of the Clinical, Off-Label Use of Ketamine as a Treatment for Psychiatric Disorders. American 
Journal of Psychiatry, 174(7), 695–696. https://doi.org/10.1176/appi.ajp.2017.17020239 
Xu, Y., Hackett, M., Carter, G., Loo, C., Gálvez, V., Glozier, N., … Rodgers, A. (2016). Effects of Low-
Dose and Very Low-Dose Ketamine among Patients with Major Depression:  a Systematic Review 
and Meta-Analysis. The International Journal of Neuropsychopharmacology, 19(4). 
https://doi.org/10.1093/ijnp/pyv124 
Zhang, X., Xu, H., Gu, J., Lau, J. T. F., Hao, C., Zhao, Y., … Hao, Y. (2016). Depression, suicidal 
ideation, and related factors of methadone maintenance  treatment users in Guangzhou, China. 
AIDS Care, 28(7), 851–856. https://doi.org/10.1080/09540121.2015.1124981 

PROTOCOL TITLE: Ketamine-assisted psychotherapy for the treatment of persistent depression 
in abstinent opioid users 
 
Version Date: August 18, 2022 
 
Page 23 of 23