Clinical trial NCT05114460
Conditions: Opioid Overdose
Sponsor: New York State Psychiatric Institute
Start date: 2021-11-01; Completion date: 2024-10-29
Enrollment: 2 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The goal of the proposed, proof-of-concept study is to test the combined effects of vaporized marijuana \[Delta-9-tetrahydracannabinol (THC)\] with NLX as a proof of concept towards the possible development of a combined overdose reversal agent with improved tolerability.

Detailed description:
The goal of the proposed, proof-of-concept study is to test the combined effects of vaporized marijuana \[Delta-9-tetrahydracannabinol (THC)\] with NLX as a proof of concept towards the possible development of a combined overdose reversal agent with improved tolerability. Marijuana plant material will be obtained from the National Institutes on Drug Abuse (NIDA). In clinical studies, oral synthetic THC reduced the severity of opioid withdrawal during opioid detoxification. Clinically, cannabinoid drugs like Marinol® (oral synthetic THC), Sativex ® (nabixomols), and Cesamet® (nabilone) are used to treat nausea and vomiting, common symptoms of opioid withdrawal. This study will investigate the ability of vaporized marijuana (V-MJ) (0.00, 12.5, and 25 mg: concentration= 11.7% THC + 0.04% CBD) to reduce the severity of opioid withdrawal precipitated by intranasal (IN) NLX (0.0 and 4.0 mg). This trial will recruit healthy participants with opioid use disorder (N=16, completers). Testing will begin following stabilization on oral morphine (120 mg/day), which will continue throughout the trial. During each testing session, a single V-MJ + naloxone dose combination will be assessed (in randomized order), with 48 hours between testing sessions. Laboratory testing sessions will consist of a modified naloxone challenge procedure, which quantifies the severity of naloxone-precipitated opioid withdrawal.

Arms: arm 1: Intranasal naloxone in combination with vaped marijuana arm 2: Intranasal naloxone in combination with vaped marijuana arm 3: Intranasal naloxone in combination with vaped marijuana (MJ) arm 4: Intranasal naloxone in combination with vaped marijuana (MJ) arm 5: Intranasal naloxone in combination with vaped marijuana (MJ) arm 6: Intranasal naloxone in combination with vaped marijuana (MJ)
Interventions: intervention 1: Naloxone intervention 2: Marijuana
Intervention descriptions: intervention 1: Intranasal Naloxone intervention 2: Vaped Marijuana

Protocol documents:
SAP_002.pdf: 
Protocol Title: The Ability of Vaped Marijuana to Reduce the Severity of Naloxone-Precipitated Withdrawal 
Protocol Number: 8061 
Version Date: 26 MAR 2020 
 
 
STATISTICAL ANALYSES 
 
Data Analysis Plan: The distributions of all continuous variables will be checked for normality, and 
transformations will be employed (if necessary) before applying specific parametric techniques. Before 
performing specific analyses, we will examine all outcomes for outliers. All statistical comparisons will be two-
sided and the critical level for rejection of the null hypothesis will be considered to be a p-value of < 0.05. Where 
needed, False Discovery Rate Analysis will be used to adjust critical p values to control for multiple 
comparisons. Any comparison where homogeneity is violated will not be considered significant. Means, 
standard deviations, proportions, and 95% confidence intervals will be used to describe all continuous 
variables.  
 
Dropouts and Missing Data: As this is an inpatient laboratory study within a controlled setting, we expect only 
minimal intermittent missing data, though we do expect to have some subjects drop out without completing all 
of the experimental conditions.   We will use all available data from subjects prior to drop-out.  We will account 
for missing data directly using mixed-effects models (MEM) (Diggle et al. 2002). MEMs do not require complete 
measurements to estimate effects and inferences are valid provided that data are “missing at random” (Little & 
Rubin, 2002). ‘Missing at random’ (i.e. the missing mechanism does not depend on the value of the 
unobserved outcome) is un-testable in most medical research and in our study as well.  One can assume 
either parametric or semi-parametric models for the missingness that does depend on the unobserved 
outcome value and do the analysis (Diggle and Kenward 1994, Kenward 1998). Comparison of the inferences 
from assuming various models for the missingness provides a measure of the validity of the efficacy estimate 
from the model that assumes missing ‘at random’. One can also compute a local sensitivity index which 
measures the change in the estimated treatment effect in a neighborhood of the ‘missing at random’ model for 
missingness (Rotnitzky et al. 1998). We will perform sensitivity analyses based on these two approaches to 
assess the effect of the assumption of missing ‘at random’ on the inference.  
 
Randomization: Once a participant is enrolled, a randomization sequence table will be generated by a blinded 
statistician. The table will determine the order of testing of the various dose combinations of dronabinol (.00, 
.35, and .70 mg), and naloxone (0.0, 0.2 and 0.4 mg). 
 
Aims, Outcome Measures, and Hypotheses 
Primary Aim: Assess the ability of inhaled dronabinol to alter the severity of naloxone-precipitated withdrawal.  
 
• 
The primary dependent variable (DV) for this aim will be the total opioid withdrawal score from the testing 
session. Repeated-measures analysis of variance (ANOVA) will be used to assess differences among 
the various dose conditions.  
 
• 
We hypothesize that there will be a dose-dependent effect of dronabinol to attenuate the severity of 
naloxone-precipitated withdrawal. 
 
Secondary Aim: Assess the safety of inhaled dronabinol in combination with naloxone.  
 
• 
The primary DVs are the SAFTEE (AEs not related to withdrawal) and physiological parameters. 
Generalized mixed-effects models with participant as a random effect and an autoregressive correlation 
structure for the within-participant observations will be used to analyze the total number of AEs and their 
severity. 
 
• 
We hypothesize that dronabinol, in combination with naloxone, will produce more AEs than placebo but 
less than naloxone alone. 
 
  


Protocol Title: The Ability of Vaped Marijuana to Reduce the Severity of Naloxone-Precipitated Withdrawal 
Protocol Number: 8061 
Version Date: 26 MAR 2020 
 
 
Secondary Aim: Assess the impact of inhaled dronabinol on naloxone’s effects on pupil diameter (i.e., μ-opioid 
receptor blockage).  
 
• 
The primary DV will be pre-to-post- medication change in pupil diameter from each testing session. 
Repeated-measures ANOVA will be used to assess differences among the various dose conditions. 
 
• 
We hypothesize that dronabinol will not significantly alter naloxone’s effects on pupil diameter (in 
comparison to placebo). 
 
 
Secondary Aim: Assess the abuse potential of inhaled dronabinol.  
 
• 
The primary DV will be pre-to-post- medication change in positive subjective drug ratings such as drug 
“Liking” and “Good Effect.” 
 
• 
We hypothesize that self-reported dronabinol “Liking” will not be significantly greater than placebo. 
 
 
Power 
To approximate a suitable number of subjects for a traditional hypothesis-testing approach, a power 
analysis was conducted using G* Power 3.1.7. Estimates of the magnitude of the medication effect on withdrawal 
were estimated using a previous study that assessed naloxone-precipitated withdrawal (Jones et al., 2016). 
Based on these data we calculated a Cohen’s D effect size of .75, which constituted a 15-point difference (mean 
SD of 20) in total withdrawal score (0-125) between any two dose conditions.  Applying this to the current 
proposal, a total sample size of 16 completers should provide 90% power to detect this difference at a p of < 
0.05.  Sixteen completers will provide 88% power to detect a 10-mm difference in positive subjective effects, e.g. 
“Liking” on a 100-mm VAS scale (alpha of 0.05). This analysis assumes a SD of 12 mm and a Cohen's D effect 
size of 0.84 based on previous visual analog scale assessments of abuse liability of opioids and cannabinoids 
(Cooper et al., 2018, Jones et al., 2017). 
Due to the exploratory nature of this study, effect size estimates will be the main research outcome for 
the secondary aims, along with the interpretation of confidence interval lengths and degree of overlap to indicate 
precision and degree of difference (i.e., threshold of clinical importance) between dose conditions (respectively). 
A sample size of 16 completers was determined to be sufficient to obtain precise 95% confidence intervals with 
a margin of error of at most 25%. Thus, with regard to the detection of differences in all the study aims, these 
calculations suggest that this study is suitably powered. 
 
Sex as a Biological Variable 
Sex-specific comparisons will be performed to provide an indicator of a Sex x Treatment interaction. The within-
subject nature of the study’s design should control for potential sex differences. Though not powered to 
specifically detect sex differences, we are still in compliance with NIH policies to enroll males and females. 
Furthermore, sex as a biological variable will be examined and reported in accordance with NIH policy 
(https://orwh.od.nih.gov/sites/orwh/files/docs/NOT-OD-15-102_Guidance.pdf). 
 

Prot_000.pdf: 
Protocol Summary Form 
8061 
Jones, Jermaine 
Page 1 of 35 
 
 
Protocol Title: 
The Ability of Vaped Marijuana to Reduce 
the Severity of Naloxone-Precipitated 
Withdrawal 
 
Protocol Number: 
8061 
 
First Approval: 
09/23/2021 
 
Expiration Date: 
09/12/2023 
Version Date: 
15 DEC 2022 
 
 
 
 
Research Area: 
Substance Use Disorders 
 
Division: 
Substance Use Disorders 
 
Contact Principal Investigator: 
Jermaine Jones, PHD 
Email: 
Jermaine.Jones@NYSPI.Columbia.edu 
Telephone: 646 774-6113 
Co-Investigator(s): 
Margaret Haney, PHD 
Sandra Comer, PHD 
Caroline Arout 
 
Research Chief: 
Frances Levin, MD 
 
 
 
 
 
 
 
Choose ONE option from the following that is applicable to your study 
If you are creating a new protocol, select "I am submitting a new protocol." As 5 Year Renewals are no 
longer required, this option remains for historical purposes. 
I am proposing an amendment only to an existing protocol 
 
 
 
 
What Department does the PI belong to? 
Psychiatry 
Within the department, what Center or group are you affiliated with, if any? 
Opioid Research Laboratory 
 
 
List investigators, if any, who will be participating in this protocol but are not affiliated with New York 
Cover Sheet 
Department & Unaffiliated Personnel 
Department 
Unaffiliated Personnel 


Protocol Summary Form 
8061 
Jones, Jermaine 
Page 2 of 35 
 
 
 
 
State Psychiatric Institute or Columbia University. Provide: Full Name, Degrees and Affiliation. 
None 
 
 
 
To create the protocol summary form, first indicate if this research will include any of the following 
procedures 
 Administration of Substance of Abuse 
 Collection of Biological Specimens 
 Internet-based Data Collection or Transmission 
 Medication Trial 
 Psychiatric Assessment 
  Use of Investigational Drug or Device 
 
 
 
Indicate which of the following populations will be included in this research 
 Medically and Psychiatrically Healthy Subjects 
 Adults over 50 
 
 
 
Will an existing internal account be used to support the project? 
No 
Is the project externally funded or is external funding planned? 
Yes 
Select the number of external sources of funding that will be applicable to this study 
 
Is the PI of the grant/contract the same as the PI of the IRB protocol? 
Yes 
Select one of the following 
The grant/contract is currently funded 
Source of Funding 
Federal 
Institute/Agency 
National Institute on Drug Abuse 
Grant Name 
The Ability of Inhaled Dronabinol to Reduce the Severity of Naloxone-Precipitated Withdrawal. 
Grant Number 
R21 DA049076-01A1 
Select one of the following 
Procedures 
Population 
Research Support/Funding 
Funding Source #1 


Protocol Summary Form 
8061 
Jones, Jermaine 
Page 3 of 35 
 
 
Single Site 
Business Office 
RFMH 
Does the grant/contract involve a subcontract? 
No 
 
 
Study Location 
 
 
Indicate if the research is/will be conducted at any of the following 
 NYSPI 
This protocol describes research conducted by the PI at other facilities/locations 
No 
 
 
Lay Summary of Proposed Research 
 
 
Lay Summary of Proposed Research 
 
To address the opioid epidemic, there has been an increased focus on the development of novel medications 
to treat opioid use disorder (OUD). However, a pharmacological approach more specific to overdose harm 
reduction (i.e., minimizing the harmful effect of drugs among active users) may be to increase the 
tolerability of the overdose reversal agent, naloxone (NLX). In emergency settings, NLX administration (in 
suspected cases of opioid overdose) often results in violent patient behavior, as individuals who are opioid 
dependent awaken in a state of opioid withdrawal (Gaddis and Watson, 1992; Osterwalder, 1996). 
Naloxone-induced withdrawal is also common in out-of-hospital settings in which non-medical persons are 
asked to administer naloxone to save the lives of their peers. Analysis of the Opioid Lab's overdose reports 
from the individual who administered NLX found that 98% of overdose victims presented notable opioid 
withdrawal-related adverse events (AEs) including: nausea, abdominal pain, vomiting, joint/muscle pain, 
and tremor. Concerns of the adverse effects of NLX administration may prevent or delay the use of this life- 
saving intervention. 
The goal of the proposed, proof-of-concept study is to test the combined effects of vaporized marijuana 
[Delta-9-tetrahydracannabinol (THC)] with NLX as a proof of concept towards the possible development of 
a combined overdose reversal agent with improved tolerability. Marijuana will not actually be vaped per se, 
but a “vaporizer” will be used to produce an aerosol from marijuana plant material, which the participant 
will inhale. Marijuana plant material will be obtained from the National Institutes on Drug Abuse (NIDA). 
In clinical studies, oral synthetic THC (Bisaga et al., 2015; Lofwall et al., 2016) reduced the severity of 
opioid withdrawal during opioid detoxification (Scavone et al., 2013). Clinically, cannabinoid drugs like 
Marinol® (oral synthetic THC), Sativex ® (nabixomols), and Cesamet® (nabilone) are used to treat nausea 
and vomiting, common symptoms of opioid withdrawal. This study will investigate the ability of vaporized 
marijuana (V-MJ) (0.00, 12.5, and 25 mg: concentration= 11.7% THC + 0.04% CBD.) to reduce the 
severity of opioid withdrawal precipitated by intranasal (IN) NLX (0.0 and 4.0 mg). The final dose of 
marijuana will be achieved in 10 puffs/vapes, in 10-12 minutes (at a temperature of 210°C). 
 
This trial will recruit healthy participants with opioid use disorder (N=16, completers). 


Protocol Summary Form 
8061 
Jones, Jermaine 
Page 4 of 35 
 
 
Testing will begin following stabilization on oral morphine (120 mg/day), which will continue throughout 
the trial. During each testing session, a single V-MJ + naloxone dose combination will be assessed (in 
randomized order), with 24 hours between testing sessions. Laboratory testing sessions will consist of a 
modified naloxone challenge procedure, which quantifies the severity of naloxone-precipitated opioid 
withdrawal (Jones et al., 2019). 
 
The slow rate of onset for oral cannabinoid administration would not have utility in an emergency. 
Therefore, the rapid pharmacodynamics of vaporized marijuana will allow the investigators the opportunity 
to investigate the potential utility of an ecologically valid combined cannabinoid + NLX opioid overdose 
emergency intervention. The investigators hypothesize that the combined administration (V-MJ + NLX) 
will produce significantly less withdrawal than NLX alone. 
 
 
 
Background, Significance and Rationale 
 
 
Background, Significance and Rationale 
Why is naloxone-precipitated withdrawal a problem? Although there are studies that suggest that the 
distribution of naloxone (NLX) has a measurable effect on overall opioid overdose death rates, deaths 
nation-wide remain high (Centers for Disease Control (CDC), 2018; Doe-Simkins et al., 2012; Walley et al., 
2013). More needs to be done to address the fatalities associated with opioid overdose. All 50 states 
currently allow medical providers to prescribe the opioid receptor antagonist NLX to persons most likely to 
witness or experience an opioid overdose. In our study team’s investigation into the utility of overdose 
education and naloxone distribution (OEND) programs, an important barrier has emerged (Jones et al., 
2014; Neale et al., 2020). Experienced opioid users have a notable baseline knowledge of opioid overdose 
and are keenly aware of the ability of NLX to elicit severe opioid withdrawal (Jones et al., 2014; Green et 
al., 2008). These individuals are also likely to have experienced NLX-precipitated withdrawal during a 
previous non-fatal overdose (Darke et al., 2014; Mars et al., 2015; Wagner et al., 2015). Additionally, many 
OEND programs inform individuals that precipitated withdrawal is a likely consequence of administering 
NLX (Clarke et al., 2014). Thus, the fear of inducing withdrawal is a significant barrier to NLX use, even in 
emergency situations (Wright et al., 2006). This fear is not unwarranted. In emergency settings, NLX 
administration often results in violent patient behavior (Gaddis and Watson, 1992; Osterwalder, 1996). 
Concerns of the adverse effects of NLX administration may prevent or delay the use of this life-saving 
intervention. Precipitated opioid withdrawal is also a concern for the overdose victim. Once revived, the 
adverse symptoms such as: joint and muscle pain, nausea, vomiting, and stomach cramps, may lead the 
individual to use additional opioids for relief, putting them at risk of a recurrence of severe respiratory 
depression (Buajordet et al., 2004). 
 
How cannabinoids may help? The endocannabinoid system is a potential novel target for reducing opioid 
withdrawal severity. Studies show that opioid and cannabinoid receptors are co-localized in multiple brain 
regions. Both receptors also have cross-modulatory pharmacological effects including: cross-agonism, - 
antagonism, -sensitization, and -tolerance (Robledo et al., 2008). Preclinical studies have demonstrated that 
tetrahydrocannabinol (THC) decreases signs of opioid withdrawal in morphine-dependent rodents 
(Bhargava, 1976; Cichewicz and Welch, 2003; Gamage et al., 2015; Hine et al., 1975). In clinical studies, 
oral dronabinol (synthetic THC: Bisaga et al., 2015; Lofwall et al., 2016) and smoked cannabis have been 
shown to reduce the severity of abstinence-induced opioid withdrawal during opioid detoxification or 


Protocol Summary Form 
8061 
Jones, Jermaine 
Page 5 of 35 
 
 
stabilization (Scavone et al., 2013). Clinically, cannabinoid receptor type-1 agonists such as, Marinol® (oral 
synthetic THC), Sativex ® (nabixomols), and Cesamet® (nabilone) are used to treat nausea and vomiting, 
common symptoms of opioid withdrawal. Joint and muscle pain are also common AEs associated with 
NLX-precipitated withdrawal. In clinical laboratory investigations of their analgesic effects, cannabinoids 
have shown promise in treating muscle pain (Cooper et al., 2013 & 2018). 
 
Rationale: This study will investigate the ability of vaporized marijuana (V-MJ) (0.00, 12.5, and 25 mg: 
concentration= 11.7% THC) to reduce the severity of opioid withdrawal precipitated by intranasal (IN) 
NLX (0.0 and 4.0 mg). If our hypotheses are supported, this study may suggest that the combination of an 
intranasal opioid receptor antagonist with a cannabinoid receptor agonist may have clinical utility as an 
overdose reversal medication that is more tolerable than naloxone alone. Reducing the adverse effects of 
naloxone administration may increase its utilization while minimizing risks for the administrator and 
recipient. 
 
 
 
 
 
Specific Aims and Hypotheses 
 
 
Specific Aims and Hypotheses 
 
Primary Aim: Assess the ability of vaped marijuana to alter the severity of naloxone-precipitated withdrawal. 
We hypothesize that there will be a dose-dependent effect of vaped marijuana to attenuate the severity of 
naloxone-precipitated withdrawal. 
 
 
 
Secondary Aim: Assess the safety of vaped marijuana in combination with naloxone. We hypothesize that 
vaped marijuana, in combination with naloxone, will produce more AEs than placebo but less than naloxone 
alone. 
 
Secondary Aim: Assess the impact of vaped marijuana on naloxone’s effects on pupil diameter (i.e., μ- 
opioid receptor blockage). We hypothesize that vaped marijuana will not significantly alter naloxone’s 
effects on pupil diameter (in comparison to placebo). 
 
 
 
Description of Subject Population 
 
 
 
 Sample #1 
 
 
Specify subject population 
Opioid-Dependent Participants with Opioid Use Disorder 
Number of completers required to accomplish study aims 
16 


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Jones, Jermaine 
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Projected number of subjects who will be enrolled to obtain required number of completers 
32 
Age range of subject population 
18-55 
 
Gender, Racial and Ethnic Breakdown 
All efforts will be made to ensure that the representation of women and of ethnic minorities are in 
proportion to the individuals with Opioid Use Disorder (OUD) in New York City. It is estimated that the 
sample will be 70% male, 50-40% Caucasian, 45%-40% Black or African American, 0-5% Asian, Pacific 
Islander and Native American, and 15% will self-identify as multi-racial. We anticipate that ≈ 30% of our 
sample will be of Latino/Hispanic ethnicity. These estimates are based upon data from non-crisis 
heroin treatment admissions, reported by the New York City Department of Health and Mental 
Hygiene. https://ndews.umd.edu/sites/ndews.umd.edu/files/SCS-Report-2018-New-York-City- 
FINAL.pdf. 
Description of subject population 
Healthy participants meeting DSM-5 OUD criteria and physical dependence on opioids will be enrolled. 
 
 
Recruitment Procedures 
 
 
Describe settings where recruitment will occur 
Potential applicants will first complete a telephone/videoconferencing assessments during which we will 
obtain information on demographics, medical, psychological and personal history, as well as details on their 
use of various prescription and illicit drugs. Participants who pass the initial virtual screening will be 
scheduled for additional in-person screening procedures at NYSPI. All in-person screening and assessments 
(medical examination, and naloxone challenge) will occur within the facilities of the Substance Use Research 
Center (SURC), located on the 3rd floor of the NYSPI. How and by whom will subjects be approached and/or 
recruited? 
 
Interested participants who respond to study advertisements by call the Opioid Research Lab screening line. 
A research assistant or volunteer will conduct a general telephone interview to see if they meet criteria for 
any active studies. These telephone screens are reviewed by a senior member of the research team to 
determine if further in-person screening is warranted. 
How will the study be advertised/publicized? 
Recruitment is primarily through word-of-mouth and advertisements in local newspapers such as 
the Village Voice and AM New York, New York and New Jersey transportation (e.g., Subway and 
Bus),as well as electronic media (e.g., Facebook, Google, StudyKik) and websites that drug users 
frequent such as Bluelight and Erowid).The study will be using RecruitMe as a platform for 
recruitment. This study will be using Moshemu, which specifically targets difficult to reach, 
stigmatized populations (specifically substance abusers). NIDA is funding the creation of this 
recruitment platform and the first researchers to sign up will be able to use the platform for free. 
The Moshemu staff will work to use online recruitment methods to attract potential research 
participants to the Moshemu platform and guide them through an initial screening process. Next, 
researchers will be connected with these participants in order to enroll them into their studies. 
Do you have ads/recruitment material requiring review at this time? 
Yes 


Protocol Summary Form 
8061 
Jones, Jermaine 
Page 7 of 35 
 
 
Does this study involve a clinical trial? 
Yes 
Please provide the NCT Registration Number 
NCT05114460 
 
 
Concurrent Research Studies 
 
 
Will subjects in this study participate in or be recruited from other studies? 
Yes 
Describe concurrent research involvement 
 
7680: Assessing the Effects of Heroin Use on Epigenetic Aging (PI: Jermaine Jones PhD) 
 
6723: Risks and Benefits of Overdose Education and Naloxone Prescribing to Heroin Users (PI: 
Sandra Comer, Ph.D.) 
 
7712: Clinical Trials of Multivalent Opioid Vaccine Components.(PI: Sandra Comer, Ph.D.) 
 
7788: Isolation of opioid-specific B cell lymphocytes and development of human opioid-specific 
monoclonal antibodies(PI: Sandra Comer, Ph.D.) A Randomized, Double-Blind, Placebo- and 
Active-Controlled, Crossover Study to Evaluate the Abuse Potential of Oxymorphone Compared to Other 
Mu-Opioid Agonists in Physically Dependent Opioid Users with Moderate-to-Severe Opioid Use Disorder 
(PI: Sandra Comer, Ph.D.) 
 
 
 
 
 
 
Name the subject group/sub sample 
Opioid Users 
Create or insert table to describe the inclusion criteria and methods to ascertain them 
 
Criterion 
Method of Ascertainment 
1. 18-55 years of age. 
 
Self-reported age and verification with legal 
identification. 
2. Diagnostic criteria for Opioid Use verification 
with legal identification. Disorder (OUD) moderate-
severe (304.00) as    per DSM-V, including 
physiological dependence and not currently seeking 
treatment for OUD. 
MINI Substance Use Module, naloxone 
challenge/visual evidence of opioid withdrawal. 
3. Self-reported opioid use for non- therapeutic 
purposes; and positive urine drug screen for opioids. 
Urine drug toxicology and clinical interviews 
4. Physically healthy. 
Laboratory tests (urinalysis, blood chemistry & 
hematology, 12- 
Inclusion/Exclusion Criteria 


Protocol Summary Form 
8061 
Jones, Jermaine 
Page 8 of 35 
 
 
 
lead ECG), physical examination, and medical 
history.  
5. Body mass index (BMI) ≥ 18 and ≤ 35 kg/m2 and 
weight ≥ 50 kg (110 pounds). 
Weight and BMI calculations. 
6. Able to perform study procedures. 
Practice Session 
7. Females must be either: 
a. Post-menopausal (amenorrhea for at least 12 
consecutive months), surgically sterile  
-or 
b. Women of childbearing potential must agree to 
use an acceptable double-barrier method of 
contraception during screening and study 
participation. 
Urine (Screening) and Serum (Admission Day) 
pregnancy tests, Nurse's assessment. 
8. Must use cannabis products on less than three 
occasions (occasion= a single administration 
period of <30 minutes) per week for the four 
weeks before screening. 
Clinical Interviews 
 
 
 
Create or insert table to describe the exclusion criteria and methods to ascertain them 
 
Criterion 
Method of Ascertainment 
1. Seeking treatment for Opioid Use Disorder. 
Clinical Interview 
2. Current or history of a psychiatric condition that 
would affect participants' ability to provide informed 
consent (e.g., mood disorder with functional 
impairment or schizophrenia) or make participant 
hazardous for the participant (e.g., recent suicidal 
ideation) or staff (e.g., significant history of 
violence). 
 
Beck’s Depression Inventory, CSSRS Screener, 
Psychiatric Examination (with psychiatrist or clinical 
psychologist) 
3. Current DSM-V diagnosis of substance use 
disorders requiring medically managed 
detoxification, other than OUD (e.g., alcohol or 
benzodiazepine dependence). 
MINI: Substance Use Module & Clinical Interviews 
4. Medical condition resulting in chronic pain 
(>3 months). 
Clinical Interviews, Medical History, Physical 
Examination. 
5. Clinically significant abnormality on physical 
examination, vital signs, screening laboratory tests, 
or 12- lead ECG. 
Physical examination, vital signs, screening 
laboratory tests, or 12-lead ECG. 
6. Significant cardiovascular, hepatic, renal, 
respiratory, gastrointestinal, endocrine, 
immunologic, dermatologic, hematologic, or 
Medical History, Physical Exam 


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neurologic disorder. 
7. Any surgical, or medical condition that may 
interfere with the absorption, distribution, 
metabolism, or excretion of the study drugs. 
Medical History, Physical Exam 
8. Baseline hypotension, orthostatic hypotension or 
syncope, hypertension (blood pressure > 140/90), 
pulmonary hypertension or heart disease. 
Medical History, Physical Exam, Nurse's 
Assessment 
9. Any of the following values for laboratory tests: 
a. positive pregnancy test, 
b. hemoglobin < 12 g/dL in males and < 11 g/dL in 
females, 
c. neutrophil count < 1.0 × 109/L, 
d. platelet count < 75 × 109/L, 
e. creatinine clearance < 50 ml/min per modified 
Cockcroft-Gault equation, 
f. aspartate aminotransferase or alanine 
aminotransferase > 3.0 × upper limit of 
Laboratory Testing 
10. Hypersensitivity to opioids, history of significant 
adverse reactions to cannabinoids, and allergy or 
contraindication to any other drugs administered as a 
part of this investigation. 
Clinical Interviews, Medical History 
11. Use of an investigational agent within 30 days. 
Clinical Interviews 


Protocol Summary Form 
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Jones, Jermaine 
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Waiver of Consent/Authorization 
 
 
Indicate if you are requesting any of the following consent waivers 
Waiver of consent for use of records that include protected health information (a HIPAA waiver of 
Authorization) 
No 
Waiver or alteration of consent 
No 
Waiver of documentation of consent 
Yes 
Waiver of parental consent 
No 
 
 
Consent Procedures 
 
 
Is eligibility screening for this study conducted under a different IRB protocol? 
No 
Describe procedures used to obtain consent during the screening process 
 
General Telephone Screening: Participants who respond to study advertisements will complete a general 
Opioid Reserach Laboratory Telephone Screener. Verbal consent to complete the telephone screen is noted 
on the screener form by a volunteer or research assistant. Telephone screens are reviewed by a senior 
member of the research team to determine if further, study-specific screening procedures are warranted. 
 
Remote Study-Specific Screening: Participants who pass the telephone screen will receive a copy of the 
8061 screening consent form via an encrypted email (if the participant has email access), to review while the 
research assistant reviews it with them over the phone. A research assistant, volunteer, nurse, or 
psychologist will note on a physical copy of the consent form, that verbal consent was obtained to initiate 
study-specific remote screening procedures. Following screening consent, participants to begin remote 
screening procedures to minimize the number of in-person visits to NYSPI. During remote screening, the 
participant will complete various screening assessments (e.g., CSSRS, BDI, PhD Interview Nurses 
assessment) with the research assistant, nurse, or psychologist through HIPAA-compliant platforms such as 
Zoom or Facetime, or telephone. The investigators will address any concerns the patient may have regarding 
confidentiality during this process such as access to a private space in which to take calls. These remote 
assessments are primarily collected in Qualtrics (e.g., PhD Interview, NIDA Assist BDI, and CSSR-S), 
while some medical history forms are completed on paper by the assessor). 
 
In-Person Screening: Prior to their first in-person visit, participants will be informed of the risk of COVID- 
19 exposure while traveling to, and while at NYSPI. This information is included in the screening consent 
form. During the in-person visit, the participant will sign a physical copy of the HIPAA form. Participants 
will be given the option of having the signed copy of the consent form sent to them via email, instead of 
receiving a physical copy. 
 
 


Protocol Summary Form 
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Describe Study Consent Procedures 
The study consent will have been reviewed with the participant extensively over the phone, during the 
screening phase of the study. A research assistant (BA/BS) will read the consent form verbatim. The 
participants will be offered the opportunity to ask questions of an investigator or physician during each of 
the in-person screening visit(s), and again when they meet with the MD or NP, who will conduct the 
consenting process. A physical copy of the study consent will be signed with a physician or NP on the day 
of admission (or the final day of screening).The physician or NP will review the inclusion/exclusion criteria, 
comparing it to the participant's screening data, prior to obtaining study consent. Participants will be given 
the option of having the signed copy of the consent form sent to them via encrypted email, instead of 
receiving a physical copy. 
 
 List of Consenters: 
Castillo, Felipe MD 
Comer, Sandra, PhD 
Jones, Jermaine, PhD 
Manubay, Jeanne, MD 
Parmon, Eric, MD 
Greiner, Miranda, MD 
Luba, Rachel PhD 
Franco-Corso, Silvia, MD 
Tindall, Claudia, NP 
Perez, Freymon, BA 
Allwood, Nicholas BA 
Martinez, Suky PhD 
Gopaldas, Manesh MD 
Jimenez, Herman RN 
 
Indicate which of the following are employed as a part of screening or main study consent procedures 
 Consent Form 
 
 
 
 
Would the consent form signature be the only link between the subject’s identity and the research data? 
No 
Is breach of confidentiality the main study risk? 
No 
Is consent for this research procedure ordinarily not required outside of the research context? Explain 
We would like to request a waiver of documentation of consent via 45CRF46.117(c), for the study-specific 
Remote Screening Procedures. Following a brief general telephone screener, some of the study-specific 
screening procedures will be conducted remotely, potential participants will review the approved screening 
consent form, but we will not be obtaining their signature. Instead, the staff member who reviews the 
consent form with the participants and obtains their verbal consent, will document and attest that verbal 
consent was obtained on the screening consent form. Study Consent will be documented with the participant 
and physician's (or Nurse Practitioner's) signature. 
 
 
 
Waiver of Documentation of Consent 


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Select the names of persons designated to obtain consent/assent 
Allwood, Nicholas 
Arout, Caroline 
Castillo, Felipe, MD 
Comer, Sandra, PHD 
Franco, Silvia, MD 
Gopaldas, Manesh 
Greiner, Miranda, MD 
Jimenez, Herman 
Jones, Jermaine, PHD 
Luba, Rachel, PHD 
Manubay, Jeanne, MD 
Martinez, Suky 
Parmon, Eric 
Tindall, Claudia 
Type in the name(s) not found in the above list 
 
 
 
Describe the procedures required for this study 
 
Screening: Healthy adults with Opioid Use Disorder will be recruited for this study in accordance with the 
Inclusion/Exclusion criteria, using the measures outlined in the "Assessment Instruments" section of the 
PSF. After reviewing screening results, a physician and the study PI will make the final decision as to 
whether the participant is eligible for the study. 
 
 
 
To minimize the number of visits to NYSPI (minimizing the risk of COVID-19 exposure for participants 
and staff), some screening measures will be conducted via telephone, Zoom, or Facetime (only HIPAA- 
compliant, CUIMC accounts will be used). Study staff (research assistant, nurse, or psychologist) will 
simultaneously complete paper copies, based on the subjects' responses, or enter data directly into the 
appropriate electronic data capture system (e.g., Qualtrics- which will contain no PHI). 
 
This study requires that some screening procedures occur on-site (e.g., physical, psychiatric evaluation, 
ECG, bloodwork). One of the final screening assessments will be the naloxone challenges (to verify opioid 
dependence). This test will only be performed after the other screening assessments have verified that the 
participant is sufficiently healthy to minimize the risk of this procedure. The day prior to their in-person 
visit(s), a research assistant or nurse will complete a COVID-19 symptom screener. Additionally, a test for 
the presence of COVID-19 and/or its antibodies will be performed prior to admission. As with any 
significant lab results, a member of the medical team will disclose and discuss a positive COVID-19 test 
result, and provide appropriate treatment referrals. 
 
Persons designated to discuss and document consent 
Study Procedures 


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Admission and Morphine Stabilization: Once eligibility is determined, participants will be admitted into the 
secure NYSPI inpatient unit for the duration of the study (approximately 4 weeks). Following admission, 
participants will begin 5-14 days of stabilization on oral morphine (30 mg, QID: 700, 1300, 1800, 2200 hrs). 
Additionally, 10-20mg PO hydromorphone doses will be available PRN to address withdrawal symptoms 
insufficiently managed by oral morphine and supplemental medications alone (to a maximum of 80 mg per 
day). Hydromorphone will be available in addition to QID oral morphine when deemed clinically 
appropriate by the study physician. The participant must exhibit at least "mild" opioid withdrawal 
according to the COWS (score >8). Once stabilized, participants will receive oral morphine daily (30 mg) 
at 700, 1300, 1800, and 2200 hrs. Prior to the initiation of testing sessions, stability on morphine will be 
established. Stability will be defined as participants exhibiting a mean COWS score not exceeding 5, 
with no hydromorphone administration. Vitals and Respiratory Rate will be assessed immediately before 
and for one hour (in 15-minute intervals) following the additional dose to ensure against oversedation. 
 
Common clinically used medications such as, clonidine, zolpidem, and Compazine will be available, along 
with methocarbamol (750-1500 mg, every 6 hours, not exceeding 6000mg in 24 hours). The use of these 
medications will be suspended by 6 PM the day before a lab session. Participants who cannot stabilize and 
will be discharged and offered the same end-of-study treatment options described below. 
 
Safety Session: Testing will not begin until withdrawal symptoms are no longer present, based upon the 
Clinical Opioid Withdrawal Scale (COWS: Handelsman et al., 1987). Prior to testing vaped marijuana in 
combination with intranasal (IN) naloxone, participants will complete a Safety Session. During the safety 
session, they will receive a test dose of vaped marijuana (25 mg). If a participant's vital signs exceed any of 
the following benchmarks outlined in the Criteria for Early Discontinuation, they will be discontinued from 
the trial (Table 1). 
 
 


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Laboratory Testing: Laboratory testing sessions will consist of a modified naloxone challenge procedure 
(A.K.A. Wang Test: Wang et al., 1974). The challenge begins with baseline assessments. Ten common 
symptoms of opioid withdrawal (gooseflesh, vomiting, tremor, sweating, restlessness, lacrimation/nasal 
congestion, yawning, warming/cooling sensations, stomach pain, and muscle ache) will be assessed by a 
research assistant trained in administering the SOWS/COWS. For safety, the physician or nurse who is 
providing medical oversight will directly observe its administration. 
 
Each symptom is coded as either “absent” or “present,” with between 1 and 6 points added when a 
symptom is observed (Table 2). Following pre-test assessments, a physician or nurse practitioner will 
administer the study drug combination (1000-1100 hrs). Assessments of withdrawal are made at 10-minute 
intervals for 50 minutes. The total withdrawal score is calculated at the end of the session. To minimize 
carry-over effects, sessions will be conducted at least 48 hours apart (>5 half-lives of both medications). See 
Table 1 for an example dosing schedule. The following dose combinations of vaped marijuana (V-MJ) and 
IN naloxone will be tested in random order: 
• Naloxone 0 mg + V-MJ 0.0 mg 
• Naloxone 0 mg + V-MJ 12.5 mg 
• Naloxone 0 mg + V-MJ 25 mg 
• Naloxone 4 mg + V-MJ 0.0 mg 
• Naloxone 4 mg + V-MJ 12.5 mg 
• Naloxone 4 mg + V-MJ 25 mg 
 


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Vaping of cannabis provides a rapid and efficient method of drug delivery from the lungs to the brain 
(Abrams et al., 2007; Azofeifa et al., 2016). This investigation will use the MIGHT Vaporizer 
(manufactured by Stoke and Bissel), which allows for precise temperature control of hot air convection 
heating. The device will be set to 210°C. Co-investigators (Dr. Arout and Haney) currently use this device 
and are confident in its safety and biocompatibility. A clinical trial from Australia (Arkell et al., 2019), 
utilized the Mighty Medic device to administer 125 mg THC (11%) to healthy volunteers. Same percentage 
as the current trial, but a lower dose. AEs were minimal (increased self-reports of being “Sedated” and 
“Anxious”). Furthermore, Carra et al., (2020) characterized the delivery kinetics, efficiency, and 
decarboxylation yields of the Mighty Medic for delta-9-tetrahydrocannabinol and cannabidiol. Thus, the 
investigators are confident that the proposed doses of vaped MJ will be pharmacodynamically efficacious 
and well-tolerated. 
 
Dose Rationale: The naloxone dose selection was based on the purpose-designed, overdose first-aid drug 
Narcan® Nasal Spray (4mg/0.1ml). 
 
The V-MJ doses were selected based on proposed efficacy and safety. In a recent trial, Spindle et al., (2018) 
conducted a controlled examination of the effects of vaporized and smoked cannabis in “infrequent” 
cannabis users (N=17). For vaporized conditions, mean peak plasma concentrations for THC were 7.5 
ng/mL at the 10-mg dose and 14.4 ng/mL at the 25-mg dose. Among these normal health volunteers, modest 
impairment of cognitive functioning and psychomotor agitation (e.g., significantly decreased task 
performance) were the most common adverse events. 
 
*Please Note* A 2 mg naloxone dose condition was dropped on the recommendation of the NIDA 


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scientific officer. 
 
 
 
During the Lab session, additionally, adverse events (AEs) unrelated to withdrawal will be quantified using 
the Systematic Assessment for Treatment Emergent Events (SAFTEE: Levine and Schooler, 1986). Pupil 
diameter will be measured using a Neuroptics®) digital pupilometer. Heart rate (HR) and blood pressure 
(BP) will be measured using a Criticare® vital signs monitor and recorded at 15-min intervals. For safety, 
vital signs (HR, BP, and pulse oximetry) will be monitored every 5 minutes for the first 30 minutes, then 
every 15 minutes for the next 1.5 hours at which point THC plasma concentrations should be negligible. 
Additional vital monitoring will occur every 30 minutes for the next 2 hours, for a total of 4 hours of post- 
dose monitoring. In the Criteria for Early Discontinuation section, we have outlined vitals parameters that 
will preclude a participant from completing additional sessions and discontinue their enrollment in the 
trial. 
 
Additional Assessments During Laboratory Sessions (completed at -30, +15, +30, +45, +60): 
 
• The subjective effects battery will consist of Visual Analog Scales and the Opioid Craving 
Questionnaire (Tiffany et al., 1993), 
• Two cognitive tasks will be used in the proposed studies. The Digit Symbol Substitution Task 
(McLeod et al., 1982) and the Divided Attention Task assesses attention (DAT; Miller, 1987). 
• Brief Psychiatric Rating Scale (BPRS) will be performed at +45 
At the end of the test testing session, the participant may receive a rescue dose of oral morphine (30 mg). If 
COWS scores remain >5 at the next measurement timepoint (+15 minutes) an additional 20 mg may be 
provided, at the discretion of a study physician. The testing session may also be terminated 20 minutes 
following naloxone administration (if withdrawal is too severe (COWS >20) and the rescue dose given at 
this time. A physician, nurse practitioner, or nurse will be notified once the COWS score goes above 9. 
The RA will notify the physician/nurse practitioner once the criterion for the morphine rescue has been met, 
who will then administer the rescue dose. If a morphine rescue is given, vital signs will continue to be 
monitored for the entire 4-hour period. If a participant receives a rescue dose during the testing session, the 
1 pm morphine dose may be held at the discretion of the physician. 
 
Suicidality and Pregnancy will be monitored weekly throughout the inpatient period using the CSSRS and a 
urine pregnancy test, respectively. 
 
Discharge: On the day of discharge, All participants receive counseling on opioid overdose risk and 
prevention, and receive an overdose response kit that includes 2 doses of the overdose reversal agent 
naloxone. Prior to discharge, all participants (completers and dropouts) will receive education concerning 
the various pharmacological treatment options for opioid use disorder. We strongly encourage participants 
to consider buprenorphine, methadone, or naltrexone maintenance and explain the benefits of these 
treatments in our discharge procedure. Prior to discharge from the inpatient unit, subjects who express 
interest in treatment will be given the opportunity to receive sustained-release naltrexone or titration onto a 
modest dose of buprenorphine/naloxone (prior to leaving the unit), with referral to a local treatment 
provider. If they refuse both of these options, they will be given a supply of buprenorphine/naloxone for up 
to 7 days. Bup/naloxone may also be given if a participant needs a bridge between discharge and entering 
treatment. 


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Follow-up: Participants will be asked to return to the laboratory 1 month after study completion to assess 
general health and drug use. The follow-up visit may be conducted virtually. 
 
 
I attest to follow the COVID-19 Safety Guidelines for Columbia Psychiatry and NYSPI Re- 
Entry outlined in the NYSPI Director’s June 1st memo, which include but are not limited to: 
 
•  Infection Control/PPE – Guidelines 
• Research participants will only come on-site if absolutely necessary for study procedures. 
• No volunteers/externs on-site during Stage 1. 
• Clinical research teams will screen their participants for COVID symptoms (night before and day of 
onsite visit, documenting this in the chart), and escort them in and out of the building. 
• COVID/COVID-like symptoms in participants will be reported to the IRB via PRISM as an SAE.  
 
 
Dose Escalation Safety Pilot. 
To help ensure the safety of the higher doses of vaped marijuana, the first three participants will receive V- 
MJ and naloxone in a dose-escalating order. The V-MJ 0 mg + naloxone 0 mg, and V-MJ 0 mg + naloxone 
4 mg dose combinations will be inserted randomly in the sequence below. 
 
• V-MJ 12.5 mg + 0 mg Naloxone, 
• V-MJ 25 mg + 0 mg Naloxone, 
• V-MJ 12.5 mg + 4 mg Naloxone, 
• V-MJ 25 mg + 4 mg Naloxone. 
A physician or nurse practitioner will provide close monitoring of each session from the adjacent 
observation room, or within the testing room itself. A summary of the findings from these first three 
participants will be reported to the IRB -on a case-by-case basis- before moving forward to the randomized 
dosing described above. Participants' plans to initiate treatment for opioid use disorder will also be included 
in our report to the IRB. 
 
Suicide Risk Management Plan 
The Columbia-Suicide Severity Rating Scale (C-SSRS) will be used to quantify the severity of suicidal 
ideation and behavior. The CSSR-S is only administered by study staff who have been trained in its 
administration. During screening and follow-up, the C-SSRS is used to assess for suicidal ideation. If there 
is expression or suspicion of suicidality outside of these two timepoints, the C-SSRS will first be 
administered, and action taken accordingly, as outlined below. If a participant endorses active suicidal 
ideation/behavior, staff will notify an Opioid Research Laboratory psychiatrist (Dr. Felipe Castillo) or 
clinical psychologist (Drs Rachel Luba or Suky Martinez), who will conduct a brief, standardized clinical 
interview that reviews the C-SSRS score and quantifies the specific suicidal plans and access to lethal 
means (e.g., firearms). If the Opioid Research Lab clinicians are unavailable, the RA is instructed to contact 
another Division clinician. The Substance Use Research Center maintains an “on-call” list of NYS licensed 
psychologists and psychiatrists who are "on duty" for the day to provide clinical coverage. This list is posted 
in the Opioid Lab research spaces, and available in our Lab’s Google Drive. 


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For participants who are deemed at imminent risk of harm to self or others, the clinician will arrange a 
transfer to the closest Emergency Room (ER). The clinician will speak with the responsible ER physician to 
provide all relevant information and request follow-up on disposition. For participants with non-active 
suicidal ideation/behavior (i.e., not at imminent risk), the clinician will complete the Stanley-Brown Safety 
Plan [Stanley B, Brown GK. Safety Planning Intervention: A Brief Intervention to Mitigate Suicide Risk. 
Cognitive and Behavioral Practice. 2012;19(2):256-264]. 
 
In either above scenario, study staff will also inquire if the participant is currently receiving mental health 
treatment, and if so, she/he will attempt to contact the participant’s mental health provider. If the participant 
is not currently receiving mental health care, they will be provided with referrals to a qualified mental health 
provider. Finally, the study staff and clinician will extensively document the safety steps that were taken, 
the referral process, and follow-up events, in the participant’s chart. 
 
When Opioid Lab clinicians are unavailable, clinical staff on 4-South will manage suicide risk and other 
clinical issues that may arise with study participants. However, 4-South staff are informed to notify an 
Opioid Lab clinician of any important clinical issues that arise with our participants. The inpatient unit is 
provided with a nights and weekends "on-call," which includes the cell phone number of the physician to be 
contacted in such situations. 
 
 
 
 
Criteria for Early Discontinuation 
 
 
Criteria for Early Discontinuation 
 
Do Not Administer Vaped Marijuana (T: -15 mins) if: 
 
• Systolic BP<110 or > 150 mm Hg; Diastolic BP < 60 or>90 mm Hg, or Heart Rate< 60 or >110 
BPM 
 
Do Not Administer Naloxone (T: 0 Mins) if: 
 
• Systolic BP<110 or > 150 mm Hg; Diastolic BP< 55 or >95 mm Hg, or Heart Rate< 60 or >110 
BPM 
 
Discontinue A Session if: 


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• Systolic BP<90 or > 180 mm Hg; Diastolic BP < 50 or >120 mm Hg, or Heart Rate < 50 or > (220- 
Subject's Age) x .85 BPM (Sustained for >10 minutes). 
• BPRS score no greater than 31 
In either of the above situations, vital signs will be monitored continuously until they return to pre-dose 
baseline, and the study physician or nurse practitioner will be notified for further management. If deemed 
necessary by medical staff, appropriate clinical management of abnormal vital signs will occur regardless of 
their severity or duration. 
 
Criteria for Early Discontinuation from the Trial:  
 
• If any of the readings above occur during the Safety session. 
• If two Vaped Marijuana+ Naloxone testing sessions have to be discontinued based on the above 
criterion. 
 
Discontinuation Criteria for Suicidality and Pregnancy 
 
• If a participant self reports the development of suicidal ideation (with intent) throughout the inpatient 
phase, study procedures will be discontinued and appropriate treatment and follow-up care arranged 
prior to discharge. 
• If a participant becomes pregnant during the inpatient period, study procedures will be discontinued 
and appropriate follow-up care arranged. 
 
COVID-19 
If a participant is admitted onto the inpatient unit and subsequently tests positive for 
COVID-19 or develop symptoms, they will discontinue study procedures and be discharged 
from the unit. The appropriate referral will be made (e.g. emergency department, home with 
outpatient follow-up via telemedicine) depending on the participants' clinical status. 
 
 
Blood and other Biological Samples 
 
 
Please create or insert a table describing the proposed collection of blood or other biological specimens 
 
Biological Sample 
Volume 
 
Blood Sample for comprehensive metabolic panel collected during 
screening. 
24 ml 
Urine samples for drug toxicology during each screening visit. 
10-15 
ml each 
Expired air samples will also be taken at each screening visit to 
detect the presence of recent alcohol consumption. 
N/A 


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Nasal swab will be collected to test for the presence of the COVID- N/A 


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19 virus or its antibodies. 
 
 
 
 
Assessment Instruments 
 
Create a table or give a brief description of the instruments that will be used for assessment 
Screening Assessments (Staff Qualified to Administer or Review):  
● NIDA-Modified ASSIST: Adapted questionnaires designed to assist clinicians serving adult patients in 
screening for drug use (PhD). 
● Addiction Severity Index (ASI; McLellan et al., 1992): A self-report structured instrument that evaluates 
the severity of functional impairment in various addiction-related areas (BA/BS). 
● Drug Abuse Screening Test (DAST-10; Skinner, 1982). A 10-item, “yes” or “no” questionnaire was 
designed to assess the degree of problems related to drug use (BA/BS). 
● Beck Depression Inventory (BDI-II; Beck et al., 1972). The BDIII is a 21-item self-report instrument that 
measures the severity of depression. Each item is rated on a 4-point scale ranging from 0 to 3 (PhD or MD 
reviews any scores above 30). 
● Substance Use Inventory (i.e., Clinical Interview by PhD, Comer et al., 2008). This locally-developed 
questionnaire will be used to determine quantity (i.e., dollars spent per day) and frequency (i.e., days) of 
substance use including alcohol, amphetamines, cocaine, marijuana, opioids, phencyclidine and sedatives. 
● Other screening assessments include medical history evaluation (RN or NP), physical examination 
(MD), ECG (MD), blood chemistry/hematology (MD), breathalyzer (BS/BA), urine pregnancy testing 
(BA/BS), and 11-panel urine drug toxicology (BA/BS). 
 
Study Assessments: 
● Modified Naloxone Challenge 
● Systematic Assessment for Treatment Emergent Events (SAFTEE: Levine and Schooler, 
1986). Adverse events (AEs) unrelated to withdrawal will be quantified using this scale. 
● Pupil diameter will be measured as a proxy of μ- opioid receptor activation. 
● Drug “Liking”, and other subjective drug effects will be assessed using a Visual Analog Scale (VAS). 
● Opioid Craving Questionnaire (adapted from Tiffany and Drobes, 1991; Tiffany et al., 1993). 
●Subjective and Clinical Opiate Withdrawal Scales (Handelsman et al., 1987; Wesson and Ling, 2003). 
Withdrawal Scales (Handelsman et al., 1987; Wesson and Ling, 2003) 
● Cognitive Tasks: Two cognitive tasks will be used: The Digit Symbol 
Substitution Task (DSST; McLeod et al., 1982) assesses psychomotor ability and the Divided Attention 
Task assesses attention (DAT; Miller, 1987). 
● Brief Psychiatric Rating Scale (BPRS: Ventura et al., 1993) used to measure psychiatric symptoms such as 
anxiety, depression, and psychoses. 
● Apple Watch or FitBit for Analysis of Sleep Quality and ECG throughout the testing session. 


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Please attach copies, unless standard instruments are used 
 
 
 
Choose from the following that will be applicable to your study 
 Drug 
Select the number of drugs used in this study 
1 
 
 
Name of the drug 
Marijuana 
Manufacturer and other information 
NIDA Drug Supply Program 
Approval Status 
IND is approved 
IND# 
156207 
Who holds the IND/IND sponsor? 
IND is held by PI/CU Investigator 
Jones, Jermaine, PHD 
 
 
 
Will research procedures result in a delay to treatment? 
Yes 
Maximum duration of delay to any treatment 
 
 
For those participants requesting outpatient treatment, appropriate arrangements will be made, including 
placement in an outpatient treatment study at our Substance Treatment and Research Service (STARS), if 
they are eligible or Narcotics Anonymous. As part of research safety measures for discharge, we will bridge 
participants to treatment with buprenorphine/naloxone sublingual films for up to 2 weeks. If a participant 
decides to pursue treatment with buprenorphine/naloxone, s/he will come in every 3-5 days to pick up the 
films. A urine toxicology sample will be collected at this visit. If a participant does not want medication 
assisted treatment for opioid dependence, we will provide them with 3-4 buprenorphine 8mg/naloxone 2mg 
sublingual films for harm reduction purposes. Induction onto Vivitrol treatment will also be available to all 
participants prior to discharge. Induction onto Vivitrol will entail an individually tailored in-patient 
detoxification from opioids prior to Vivitrol. 
 
Maximum duration of delay to standard care or treatment of known efficacy 
Off label and investigational use of drugs/devices 
Drug #1 
Research Related Delay to Treatment 


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4-6 Weeks 
Treatment to be provided at the end of the study 
This is not a treatment study. However, counseling about different treatment options and referrals 
for treatment are available to participants at any time before, during, or after their participation in 
this study. Participants will also be informed that they do not have to participate in this study in 
order to get a referral to help stop taking drugs. Furthermore, our lab is an official New York State 
Dept. of Health naloxone training and distribution site, therefore, they will receive overdose 
education and naloxone without engaging in any study procedures. Prior to discharge, participants 
will receive counseling about the different treatment options for opioid use disorder (Vivitrol, 
buprenorphine, methadone, behavioral therapy, etc.). Additionally, our standard discharge 
procedure includes education about the risks of opioid overdose, how to identify opioid overdose, 
and how to use a naloxone kit provided to them as certified 
opioid overdose responders. 
 
For those participants requesting outpatient treatment, appropriate arrangements will be made, including 
placement in an outpatient treatment study at our Substance Treatment and Research Service (STARS), if 
they are eligible or Narcotics Anonymous. As part of research safety measures for discharge, we will bridge 
participants to treatment with buprenorphine/naloxone sublingual films for up to 2 weeks. If a participant 
decides to pursue treatment with buprenorphine/naloxone, s/he will come in every 3-5 days to pick up the 
films. A urine toxicology sample will be collected at this visit. If a participant does not want medication- 
assisted treatment for opioid dependence, we will provide them with 3-4 buprenorphine 8mg/naloxone 2mg 
sublingual films for harm reduction purposes. Induction onto Vivitrol treatment will also be available to all 
participants prior to discharge. Induction onto Vivitrol will entail an individually tailored in-patient 
detoxification from opioids prior to Vivitrol. 
 
 
 
Clinical Treatment Alternatives 
 
 
Clinical treatment alternatives 
This is not a treatment study. Treatments for OUD include medications (naltrexone, buprenorphine, or 
methadone) and/or psychotherapy. Participants will be informed about these various treatment option at 
several points during the screening process and throughout the study. 
 
 
Risks/Discomforts/Inconveniences 
 
 
Risks that could be encountered during the study period 
1) Naloxone Challenge Testing Paradigm: For this study it is important that we assess physical opioid 
dependence during screening. The naloxone challenge will also be an important testing procedure 
throughout the study enrollment period. The naloxone challenge is a slightly modified version of the Wang 
Test [Wang et al., (1974) Rating the presence and severity of opiate dependence. Clinical Pharmacology and 
Therapeutics 16(4), 653-658.] This test will be performed under the supervision of a research nurse and will 
take approximately 50 minutes to complete. A dose of naloxone will be administered and signs and 
symptoms associated with opioid withdrawal (“gooseflesh,” “vomiting,” “tremor,” “uncontrollable 


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yawning,” etc.) will be scored every 10 minutes. During the procedure, we will measure blood pressure, 
heart rate, and blood oxygen saturation using an automated blood pressure machine and pulse oximeter both 
immediately before and up to 30 min after the naloxone dose. If significant withdrawal is noted, the effects 
of naloxone will then be alleviated by the administration of morphine (up to 50 mg p.o.). For a recent 
publication, we reviewed the most recent naloxone challenges completed (N=29) by the Opioid Laboratory 
(Jones et al., 2020), all of which were completed without unanticipated AEs/SAEs. 
 
To the investigator's knowledge, this will be the first clinical laboratory investigation that will co-administer 
naloxone and marijuana to an opioid-dependent population. Therefore, there may be novel, unanticipated 
adverse effects. 
 
2) Marijuana Administration: Smoking is the principal route of cannabis use, providing a rapid and efficient 
method of drug delivery from the lungs to the brain. Generally, smoked THC is well tolerated even at doses 
similar to the proposed doses of vaped marijuana in the current study. Huestis et al. (1992) examined the 
disposition of THC after smoking a single cigarette (multiple inhalations) containing 1.75% THC (ca. 16 
mg) or 3.55% THC (ca. 34 mg) with few AEs and no SAEs. 
 
In studies of vaped marijuana in normal healthy volunteers, modest impairment of cognitive functioning and 
psychomotor agitation (e.g., significantly decreased task performance) were the most common adverse 
events. Increases in HR and decreases in Systolic BP have also been reported, however, these changes were 
not clinically significant (Farokhnia et al., 2020, Spindle et al., 2018). 
 
Spindle et al., (2018) conducted a controlled examination of the effects of vaporized and smoked cannabis 
in “infrequent” cannabis users (N=17). For vaporized conditions, mean peak plasma concentrations for THC 
were 7.5 ng/mL at the 10-mg dose and 14.4 ng/mL at the 25-mg dose. For smoked cannabis conditions, 
mean peak THC concentrations were 3.8 ng/mL at the 10-mg dose and 10.2 ng/mL at the 25-mg dose. 
Among these normal health volunteers, modest impairment of cognitive functioning and psychomotor 
agitation (e.g., significantly decreased task performance) were the most common adverse events. Two 
participants vomited (1 after 25-mg THC vaporized inhalation, and 1 after 25-mg THC smoked inhalation) 
and another experienced hallucination after inhaling 25 mg of vaporized cannabis. 
 
Concerning physiological measures, significant increases were seen in HR at the 25 mg smoked dose (mean 
19.1 beats/ min) and both doses of vaporized cannabis (10mg, 23.3 beats/min, and 25mg beats/min). 
Systolic BP decreased after the 10 mg smoked cannabis dose (mean −10.1 [23.9] mmHg vs placebo) but did 
not differ across vaporized doses (mean: 10mg, −7.7; 25mg, −6.1 mmHg). Though statistically significant, 
these values did not meet AE/SAE criteria and no participants were prematurely terminated due to their 
physiological response to smoked or vaporized cannabis. See also Farokhnia and Colleagues (2020) who 
examined smoked, and vaporized cannabis [6.9% THC (~50.6 mg)] among occasional (45%) and frequent 
(55%) with few AEs and no SAEs. 
 
Finally, a clinical trial from Australia (Arkell et al., 2019) utilized the Mighty Medic device to vape 125 mg 
THC (11%) in a sample of healthy volunteers. Same percentage as the current trial, and a lower dose. AEs 
were minimal (increased self-reports of being “Sedated” and “Anxious”). 


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Adverse effects such as dysphoria, delirium, anxiety, and psychosis have been observed following the 
administration of high doses of THC and with the use of higher potency/concentrated marijuana products 
(Ashton 2001; Barkus 2016; Devin et al., 1987; Grotenhermen, 2003). 
 
 
There are many unknowns about vaping, including what chemicals make up the vapor and how they affect 
health over the long term. The Centers for Disease Control and Prevention (CDC) has noted an outbreak of 
lung injuries and deaths associated with vaping among people who use e-cigarettes, and THC vaping 
devices. These cases appear to predominantly affect people who modify their vaping devices or use black 
market modified e-liquids. Finally, there is a small risk of electric shock or being burned while using the 
Mighty Medic Device. Co-Investigators Haney and Arout have administered the higher dose of marijuana 
(25 mg), using the MIGHTY vaporizer, to approximately 16 participants to date. They report no 
unanticipated AEs or SAEs. 
 
In summary, the investigators feel that there is sufficient data on the safety and tolerability of rapid-delivery 
THC inhalation routes (e.g., smoked and vaporized) to justify the current design and eligibility criteria. 
 
 
3) Increased Sensitivity to Opioids and Discharge: Opioid-dependent participants may be less tolerant to the 
effects of opioids at discharge. Participants will be told that this increased sensitivity to opiates could result 
in overdose and death and that extreme caution must be exercised after they leave the hospital if they choose 
to use any opioid again. 
 
4) Morphine Stabilization: It is possible that during the initial morphine 
maintenance stabilization phase, some participants may experience mild opioid withdrawal. These 
symptoms include nausea, vomiting, teary eyes, runny nose, loose stool, stomach cramps, 
shakiness, anxiety/irritability, increased heart rate, sweating/chills, restlessness, and body 
aces/discomfort. 
 
The most serious side effects of morphine administration include: respiratory depression or death. More 
common side effects may include allergic reaction and respiratory depression. The most frequently reported 
adverse experiences associated with opioid administration are: nausea, vomiting, headache, dry mouth, 
itchiness, drowsiness, sweating, dizziness, stimulation, sleepiness, lightheadedness, restlessness, a feeling of 
well-being, talkativeness, difficulty urinating and constipation. 
 
5) COVID-19 Related Risks: Most participants will need to take public transportation to arrive 
at NYSPI. This will carry with it the risk of exposure to COVID-19. Exposure risk while participants are at 
NYSPI for screening will be minimal given the procedures the institute has in place (e.g., masks inside at all 
times for participants and staff, staff symptom attestation, social distancing, etc.,). In-person 
interaction with study staff has also been minimized through the use of virtual screening 
procedures when possible. The risk of COVID-19 exposure while on 5-South should be minimal 
as COVID-19 testing prior to admission is being implemented for both research 
participants and patients. We will do everything that we can, in line with NYSPI policy, to 
minimize risk to research participants and staff posed by COVID-19. 


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6) Confidentiality: Another risk to this study involves the confidentiality of private and personal 
information. 
 
7) Pregnancy: Female participants must not be pregnant to be included in the study. 
 
8) Blood Drawing. During blood drawing, there is a risk of slight discomfort and/or bruising at the site 
where the needle is inserted. Approximately 216 ml will be taken during the study (24 ml screening +192 ml 
inpatient)= (14.6 tablespoons or one cup). When someone donates blood, two cups (32 tablespoons) are 
taken on one occasion. 
 
9) Nasal Swab: To test for COVID-19 a 6-inch cotton swab will be placed up both sides of the 
nose; participants may find this uncomfortable. 
 
10) Inpatient Facility: The risks involved in exposure to the inpatient unit and laboratory are minimal, but 
participants may become bored or restless. 
 
11) Psychological distress: The structured interviews, and questionnaires should add no physical risk. 
However, because many of the interviews and assessments are time-consuming to complete and involve 
topics of a sensitive nature, some people have found them to be physically or emotionally tiring. 
 
Describe procedures for minimizing risks 
1 & 2) Naloxone Challenge Testing Session + Marijuana Administration: During these testing sessions, vital 
signs (heart rate, blood pressure, and arterial oxygen saturation) will be monitored. Before drug 
administration, all vitals must be within normal ranges for drug administration to occur. Testing sessions 
will be continuously monitored by a research assistant and nurse, with a physician observing for the first 2 
hours after experimental drug administration, and on-call throughout the entire testing session. Resuscitation 
equipment and supplemental oxygen are available in the testing area, for emergency purposes. 
 
The specific risks that may be associated with vaporized marijuana will be mitigated using the procedures 
below: 
 
• The time that each participant will spend vaping is less than 10-12 minutes (per testing session). 
Thus, each participant will only have minimal exposure to the aerosolized drug product. 
• All participants will be trained in the proper use of the vaporizer, prior to testing. 
• Participants will be excluded from the trial if they suffering from respiratory tract or lung disease. 
• Participants will be closely monitored for symptoms of respiratory irritation (e.g., cough, shortness 
of breath, chest pain) during or after the usage. 
 
Our careful participant selection and selection of doses should preclude the occurrence of SAEs Drs. 
Manubay, Mogali, or Castillo will screen all potential volunteers to ensure they meet medical 
inclusion/exclusion criteria. Other physician coverage is available as a backup, and the Attending Psychiatry 
service will cover daily rounds on the NYSPI inpatient unit where these volunteers will reside. Nurses will 
provide 24-hour/7-day supervision. 


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3) Increased Sensitivity to Opioids and Discharge:  Upon discharge, all participants (completers and non- 
completers) receive education on opioid overdose risk and prevention, including a New York State 
Department of Health Overdose Response Kit that includes 2 doses of naloxone. As this study would enroll 
only participants not seeking treatment for their opioid use (because an opioid is administered as a part of 
the study), most will return to illicit opioid use upon discharge. All participants are given a strong warning 
about the growing prevalence of fentanyl adulteration within the illicit drug market. We strongly encourage 
participants to consider buprenorphine, methadone or naltrexone maintenance and explain the benefits of 
these treatments in our discharge procedure. Those who are interested in treatment for their drug use at the 
end of the study can meet with the NYSPI Social Work department to find a treatment provider. For those 
who are interested, induction on buprenorphine or naltrexone will be made available to them before leaving 
the inpatient unit. All participants will return to NYSPI at 1-month post-discharge for a safety follow-up 
visit. Analysis of our participants following discharge has been conducted across a number of our previous 
studies (Roux et al., 2012). We have found the discharge procedures mentioned above to be effective at 
negating the risk of overdose, encouraging participants to engage in treatment, and lowering overall illicit 
opioid use. 
 
4) Morphine Stabilization:  To assist with stabilization, oral morphine dosing (30 mg, four times/day) may 
be extended for up to 3 days for those participants who require additional stabilization. Participants who are 
not able to achieve stabilization during this time and experience discomfort/withdrawal will be discharged 
from the protocol. Participants will also have access to commonly used medications for opioid withdrawal, 
throughout the stabilization period. 
 
The study will only enroll participants whose street opioid use exceeds that of the morphine maintenance 
dose. The dose of morphine was selected with care to preclude those that produce clinically relevant 
respiratory depression and has been administered in prior studies without serious adverse events (Jones et 
al., 2012). 
 
5) COVID-19 Related Risks: NYSPI is committed to minimizing risk to research participants and staff 
posed by coronavirus 2019 (COVID-19). Participants will be notified of the risk of COVID-19 exposure 
traveling to and from NYSPI and while at NYSPI. We will encourage participants to exercise caution when 
traveling in public and follow public health guidelines, such as wearing masks in public and avoiding 
crowds. NYSPI is taking the following steps to minimize 
the risk of COVID-19 to our patients and staff: 
 All research at NYSPI has been modified to reduce in-person visits and procedures. 
 We are monitoring research participants and staff for signs and symptoms of 
COVID-19. 
 We are taking extra precautions at NYSPI to reduce the risk of COVID-19 infection, 
including but not limited to physical distancing, the requirement of face-covering for all study 
participants, and appropriate PPE for all staff. 
 We have increased our routine cleaning and disinfection procedures. 
 
6) Confidentiality: We will do everything we can to keep others from learning about subjects' 
participation in the research. Concerning virtual study procedures, to ensure confidentiality, 
only HIPAA-compliant videoconferencing and web-based platforms (when needed) will be 


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used (e.g, WebEx, Facetime). Electronic Data Capture systems will be encrypted. Any 
electronic communications sent to participants will be encrypted. 
 
7) Pregnancy: Urine pregnancy tests will be performed at each screening visit and a serum pregnancy test 
upon the day of admission. For women of childbearing potential, a nurse evaluates the participants' methods 
of birth control and evaluates their willingness to, and reliability to practice effective birth control. 
 
8/9 Blood Drawing and Nasal Swab:  To minimize risks only a nurse or trained phlebotomist will perform 
these procedures. 
 
10) Inpatient Facilities: The inpatient unit has procedures in place to minimize boredom on the unit. The 
study staff will also participants will be provided with access to tablets that contain various forms of 
entertainment (e.g movies, games). 
 
11) Psychological distress: Patients are informed prior to study entry that they can refuse to answer any 
questions and that they can request to stop at any time. If a participant becomes agitated during any of the 
interviews or assessments, he or she will be provided with therapeutic assistance. 
 
 
 
Methods to Protect Confidentiality 
 
 
Describe methods to protect confidentiality 
All volunteer PHI is confidential and will be protected according to the guidelines established by 
HIPAA. This allows the investigators on this project to use or share health information with the 
U.S. Department of Health and Human Services representatives, the NYSPI IRB, the NY Office of 
Research Integrity, the FDA, other research collaborators, or when required by law. 
 
Each subject will be assigned a unique identifying number to minimize the use of PHI. Data containing 
volunteer names are kept separately from coded data so that the two cannot be joined. All written 
documents, including PHI, will be stored in locked cabinets at the NYSPI. Key access will be limited to 
immediate laboratory personnel. Electronic information will reside on a stand-alone, password-protected 
computer. Electronic transmission via e-mail or fax with volunteer PHI will have a statement of 
confidentiality and will be encrypted. Any information or materials emailed to participants will be 
encrypted. Only HIPAA-compliant videoconferencing platforms will be used (e.g. CUIMC Zoom accounts). 
Only secure, encrypted, HIPAA-compliant electronic databases will be used (e.g., CUIMC Qualtrics 
accounts). 
 
Will the study be conducted under a certificate of confidentiality? 
Yes, we have already received a Certificate of Confidentiality 
 
 
Direct Benefits to Subjects 
 


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Direct Benefits to Subjects 
This study was not designed to benefit participants directly. However, we have shown that drug use 
significantly declines after participation in our inpatient laboratory studies: specifically, 58% of participants 
reported a nearly 50% decrease in use from pre-admission levels (Roux et al., 2012). 
 
 
Compensation and/or Reimbursement 
 
 
Will compensation or reimbursement for expenses be offered to subjects? 
Yes 
Please describe and indicate total amount and schedule of payment(s). 
Include justification for compensation amounts and indicate if there are bonus payments. 
Participants are compensated (in Cash) for each visit of the screening process ($25-50/visit, depending on its 
duration) for approximately 3 visits plus $50 for the follow-up visit. If a participant is disqualified prior to 
their in-person screening, their compensation may be sent to them in the form of an Amazon gift card or will 
be wired to them. 
 
Participants will be paid $25/day with a $50/day bonus for completion of the study. Use of a per 
diem bonus is necessary to keep participants from leaving the study during the last several days 
when the money remaining to be earned would otherwise be proportionally small. 
 
Payments will be separated into several installments ($600 per week) at the end of the study in 
order to prevent large one-time payments. To minimize the number of visits to NYSPI to receive their study 
compensation, participants may request wire delivery of their $600 payments using a secure service like 
Western Union. 
 
Total payments for study completers will be approximately $1,200-1,700. 
 
 
 
References 
 
 
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