Cannabis, Schizophrenia and Reward: Self-Medication and Agonist Treatment?
Phase: PHASE1
Conditions: Schizophrenia, Dual Diagnosis, Psychotic Disorder, Cannabis Use Disorder
Sponsor: Dartmouth-Hitchcock Medical Center

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Official Title: 
Cannabis, Schizophrenia and Reward: Self-Medication and Agonist Treatment? 
NCT number: 
NCT01964404 
Document Type:  
Study Protocol and Statistical Analysis Plan 
Date of the 
Document: 
Version Date:  4.30.2021 
IRB Approval Date: 05/27/2021 
 
 
 

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 Dartmouth College and Dartmouth-Hitchcock Medical Center 
Committee for the Protection of Human Subjects 
 
CPHS Study Plan for Full Committee Review 
Template v. 02/11/2013 
 
Instructions:  
The following information in the format provided below is an application for CPHS review.  Read through each section and 
respond to each item (even if to indicate NA - not applicable). Please also review the CHECKLIST for Full Committee 
Submission.  We have provided some guidance information under each question.   
 
Please define all acronyms at first use and attach a glossary if more than 3 acronyms are used in this application. 
 
When revising a CPHS reviewed Study Plan for further review, please track the changes.  To turn on tracking in this 
document in Microsoft Word:  
1) Display the forms and reviewing toolbars. 
2) Unlock the form by clicking on the lock icon on the forms toolbar.  
3) Turn on change tracking by clicking the icon on the reviewing toolbar.  
4) Lock the form by clicking again on the lock icon on the forms toolbar.   
 
Attachments:  
Complete and submit Attachment(s) if applicable to the research study. 
Attachments may be downloaded from this webpage: http://www.dartmouth.edu/~cphs/tosubmit/forms/StudyPlanAttach 
 Attachment A:  Nonsignificant Risk Devices 
 Attachment B:  Placebo 
 Attachment C:  Genetic Research 
 Attachment D:  Employees and Students 
 Attachment E:  Illiterate Participants 
 Attachment F:  Research Involving Children 
 Attachment G:  Research Involving Individuals With Impaired Decision-Making Capacity  
 (formerly referred to as incompetent) 
 Attachment H:  Request for Waiver of Participant Consent  
 Attachment I:  Request for Waiver of Participant Signed Consent Form 
 Attachment J:  Drugs or Biologics 
 Attachment L:  International Research 
 Attachment M:  Pregnant Women, Fetuses and Neonates 
============================================================== 
 
Local Principal Investigator:   Mary F. Brunette, M.D.     
 
 
 
 
Department:  
 
       Psychiatry     
Study Title:  Cannabis, Schizophrenia and Reward: Self-Medication and Agonist Treatment?     
Funding Source (Sponsor):   National Institute on Drug Abuse (NIDA)     
 
1. Abstract.   
Provide an abstract of the proposed research in language that can be understood by a non-scientist.  
The abstract should summarize the objectives of this project and the procedures to be used, with an 
emphasis on what will happen to the subjects. (Maximum 250 words)  

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  Substance use disorders, particularly cannabis and alcohol, are strikingly common in patients 
with schizophrenia (SCZ) and contribute to its overall morbidity and cost to society.  We have 
proposed a neurobiologic formulation suggesting that cannabis and other substance use in 
these patients may ameliorate a dysfunction in the brain reward circuit (BRC) (thus serving a 
“self-medication” function for them), while also worsening their symptoms and course of SCZ. 
 
In this translational research proposal, based on our formulation of the basis of cannabis and 
other substance use in patients with SCZ, we seek to confirm and expand upon data obtained 
in our pilot study suggesting that cannabis and the cannabinoid agonist dronabinol, given in 
low dose to patients with SCZ and co-occurring cannabis use disorder (CUD), will in fact 
ameliorate the BRC dysregulation in these patients and, thereby, provide evidence in support 
of the role of cannabis as a “self-medication” agent for them. Moreover, by also testing the full 
range of effects produced by dronabinol in these patients (effects on brain reward circuitry 
assessed with task-based fMRI and resting state connectivity (RSC)), as well as on reward 
responsiveness, mood, craving, cognition, psychiatric and extrapyramidal symptoms), we will 
provide clues as to whether dronabinol should be tried in low doses as an adjunctive agent 
(with an antipsychotic medication) to limit cannabis use in patients with SCZ. 
 
This study will involve 8 groups of 25 participants each. Groups 1-3 will have diagnoses of 
SCZ and CUD (SCZ-CUD); Group 4 will have SCZ only, Groups 5-7 will have CUD only and 
Group 8 will be healthy control participants.  Following screening and baseline 
neuropsychiatric testing, participants will have two tests days (T1 and T2) that will include 
task-based fMRI, including assessment of RSC, and measuring a number of other parameters 
including reward responsiveness, mood, craving, symptoms and cognition.  The assessments 
at T1 will be virtually the same for all groups.  At T2 Groups 1-3, and Groups 5-7 will be 
randomly assigned to one of the following conditions prior to the assessments: receiving 15mg 
of dronabinol and smoking a placebo marijuana cigarette, receiving two placebo capsules and 
smoking a real marijuana cigarette, or receiving two placebo capsules and smoking a placebo 
marijuana cigarette.  Group 4 and Group 8 will receive no drug or placebo at T2.  Those 
participants receiving drug will have safety assessments before the drug is administered, after 
the drug is administered but before leaving the research clinic for the day, and again a week 
later. 
 
 
2. Objectives & Hypotheses:   
 List your research objectives and hypotheses. 
   In this proposal, we seek to confirm and expand upon our pilot, small "N" pharmacology 
laboratory investigation of the effects of cannabis and the cannabinoid agonist dronabinol in 
patients with SCZ-CUD. 
 
Aim 1 of this study will assess the status of the BRC in patients with SCZ-CUD and in 
healthy controls, as well as in those with SCZ (without CUD) and with CUD (without SCZ): 

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(1a) To confirm that (i) task-related fMRI activity linked to a monetary brain reward probe; (ii) 
inter-regional resting state functional connectivity; and (iii) a behavioral measure of reward 
responsiveness will be decreased in patients with SCZ-CUD as compared to healthy controls; 
and (1b) to explore these measures in those with SCZ (without CUD) and in those with CUD 
(without SCZ). 
 
Aim 2 will assess the effects of cannabis and dronabinol on the BRC in patients with SCZ-
CUD and in those with CUD (without SCZ): (2a) To confirm whether dysfunctional (i) task-
related fMRI activity linked to a monetary brain reward probe, and (ii) inter-regional resting 
state functional connectivity will be ameliorated when patients with SCZ-CUD smoke a 
cannabis cigarette, or take a dronabinol pill; (2b) to explore whether a behavioral measure of 
reward responsiveness will be improved when patients with SCZ-CUD smoke a cannabis 
cigarette, or take a dronabinol pill; and (2c) to explore the effects of cannabis and dronabinol 
on these measures in participants with CUD (without SCZ) and to compare the results to those 
from (2a).  
 
Aim 3 will assess other effects of dronabinol in patients with SCZ-CUD: To determine (3a) 
whether measures of cannabis craving, mood and negative symptoms will improve; and (3b) 
whether measures of psychotic symptoms and cognitive deficits will increase (worsen). 
 
By probing BRC dysregulation and testing the effects of smoked cannabis on this 
dysregulation, this study will help elucidate whether "self-medication" may be an important 
component of cannabis use in patients with SCZ. Moreover, by further elucidating the 
physiological effects of dronabinol, this research can lead to development of therapeutic 
agents, potentially including dronabinol, other cannabinoids or non-cannabinoid agents that 
may ameliorate a BRC deficiency and thus limit cannabis use in these patients. This is of great 
importance because, despite the data suggesting that the atypical antipsychotic clozapine 
(CLOZ) limits cannabis use in patients with SCZ, its side effects discourage many clinicians 
from using it. Finding new medications, safer than CLOZ, that may be able to limit cannabis 
use in these patients is thus of great public health importance. 
 
     
3.  Introduction:   
a) Explain the background of this project so that we will understand why it is important to perform this 
research project.  b) Summarize previously published data and pilot studies.  Be sure to include a 
discussion of any data that do not support the study hypothesis.  If a study similar to the one being 
proposed has already been completed, explain why the proposed study is necessary.  c) For studies 
designed to compare or evaluate therapies, there should be a statement of the relative advantages or 
disadvantages of alternative modes of therapy.  d) If not obvious, explain why human subjects are 
necessary.  Include references for all published data cited.  If a formal protocol for the study exists, page 
references to the protocol are acceptable. 

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  NOTE: This section is an abridged version of the materials submitted for the grant proposal.  
For the full background and description of the literature, please see the grant submission. 
 
Schizophrenia (SCZ) is a severe psychiatric disorder occurring in 1% of the population. 
Patients with SCZ are quite vulnerable to substance use disorders (SUDs); 1 6, 17 It is estimated 
that, 47% of patients with SCZ have serious problems with alcohol or drug use during their 
lifetime compared to 16% of the general population. Cannabis use disorder (CUD) occurs 
commonly in patients with SCZ 18, 19 with lifetime rates three to ten-fold over the lifetime 
prevalence in the general population.16 Co-occurring CUD in patients with SCZ has been 
associated with clinical exacerbations, non-compliance with treatment, poor global 
functioning, and increased relapse and rehospitalization rates.1, 8, 16, 18, 21, 23, 29-36 
 
Basis of cannabis (and other substance) use in SCZ: We have proposed a neurobiologic 
formulation of the self-medication hypothesis of why person with SCZ have a higher rate of 
SUDs.43  Many brain areas that are dysfunctional in SCZ (particularly decreased prefrontal 
cortex (PFC) activity and hyperactive mesolimbic system)e.g.,44-46 are part of the dopamine 
(DA)-mediated "brain reward circuit" (BRC).47  While cannabis's actions are complex, and may 
involve many other neural systems, it appears that cannabis, like alcohol, cocaine and other 
drugs of abuse, produces its reinforcing effects on animal behavior via midbrain DA neurons 
projecting into the prefrontal cortex and limbic system.49-58 In patients with SCZ, cannabis and 
other substance use, which increase DA activity in the PFC,e.g.,52-54, 59 may also enhance 
functioning of the dysfunctional BRC by an increase in the neuronally-based "signal detection" 
of these DA-rich systems.60, 61  
 
Thus, the "basis" of the use of these substances in patients with SCZ may be related to the 
difficulty that these patients have in experiencing "normal" levels of reward from the 
environment and to the ability of cannabis and other substances of abuse to ameliorate this 
"reward system" deficit.43, 47, 62, 63 This proposal gives us the opportunity to gather data 
supportive of this theory, and, potentially, to create a new medication development strategy 
for agents that may ameliorate this deficit and thereby limit cannabis use in these patients. 
 
Brain reward circuit dysfunction in SCZ: A number of studies have provided support for a 
BRC abnormality in SCZ. Structural neuroimaging studies have demonstrated abnormal 
volumes in several regions of the brain implicated in reward processing.64, 65  Other studies, 
including our own, using olfactory and monetary probes of the BRC, measures of resting state 
functional connectivity, and behavioral assessment of reward responsiveness, have provided 
further evidence consistent with a BRC dysfunction in patients with SCZ. e.g., 4-8, 66-73  
 
Functional (f)MRI – monetary incentive delay (MID) studies: A growing body of literature 
employing fMRI in healthy subjects has provided evidence that monetary probes (e.g., the 
monetary incentive delay (MID) task) activate several brain regions linked to the processing of 
reward.74-79  A number of fMRI studies 4-7, 71, 72 have found that patients with SCZ, with no 

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history of substance use disorder (SUD), have a deficit of response within the nucleus 
accumbens during anticipation of monetary reward, despite an ability to perform the task 
normally.  Moreover, our group has also demonstrated a BRC deficit in the nucleus accumbens 
of patients with SCZ and CUD. The proposed study will allow us to confirm and extend this 
finding. 
 
Resting state functional connectivity (RSC) studies: RSC analysis uses estimates of inter-
regional synchrony to detect neural circuit abnormalities without the complexities sometimes 
encountered when using task-based functional analysis methods, e.g., such as differential 
performance levels.85, 86 Using RSC in normal controls, Di Martino and colleagues91 identified 
cortical-striatal circuits, including one consistent with the BRC that they termed the "reward-
related motivational circuit” (comprised of the nucleus accumbens, anterior cingulate cortex 
and lateral orbitofrontal cortex). To our knowledge, our pilot data (see below) are the first to 
suggest that RSC can in fact delineate decreased inter-regional synchronization in the BRC in 
patients with SCZ-CUD. The proposed study will allow us to confirm and expand upon these 
pilot data.  
 
Probabilistic Reward Task studies: A number of studies have used a behavioral measure of 
reward responsiveness, the Probabilistic Reward Task,93 to probe the integrity of the BRC in 
SCZ. Specifically, the task measures the extent to which a participant biases their responding 
toward more rewarded versus less rewarded stimuli, consistent with the view that response 
frequency is increased towards reinforcers.94 On this measure, patients with SCZ show 
improved reward responsiveness following treatment with varenicline,95 and our pilot data, as 
well as AhnAllen et al.,73 suggest the ability of this measure to serve as a behavioral probe of 
the BRC deficit in patients with SCZ. We note that although one study97 did not observe 
abnormal response bias on the task in patients with SCZ, this study did not regulate the use of 
nicotine (which is known to improve performance on the task).98 By contrast, our study 
regulated nicotine use, and our proposed study will as well. 
 
Effects of cannabis or THC on BRC in SCZ: There has been limited investigation of the effects 
of cannabis on neural activity in SCZ. In one study, in which a patient with SCZ secretively 
smoked cannabis between two SPECT scan sessions, striatal DA D2 receptor binding 
significantly decreased after cannabis use, suggesting increased synaptic DA activity.99-102 PET 
studies involving acute delta-9-tetrahydrocannabinol (THC) administration in non-SCZ 
cannabis users have observed increased blood flow in frontal, cerebellar, anterior cingulate, 
and other paralimbic regions during rest,103-107 with, however, conflicting data about release of 
striatal DA.108-110 Our pilot data (below) are the first to suggest that cannabis and the 
cannabinoid agonist dronabinol may increase activation of and connectivity within the BRC in 
patients with SCZ-CUD, and thus ameliorate their BRC dysfunction. This proposal will allow 
us to expand upon these pilot data. 
 

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Treatment of patients with SCZ and CUD: The treatment of SCZ involves the use of 
antipsychotic drugs, which appear to be of limited value in controlling substance use. 111 By 
contrast, a number of studies, including several from our group, suggest that the atypical 
antipsychotic CLOZ may be helpful in limiting cannabis and other substance abuse in patients 
with SCZ.112-122 Moreover, we completed a randomized study of CLOZ vs. other antipsychotics 
in 35 patients with SCZ and CUD, which indicated that patients treated with CLOZ had fewer 
days of cannabis use compared to those treated with other agents (p<.06).123 Regarding other 
atypical antipsychotic medications, the available data are somewhat mixed and not overly 
promising.111, 124-135 Thus, CLOZ remains the only antipsychotic where there is consistent 
evidence of a substantive decrease in cannabis and other substance use. However, given 
CLOZ's side effects, which limit its clinical use, a search for other agents that are at least as 
effective as CLOZ for limiting cannabis use, but are safer, is appropriate. This proposal may 
help facilitate that search.  
 
Cannabis and dronabinol – testing the BRC hypothesis: As described above, we have 
hypothesized that patients with SCZ have BRC dysregulation underpinning their cannabis 
use, and that cannabis use in these patients serves to "self-medicate" this BRC abnormality. To 
build upon the supportive data from our pilot study, in this protocol we will assess measures 
of BRC functioning in patients with SCZ-CUD (and in those with CUD alone) both during 
cannabis abstinence and after smoking a cannabis cigarette. 
 
Dronabinol – a potential treatment? Our formulation of the action of CLOZ suggests it is able 
to decrease cannabis use in patients with SCZ because of a putative ability to ameliorate a BRC 
deficit in these patients. Our pilot data further suggest that the THC agonist dronabinol, if 
given at low dose, may have a similar effect. We propose to confirm and extend, in a 
laboratory setting, the data from our small "N”, pilot study regarding the effects of low doses 
of dronabinol on: (1) activation of BRC during an fMRI monetary incentive delay task and 
connectivity within BRC during rest; (2) reward responsiveness; (3) craving for cannabis, as 
well as the ”high” and “liking” it produces; (4) mood; (5) cognition; (6) psychiatric symptoms; 
and (7) extrapyramidal (EPS) side effects of medication. If dronabinol can be clearly 
demonstrated to improve BRC functioning and, potentially, measures of mood, craving or 
negative symptoms, without worsening cognition or psychotic symptoms, it would be 
appropriate to determine in a prospective trial whether it would be a useful adjunctive 
treatment (given with an antipsychotic medication) for patients with SCZ and co-occurring 
CUD. 
 
OVERVIEW OF PROPOSED STUDY 
In this translational research proposal, based on our formulation of the basis of cannabis and 
other substance use in patients with SCZ, we seek to confirm and expand upon data obtained 
in our pilot study suggesting that cannabis and the cannabinoid agonist dronabinol, given in 
low dose to patients with SCZ and co-occurring CUD, will in fact ameliorate the BRC 
dysregulation in these patients and, thereby, provide evidence in support of the role of 

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cannabis as a "self-medication" agent for them. Moreover, by also testing the full range of 
effects produced by dronabinol in these patients (effects on brain reward circuitry assessed 
with task-based fMRI and RSC), as well as on reward responsiveness, mood, craving, 
cognition, psychiatric and extrapyramidal symptoms), we will provide clues as to whether 
dronabinol should be tried in low doses as an adjunctive agent (with an antipsychotic 
medication) to limit cannabis use in patients with SCZ. 
 
This innovative study proposes to include control groups with SCZ (without CUD) and CUD 
(without SCZ) in the study will allow us to begin to tease apart the differential influences of 
SCZ and CUD on BRC dysfunction. Moreover, by further elucidating the effects of cannabis 
and dronabinol on the BRC in patients with SCZ-CUD (as well as in those with CUD alone), 
this innovative translational research project may also lead to other agents that ameliorate 
dysregulated brain reward circuitry in patients with SCZ and thus may also be able to 
decrease their cannabis use. This is of importance since the only medication that has been 
shown to limit cannabis use in these patients – CLOZ – is not able to be used routinely in these 
patients due to its severe side effects. 
 
Preliminary Studies: 
The PI and colleagues have focused on issues related to SCZ and co-occurring alcohol and/or 
CUD and on alcohol use disorder without SCZ over the past 12 years, with studies funded by 
NIH and industry. They have addressed the effect of CLOZ and related compounds on alcohol 
drinking in rodents; the development of an animal model of SCZ and alcohol abuse; clinical 
trials of medications for SCZ and alcohol or cannabis use disorders; medication trials for 
alcohol use disorder; and neuroimaging studies of the BRC in patients with SCZ and co-
occurring CUD. Here we briefly describe those studies most relevant to this application. 
 
FMRI (MID) assessment of BRC in patients with SCZ and CUD: Under funding from NIDA, 
we assessed BRC functioning in 14 patients with SCZ and CUD and in 10 normal controls, 
using a monetary incentive delay (MID) task linked to fMRI, similar to the technique reported 
by Knutson et al.83, 153 Results are presented in Figure 1 for the anticipation of winning a reward 
relative to no reward using a nucleus accumbens ROI. Significant (p.<0.01) activation in the 
healthy control group is seen in the nucleus accumbens bilaterally (1a), but very little 
activation is seen in the patient group (1b), and comparison of the groups shows decreased 
accumbens activation bilaterally in the patient group relative to the controls (1c). This finding 
is consistent with prior fMRI studies of reward processing in healthy adults and patients with 
SCZ.4-8 

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Cannabis or dronabinol in patients with SCZ and CUD:  We obtained pilot data in 15 
subjects with SCZ and CUD. We built an MRI-compatible vented hookah-like device and hood 
to allow for cannabis smoking in the scanner room. Using this device, we determined that 
smoking two-thirds of a 3.6% cannabis cigarette (utilizing the Foltin method155) produces a 
moderate “high” in patients who abstained from cannabis for at least 7 days, but without 
producing untoward psychosis. We also determined that a 15 mg dronabinol pill, in contrast 
to a 5 mg or a 10 mg pill, produces a moderate level of "liking" in patients who had abstained 
from using cannabis for at least 7 days, but does not increase psychotic symptomatology. THC 
plasma levels from the 3.6% (THC) cannabis cigarette peaked shortly after smoking.  This 
confirmed the decision for the dose of the dronabinol pill and (THC) cannabis cigarette; and 
provided data to indicate the proper timing of smoking a cannabis cigarette to ensure an 
adequate THC plasma level during our pilot scanning protocol. We also gathered pilot 
imaging and reward responsiveness data from 12 subjects with SCZ-CUD, and 12 normal 
controls, utilizing a protocol similar to that proposed below. Baseline data (T1, obtained after 
at least 7 days of cannabis abstinence and before they smoked a cannabis cigarette or took a 
dronabinol pill) revealed that patients with SCZ-CUD have a deficit in BRC functioning using 
the MID paradigm, similar to that noted in Figure 1. 
 
Patients also showed significantly (p < 0.05, FDR corrected) decreased resting state functional 
connectivity of the bilateral nucleus accumbens seed regions91 with ventral anterior cingulate 
cortex (ACC), orbital frontal cortex (OFC), anterior PFC, parahippocampal cortex and insular 
cortex, as compared to control subjects. (By contrast, hyperconnectivity was detected in the 
default mode network (DMN), as we have reported previously in patients with SCZ [without 
CUD])90   Moreover, using a behavioral measure, the Probabilistic Reward Task,93 we observed 
reduced baseline reward responsiveness in the patients compared to the normal controls, as 
indicated by the greater response bias in the control group than the patient group. 
One week after baseline testing (T1), while still abstinent from cannabis, 6 patients received a 

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cannabis cigarette and 6 received a dronabinol pill. During anticipation of reward in the MID 
task, patients who smoked cannabis showed significantly increased fMRI activation relative to 
baseline in several regions of the BRC including the ventral tegmental area and the medial 
prefrontal cortex, while those given dronabinol showed increased activation in BRC regions 
such as the caudate and the medial prefrontal cortex. Patients in both the cannabis and 
dronabinol groups demonstrated increased RSC (p < 0.05, FDR corrected) between the nucleus 
accumbens and the OFC, ventral ACC, anterior PFC and parahippocampal cortex (Fig. 2b and 
2c). (By contrast, hyperconnectivity in the DMN decreased with both cannabis and 
dronabinol.) Moreover, the observed increases in RSC of the BRC correlated with plasma THC 
levels taken immediately prior to the resting scan. Together, these pilot data provide 
preliminary support for our hypothesis that patients with SCZ may use cannabis in an attempt 
to normalize dysregulated BRC, and, moreover, that dronabinol, used in low doses, may have 
similar effects without producing an increase in psychosis. 
 
 
4.  Design, procedures, materials and methods:   
Use a level of detail similar to what would be used when submitting an article for publication in a peer 
reviewed journal.  Explain the study procedures, data collection, and analysis process.  Please define 
terms and explain concepts which might be confusing to reviewers who are not expert in the area of the 
study. If a formal protocol for the study exists, page references to the protocol are acceptable. 
 
   Overview: This study is an investigation of the effects of cannabis and of the cannabinoid 
agonist, dronabinol, in "dual diagnosis" participants with SCZ and co-occurring CUD, at the 
Dartmouth-Hitchcock Medical Center (DHMC) the University of Vermont (UVM) and the 
White River Junction Veterans Administration Medical Center (WRJ VAMC). The study, 
involving a total of 200 participants (out of 400 recruited), will include 8 participant groups 
(N=25/group):  
Groups 1, 2 and 3 – participants with SCZ-CUD 
Group 4 – control participants with SCZ (without CUD)  
Groups 5, 6 and 7 -- control participants with CUD (without SCZ) 
Group 8 -- healthy control participants.  
Participants will be studied using the MID task and Paced Motor task linked to fMRI, resting 
state functional connectivity, and the Probabilistic Reward Task (a measure of reward 
responsiveness). Additional assessments will include measures of psychiatric symptoms, 
craving for cannabis, mood, "high", "liking", cognitive measures, extrapyramidal (EPS) side 
effects of antipsychotic medications, and plasma levels of THC. 
 
Following medical center guidelines, participants will be asked about symptoms of COVID-19, 
exposure to someone with COVID-19 and travel, and will also be assessed for fever; visits will 
not occur if they have symptoms or recent exposure.  Participants will be required to wear a 
mask covering their mouth and nose, and research staff will wear protective equipment per 
medical center guidelines during study visits.   

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After completing the informed consent process, participants will be screened for study 
eligibility.  The Baseline Neuropsychiatric Testing Visit will occur once participants have 
achieved 7 days of abstinence from cannabis and other substances.  Once participants have 
achieved 14 days of abstinence, they will be assessed with the fMRI protocol and other 
measures twice -- at Time 1 (T1) and Time 2 (T2), each separated by a target duration of 7 days 
(minimum 2 days with no set maximum time interval between scan days) with continued 
criteria of 14 days of abstinence before T2). At T1, the assessment will occur without any 
intervention. At T2, the assessment will occur after administration of a double-blinded 
cannabis cigarette and a placebo pill for participants in Group 1; a double-blinded placebo 
cigarette and a dronabinol pill for participants in Group 2; and a double-blinded placebo pill 
and a placebo cigarette to participants in Group 3. Participants in control Groups 4 and 8 will 
receive no intervention at Time 2. Participants in control Groups 5, 6 and 7 (CUD without SCZ) 
will be studied in the same fashion as those in Groups 1, 2 and 3, i.e., with an intervention at 
T2.  
 
Protocol: Screening assessments (including medical history and physical assessment) will 
confirm inclusion and exclusion criteria. If participants, who are otherwise eligible, require 
more time to meet certain eligibility criteria (e.g., additional time to meet one month on a 
stable dose of antipsychotic), they may proceed to the Abstinence Period and Baseline 
Neuropsychiatric Assessment Visit, however, participants must meet all applicable eligibility 
criteria before proceeding to the T1 scan day.  Patient eligibility will be reviewed by a study 
physician prior to the T1 Scan Day. 
 
Abstinence Period: All study participants will be asked to refrain from any cannabis, alcohol, 
other substance use (except nicotine and caffeine) for a period of 14 days after the screening 
assessments until the day of T1, described below. (Note: If the study proves not to be feasible 
with a period of 14 days of abstinence, the PI will decrease the interval to 7 days as in the 
previous study.)  Participants who are in the groups that use marijuana will be told that it can 
take days or weeks for THC to no longer be detected in the body, instructed about the 
schedule of assessments to assess/reinforce their abstinence, and educated about cannabis 
withdrawal.  Participants will be assessed for cannabis withdrawal at each visit.)  A Timeline 
Followback (TLFB) interview and urine/breath tests (to confirm substance abstinence) will be 
obtained approximately 6 times (up to 3x per week with a minimum of once per week) during 
this period and approximately 3 times per week with a minimum of once per week during the 
period betweenT1 and T2 for participants with a CUD. (See details below for Groups 4 and 8 
who do not have any history of a substance use disorder) Those whose tests indicate 
abstinence will receive a $30 credit to encourage continued abstinence. Study participants and 
control participants will only progress to the Scan Days of the study if they achieve 14 days of 
substance abstinence and will only progress to the Baseline Neuropsychiatric Assessments if 
they achieve 7 days of substance abstinence.  
 

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The criteria for determining abstinence will be as follows: 
 For alcohol and substances other than cannabis and synthetic cannabinoids, if the 
person reports being abstinent on the TLFB since last assessment and tests negative for 
the substance, they will be considered abstinent.   
 For cannabis, the following two criteria must be met for the person to be consider 
abstinent: 
o The person reports being abstinent on the TLFB since last assessment and; 
o The dipstick test for cannabis is negative or if the dipstick test is positive, results 
of quantitative testing at the reference lab indicate abstinence (e.g. downward 
trend in THC level and/or low levels of THC in the participant's urine.   
 For synthetic cannabinoids (aka K2/Spice) the following procedure will be followed. 
1. If patients deny ever using synthetic cannabinoids in the past year at the 
Screening Visit and this is confirmed by the reference lab, then abstinence for 
synthetic cannabinoids will consist of the participant's self-report on TLFB. The 
only additional specimens to be sent to the reference lab are those at the Baseline 
Neuropsych Testing and on the two scan days.  Participants will be paid based 
solely on their report on the TLFB and no payments to participants for abstinence 
will be held pending completion of this testing (see below).  
2. If patients report using synthetic cannabinoids in the past year at the Screening 
Visit, then abstinence for synthetic cannabinoids will consist of the participant's 
self-report on TLFB and sending a urine specimen from each visit to the 
reference lab for testing. Participants will be paid based on both their report on 
the TLFB and the result from the reference lab.   
3. If patient denies use of synthetic cannabinoids at screening, but tests positive for 
these drugs or later admits to use, the procedure outlined in #2 (above) will be 
followed. 
 There is a delay of 4-7 days in obtaining quantitative results from the reference lab.  Payments 
for abstinence will not occur until there is enough information to state that the participant has 
been abstinent.  Baseline neuropsych testing, will be conducted while reference lab results are 
pending as long as all other assessments indicate that the patient has been abstinent. At the T1 
and T2 scans the urine must test negative on site in order to proceed with scanning. 
 
 
The criteria for determining abstinence for Study Group 8 (Healthy Controls) will be based on 
the participant's report of abstinence from alcohol and drugs and confirmation by a negative 
test on the breathalyzer and urine dipstick test for cannabis and other drugs.  Participants in 
Group 8 will not be required to have additional visits 3x per week to encourage abstinence. 
The criteria for determining abstinence for Study Group 4 (Schizophrenia Only) will be the 
same with the exception that staff will attempt to contact participants once during each week 
to assess and encourage further abstinence.   
 

v.4.30.2021 
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Any substance use other than cannabis by a participant who is abstinent from cannabis shall 
be reviewed with Dr. Brunette.  Use that is likely to affect the risks to participants or the results 
of assessments will result in postponement of T1 and T2 Days.  An isolated instance of using a 
substance a few days prior to testing is unlikely to affect the study results or risk; whereas 
continued regular use of a substance could produce such an effect.   
  
Baseline Neuropsychiatric Testing: After a minimum of 7 days of abstinence, patients will 
come into the laboratory or their local clinic as applicable for the Baseline Neuropsychiatric 
Assessments. This testing will include extrapyramidal side effect (EPS) assessment and 
cognitive testing. If necessary, it may be possible to conduct some or all of this testing during 
the Scan Days. 
Based on participants' prior exposure to MRI scanning, research staff will introduce 
participants to the scanner procedures, show them the scanner, and teach them relaxation 
techniques (if they are concerned about being anxious in the scanner.)  If the scanner is not 
available for this purpose during the Baseline Visit, this will be done at the first MRI Visit.   
 
Scan Days - Day of T1: T1 will occur as soon as possible after at least 14 days of abstinence.    
Please note that the exact schedule may need to be modified due to unforeseen events, such as 
participants arriving late or encountering some form of difficulty and participant schedules.  
Participants who are caffeinated beverage drinkers will be given a caffeinated beverage 
(coffee, tea, soda, etc) in order to prevent caffeine withdrawal which may affect the brain 
reward circuit. (The exact schedule of caffeine, nicotine and food intake may need to be varied 
to account for changes in the schedule.)  All patients with SCZ will be asked to take their usual 
morning antipsychotic medication at approximately the same time as usual. When participants 
arrive at the hospital for their scan, they will undergo urine/breathalyzer/pregnancy testing 
and they will be given breakfast (or similar meal as applicable). Assuming confirmation of 
continued abstinence (and non-pregnant status), an intravenous line will be inserted with a 
heparin lock to allow for blood draws (to make the conditions similar to T2, in which 
participants in Groups 1, 2, and 3, and in Groups 5, 6, and 7 are given an intervention 
(dronabinol or a cannabis cigarette) and have several tubes of blood drawn.) Lidocaine may be 
applied to or injected into the skin prior to inserting the needle for patient comfort.  At T1, a 
single specimen of blood will be drawn from all groups to assess participant THC level.  Also, 
if the participant uses nicotine products they will be asked to use these nicotine products at 
specified times and blood will be drawn to assess the person's nicotine level.  All participants 
will be asked to rate their mood. Participants with CUD will be asked to rate their craving, 
liking and high.  Staff will take vital signs.  Participants with SCZ will be rated with brief 
assessments for psychotic and negative symptoms, as well as EPS. At intervals throughout the 
day, they will again rate their high, liking, mood and craving and their vital signs will be 
assessed.  The fMRI protocol is described below. After leaving the scanner, they will rate their 
high, liking, mood and craving, their vital signs will be taken and they will be assessed for 
reward responsiveness, rated for psychotic and negative symptoms, as well as EPS, and brief 

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cognitive testing (see below) will be performed. A schedule of events explaining which tasks 
will occur with the various groups is attached. 
 
Participants will be instructed to continue to maintain abstinence and will be given an 
appointment for the next fMRI testing day, as well as for a visit at their local clinic to give a 
urine drug screen and breathalyzer (if appropriate).  To assess for possible adverse events 
from the procedures, participants in all groups will be contacted the day after discharge from 
the laboratory.   
 
Note: If participants need an abbreviated schedule for Scan 1 to work around schedule 
constraints (work, school, childcare), we will accommodate this by eliminating time gaps 
between the events of the day.  The study team may also move the start of the day earlier or 
later to accommodate participant schedules. 
 
Day of T2 (to occur approximately 7 days after T1): 
 
Groups 1, 2 and 3 (dual diagnosis participants): Prior to receiving the study capsules and 
study cigarette all participants in these groups will be assessed by a study physician to 
determine that they are stable and can safely continue with the study visit.  Participants in 
Group 1 will receive 2 (double-blinded) placebo capsules  and a 3.6%* cannabis cigarette; 
participants in Group 2 will receive two  7.5 mg dronabinol capsules and a placebo cigarette; 
and participants in Group 3 will receive two placebo capsules and a placebo cigarette. 
Research assessment staff will be blind to group assignment.  The pill and cigarette will be 
dispensed at times to facilitate peak THC levels during the scans.  All other procedures 
outlined for the T1 testing period, above, will apply. When smoking the cannabis or placebo 
cigarette, participants will be instructed in the use of the "Foltin" method:155 "light the cigarette" 
(approximately 30 seconds); "prepare to smoke" (approximately 5 seconds); "inhale" 
(approximately 5 seconds); "hold smoke in lungs" (approximately 10 seconds); and "exhale". 
They will smoke 3 puffs in this manner, or until they have consumed 2/3 of the cannabis 
cigarette.14 Blood draws will occur for assessment of THC at set intervals.  If the participant 
uses nicotine products blood will also be drawn to assess the person's nicotine level. 
 
* We will obtain our cannabis cigarettes (and placebo cigarettes) from NIDA based on their 
available stock.  We will aim for approximately 3.6% THC cigarettes for the active THC 
cigarettes.   
 
Groups 4 and 8 (control participants with SCZ without CUD, and normal controls): These 
control participants will follow the same protocol as participants in Groups 1, 2 and 3, except 
that they will not be given capsules or a cannabis cigarette at T2. Although they will have an 
intravenous line inserted, but only a single blood specimen drawn to confirm abstinence from 
THC.  If the participant uses nicotine products, blood will also be drawn to assess the person's 
nicotine level.   Control participants with SCZ (Group 4) who are regular cigarette smokers 

v.4.30.2021 
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will smoke a cigarette prior to the fMRI protocol as described for Groups 1, 2 and 3. Normal 
control participants (Group 8) will not be cigarette smokers. 
 
Groups 5, 6 and 7 (control participants with CUD without SCZ): These control participants will 
follow the same protocol as participants in Groups 1, 2 and 3, including the intervention at T2. 
Those who regularly use nicotine products will use these nicotine products prior to the fMRI 
protocol and have blood drawn to assess the person’s nicotine level as described for patients in 
Groups 1, 2 and 3.  
 
At the end of the T2 testing sessions, participants in Groups 1 - 3 and 5 - 7 will be assessed by 
an MD to ensure that they are able to safely leave the laboratory. Lorazepam and haloperidol 
will be available in case of untoward reactions to dronabinol or cannabis. All scans occur at a 
medical center thus treatment will be available as needed based on the presenting medical 
issue.  If participants are deemed unstable clinically, they will be observed further until stable 
or they will be admitted overnight. To monitor for reactions from the drug or procedures, all 
groups will be contacted the day following T2 and again approximately one week after T2 for 
a brief check-in.  At the one-week call, Group 1-3 participants will be assessed for cannabis and 
other substance use (TLFB), psychiatric symptoms (using items from the PANSS Positive 
Scale) and adverse events.   Group 5-7 participants will be assessed for cannabis and other 
substance use (TLFB), and adverse events. If participants are having clinical difficulties, we 
will ensure that appropriate treatment is initiated.  Participants will be contacted 
approximately 30 days after the end of the protocol to assess for any changes in adverse 
events. 
 
We may repeat assessments in cases of unplanned technical difficulties or need to further 
evaluate or monitor participants and would compensate accordingly. 
 
If we experience technical difficulties with the MRI scanner we may ask the participant to 
return to repeat appropriate study measures and the MRI scan and we would compensate 
accordingly. 
 
In order to provide flexibility to study participants who may not be able to attend an 
appointment on the exact date of the protocol, we will allow some flexibility for scheduling 
appointments, but the window between Scan Days will be at least 2 days. If a participant 
misses a study Scan day due to illness or other unforeseen factors, s/he will be rescheduled as 
soon as possible. Because this population is typically unstable and often misses appointments, 
we expect scheduling difficulties and missed appointments to occur frequently.  Research staff 
will work with participants to support their attendance.  The maximum allowed time between 
the Screening Visit and the T1 Scan is 10 weeks.  If a study participant goes beyond this time 
frame, then he or she will need to be reconsented.  Also, any assessments required to establish 
eligibility and medical stability for the study will need to be repeated.  Tasks for which the PI 

v.4.30.2021 
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believes there is no scientifically valid reason to repeat (e.g., WRAT or Baseline 
Neuropsychiatric Testing) will not be repeated. 
 
Structural and Functional MRI Protocol: 
Implementation: The neuroimaging protocol will be carried out at DHMC and UVM, overseen 
by our lead neuropsychologist. Our laboratory includes a "smoking hood", which allows for 
cannabis smoking in the scanner room and venting of smoke outside the laboratory. Within 
the scanner, participants will undergo a resting state scan, and the MID task, Paced Motor 
task, Aterial Spin Labeling (ASL), and (only at T1) a structural scan. 
 
FMRI Imaging Parameters: MRI is a well-known noninvasive procedure typically used to 
image neuroanatomical structures.  This is accomplished via the use of a high magnetic field 
and high frequency radio waves passing through the brain.  
 
RSC and Data Processing: Participants will be asked to lie in the scanner for approximately 8 
minutes with eyes open, maintaining fixation,192 trying to not think of anything in particular, 
and not fall asleep.193  It has been recently demonstrated that artifacts from participant motion 
result in substantial and structured changes in RSC data despite  standard compensatory 
spatial registration and regression of motion estimates from the data.194-196 Quality Assurance 
(QA) procedures will be implemented to detect outliers in global signal intensity and motion 
time series with artifact mitigation software, with the identified outliers subsequently treated 
as confounds in the first level Generalized Linear Model (GLM.) Physiological sources of noise 
will be estimated and also treated as confounds. Anatomical volumes will be segmented into 
grey matter, white matter, and cerebrospinal fluid (CSF) areas. The time series characterizing 
estimated participant motion, as well as the blood oxygen level dependent (BOLD) time series 
within the participant-specific white matter mask and CSF mask, will be used as temporal 
covariates and removed from the BOLD functional data using linear regression, and the 
resulting residual BOLD time series will be band-pass filtered. Correlation maps will be 
produced by extracting the residual BOLD time course from seed regions, and computing 
correlation coefficients between that time course and the time course of all other voxels. 
Correlation coefficients will be converted to normally distributed scores to allow for second-
level GLM analyses. We will assess RSC of the BRC using anatomically defined seed regions of 
interest (ROIs) (e.g., bilateral nucleus accumbens) defined by the literature.4, 91  
 
MID Task: Participants will complete an event-related fMRI MID task similar to that used in 
numerous studies of healthy participants,83, 166, 198 patients with SCZ4-8, 71, 72 and in our 
preliminary studies. Prior to scanning, instructions and the opportunity for a practice trial will 
be provided. In the scanner, visual stimuli will be presented electronically (e.g. through an 
MR-compatible goggle system) and response recorded electronically through an MR-
compatible button response system. During the task, the participant is shown cues that 
indicate how much money can be won or lost on a given trial.  This is followed by a fixation 
point of variable interval (estimated range of delay is 3000-7500ms) and then a square target 

v.4.30.2021 
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stimulus. Following the disappearance of the target, feedback is provided as to the amount of 
money won for correct responses to the target (responding while target is displayed). An 
incorrect response is also indicated. Feedback is followed by a variable inter-trial interval (ITI). 
Each cue is presented an equal number of times in a pseudo-randomized order. Following 
completion of the session, participants will be told that they won $35 during the task (the 
amount is fixed at $35 to ensure that all participants receive the same amount irrespective of 
performance capacity). 
 
Pulsed Arterial Spin Labeling (PASL): Since it is not known if cannabis or dronabinol will 
induce neurovascular changes, we will use PASL 203-209 to characterize resting regional cerebral 
blood flow (CBF) during each scan session.210-212 ASL methods measure CBF by using water in 
arterial blood as an endogenous tracer.206, 213 PASL, which alternates control and labeling scans 
that are then compared to quantify perfusion,214, 215 will be implemented.216 Derived perfusion 
images will be coregistered to the fMRI and anatomic scans and analyzed by tissue 
compartment and project-specific ROIs. Masks derived from segmented anatomic maps will 
be used to estimate global and local gray matter and white matter perfusion values. Perfusion 
will also be determined for the same ROIs targeted in the fMRI experiments.  
 
fMRI Paced Motor Task (PMT): Participants will complete a visually-triggered sequential finger 
movement fMRI task in which periods of finger movement alternate with rest for a total of 8 
minutes. 
 
Structural MRI Imaging Parameters: Structural scans will be acquired during the baseline scan 
session only. We will also acquire survey images as a screen for focal lesions. T1-weighted 
anatomic reference images will be acquired in the same planes and thickness during each scan 
session. The magnet's repositioning system will be used to ensure comparable head 
positioning across the scan sessions. 
 
Eye Camera:  We will use an MRI-compatible camera with integrated LED infrared light (MRC 
Systems, Germany; model 12M-I) that can be used inside the bore of the scanner. This will 
allow us to monitor and record participant’s eyes to determine whether they are keeping them 
open/closed per instructions during the scan session.  The camera is based on a single light-
emitting-diode (LED) which is embedded in the titanium housing and emits diffuse light.   
 
 
GENETIC TESTING 
Each participant will be asked whether he/she would be willing to donate a small amount of 
blood for the relation of genetic markers for mental health, substance abuse, and brain 
function.  There is a separate consent form for this part of the study.  DNA will be extracted 
from this blood sample and stored in a freezer at DHMC, labeled only with the subject’s ID 
number, and the date of blood draw.  There are several methods that may be used to genotype 
the study population.  We will choose the most cost-effective, accurate and scientifically 

v.4.30.2021 
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appropriate methods at the time of processing.   Options will include standard or custom 
single SNP and genome-wide arrays, as well as intermediate density sampling such as the 
custom 3300-SNP microarray designed by the PI and colleagues at Dartmouth. Genotyping 
will be carried out within Dartmouth and/or other qualified genotyping facilities, such as 
Illumina or Affymetrics, as appropriate depending on the assay conducted.  If blood is sent to 
a facility such as Illumina or Affymetrics for testing, unused portions of the samples will be 
destroyed or returned to Dartmouth.  The samples will be stored in de-identified form at 
Dartmouth until all the studies and assays associated with the research program have been 
completed.  Analyses will be conducted at the single SNP level and at the level of complex 
gene-gene interactions and multivariate biological pathways in conjunction with the 
Computational Genetics Lab at Dartmouth. 
 
 
5.  Inclusion/Exclusion Criteria:   
Please provide detailed description of inclusion and exclusion criteria. If a formal protocol for the study 
exists, page references to the protocol are acceptable. 
   Inclusion Criteria: 
 
Groups 1-3 - Participants with SCZ-CUD 
1. Ages 18 – 55 years old, inclusive 
2. Diagnosis of schizophrenia or schizoaffective disorder as confirmed with the Structured 
Clinical Interview for the DSM (SCID) 
3. Diagnosis of cannabis abuse or dependence as confirmed by the SCID 
4. Use of cannabis within the month prior to screening based on the TLFB 
5. Willing to remain abstinent for the 7 days before the baseline assessments and 14 days 
before the two scan days. Note: If the 14 day period of abstinence is too great a barrier for 
participants, the PI may decrease the amount to 7 days. 
6. Psychiatrically stable as indicated by being treated as an outpatient for the past  month as 
determined by a study physician's review 
7. Currently stable in treatment (either on an antipsychotic or not)  for the past month as 
determined by a study physician's review 
8. Not seeking treatment for their CUD.  
 
Group 4 - Control participants with SCZ 
1. Ages 18 – 55 years old, inclusive 
2. Diagnosis of schizophrenia or schizoaffective disorder as confirmed with the SCID 
3. Willing to remain abstinent for the 7 days before the baseline assessments and for 14 days 
before the two scan days. Note: If the 14 day period of abstinence is reduced for the groups 
with a CUD, it will be reduced for Group 4 also. 
4. Psychiatrically stable as indicated by being treated as an outpatient for the past  month, as 
determined by a study physician's review 

v.4.30.2021 
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5. Currently stable in treatment (either on an antipsychotic or not)for the past month as 
determined by a study physician's review 
  
Groups 5-7 - Control participants with CUD 
1. Ages 18 – 55 years old, inclusive 
2. Diagnosis of cannabis abuse or dependence as confirmed by the SCID 
3. Use of cannabis within the month prior to screening based on the TLFB 
4. Willing to remain abstinent for 7 days before the baseline assessments and 14 days before 
the two scan days. Note: If the 14 day period of abstinence is too great a barrier for 
participants, the PI may decrease the amount to 7 days. 
5. Not seeking treatment for their CUD.  
 
Group 8 – Healthy control participants 
1. Ages 18 – 55 years old, inclusive 
2. Willing to remain abstinent for the 7 days before the baseline assessments and 14 days 
before the two scan days. Note: If the 14 day period of abstinence is reduced for the groups 
with a CUD, it will be reduced for Group 8 also. 
 
Exclusion criteria:  
 
Groups 1-3 with SCZ-CUD 
1. Positive symptoms of psychosis (> 4 [moderate]) on any item of the PANSS psychosis 
subscale (once abstinent) except for the hallucination item.  We will exclude for a rating > 5. 
for this item.  
2. Current cocaine/stimulant dependence.   (Note: Current alcohol, synthetic cannabis, 
nicotine, and caffeine abuse or dependence are allowed; current cocaine/stimulant or other 
drug abuse is allowed provided the person can achieve the required abstinence; past 
dependence on cocaine/stimulants or other drugs  is also allowed) 
3. Pharmacological treatment for addiction (e.g., disulfiram, naltrexone, acamprosate, 
topiramate, varenicline, buproprion) as determined by a study physician's review. 
4. Mental retardation 
5. History of head injury with period of unconsciousness or focal brain injury as determined 
by a study physician's review.  
6. Metal objects within the body that would contraindicate an MRI 
7. Pregnancy or currently nursing 
8. Is deemed inappropriate for the study by the PI (e.g., due to other medical conditions, 
medication, psychiatric concerns, or other circumstances that could cause safety concerns 
or impair the person's ability to participate in the study.) 
9. Taking clozapine 
10. Any condition that would contraindicate use of cannabis or dronabinol.  
11. Patients seeking treatment to limit their cannabis use.  
12. History of a seizure disorder as determined by a study physician's review 

v.4.30.2021 
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13. Is assessed as being suicidal or violent as determined by a study physician's review. 
 
Group 4 - Control participants with SCZ 
1. Positive symptoms of psychosis (> 4 [moderate]) on any item of the PANSS psychosis 
subscale (once abstinent) except for the hallucination item.  We will exclude for a rating > 5. 
for this item. 
2. Any history of a substance use disorder other than nicotine and caffeine. 
3. Pharmacological treatment for addiction (e.g., disulfiram, naltrexone, acamprosate, 
topiramate, varenicline, buproprion) as determined by a study physician's review.  
4. Mental retardation 
5. History of head injury with period of unconsciousness or focal brain injury as determined 
by a study physician's review 
6. Metal objects within the body that would contraindicate an MRI 
7. Pregnancy or currently nursing 
8. Is deemed inappropriate for the study by the PI (e.g., due to other medical conditions, 
medication, psychiatric concerns, or other circumstances that could cause safety concerns 
or impair the person's ability to participate in the study.) 
9. History of a seizure disorder as determined by a study physician's review 
10. Taking clozapine 
11. Is assessed as being suicidal or violent as determined by a study physician's review. 
 
Groups 5-7 - Control participants with CUD 
1. Any Axis I psychiatric diagnosis other than a CUD. (NOTE: Current alcohol, synthetic 
cannabinoid, nicotine, and caffeine abuse or dependence are allowed.   Other substance 
abuse is allowed provided the person can achieve the required abstinence; past 
dependence on cocaine/stimulants or other drugs is also allowed.  Also, past (but not 
current) diagnoses of ADHD, depressive disorders and anxiety disorders are allowed.) 
2. Taking any psychotropic medication 
3. Pharmacological treatment for addiction (e.g., disulfiram, naltrexone, acamprosate, 
topiramate, varenicline, buproprion) as determined by a study physician's review 
4. Mental retardation 
5. History of head injury with period of unconsciousness or focal brain injury as determined 
by a study physician's review 
6. Metal objects within the body that would contraindicate an MRI 
7. Pregnancy or currently nursing 
8. Is deemed inappropriate for the study by the PI (e.g., due to other medical conditions, 
medication, psychiatric concerns, or other circumstances that could cause safety concerns 
or impair the person's ability to participate in the study.) 
9. History of a seizure disorder as determined by a study physician's review 
10. Is assessed as being suicidal or violent as determined by a study physician's review. 
11. Has a legal guardian. 
12. Any condition that would contraindicate use of cannabis or dronabinol. 

v.4.30.2021 
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Group 8 – Healthy control participants 
1. Any Axis I psychiatric diagnosis (caffeine dependence is allowed) 
2. Taking any psychotropic medication 
3. Pharmacological treatment for addiction (e.g., disulfiram, naltrexone, acamprosate, 
topiramate, varenicline, buproprion) as determined by a study physician's review  
4. Mental retardation 
5. History of head injury with period of unconsciousness or focal brain injury as determined 
by a study physician's review 
6. Metal objects within the body that would contraindicate an MRI 
7. Pregnancy or currently nursing 
8. Is deemed inappropriate for the study by the PI (e.g., due to other medical conditions, 
medication, psychiatric concerns, or other circumstances that could cause safety concerns 
or impair the person's ability to participate in the study.) 
9. History of a seizure disorder as determined by a study physician's review 
10. Current tobacco smokers 
10.  Is assessed as being suicidal or violent as determined by a study physician's review. 
11. Has a legal guardian. 
 
Note: Since the overwhelming majority of patients with SCZ smoke cigarettes (as do many 
with CUD), we will allow participants in Groups 1 – 7 to be tobacco smokers and we will 
control for smoking in our data analysis (see below). We exclude current tobacco smoking in 
the normal control participants since the fact of cigarette smoking could select participants 
with a dysregulated BRC as a basis for their cigarette smoking.   
 
 
6.  Financial Considerations:  
Disclosure of financial impact on the participant is critical to informed consent.  Insurance cannot be 
billed for research-related services outside the standard of care or paid for by the funding agency for the 
study.  The department, the study or the participant may be responsible for payment for research-related 
services.  Participants should know which tests, visits, or procedures will be billed to them or their 
insurance and which ones will be paid by the funding agency for the study or the department.  
 
a)  List tests, visits, and procedures performed for only research purposes.  These services are outside the 
standard of care.  They would not be performed if the individual were not a research participant, and 
may not be billed to a health insurance plan.  
Note:  6a information must also be in "How is this different . . ." section of the consent form. 
  This is not a treatment study.  All tests and procedures for this study are performed only for 
research purposes outside of standard care and will not be billed to the participant or his/her 
insurance.     
 

v.4.30.2021 
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b)  List the tests, visits, and procedures that may be standard care, but for which the funding agency for 
the study is paying.   
 None     
 
c)  Will the funding agency for the study be responsible for the above costs?  
 Yes   
 No      
If  No,  describe who will be responsible (i.e., department or participant). 
      
 
 
7.  Statistical Methods and Review Statement:   
a) Specify the primary endpoint, as well as other endpoint(s). 
 Activation of BRC (particularly the nucleus accumbens) in anticipation of monetary 
reward. 
 Resting state connectivity within the BRC 
 Scores on the Rewards Responsiveness  task         
 
b) State the statistical analysis plan, including all hypothesis tests (e.g., t-test, chi-square), and 
estimation methods related to the primary endpoint. If a formal protocol for the study exists, page 
references to the protocol are acceptable. 
   We will assess participants comprising 8 groups at Time 1 (T1) and Time 2 (T2): Group 1 (G1) 
–SCZ-CUD given placebo dronabinol and active cannabis; Group 2 (G2) –SCZ-CUD given 
active dronabinol and placebo cannabis; Group 3 (G3) –SCZ-CUD given placebo dronabinol 
and placebo cannabis; Group 4 (G4) –SCZ given no intervention; Group 5 (G5) – CUD given 
placebo dronabinol and active cannabis; Group 6 (G6) –CUD given active dronabinol and 
placebo cannabis; Group 7 (G7) –CUD given placebo dronabinol and placebo cannabis; and 
Group 8 (G8) –normal control participants given no intervention. 
 
Aim 1 (Time 1 Group Differences): To determine whether at T1 dual diagnosis patients with 
SCZ-CUD (G1 - G3 combined) show (as compared to normal controls, G8):  
(i) 
reduced fMRI activation of BRC (particularly the nucleus accumbens) to anticipation of 
monetary reward, as determined via group mixed effects ANOVA on contrasts of 
interest (e.g., anticipating reward > anticipating no reward);  
(ii) 
decreased resting state connectivity within the BRC as evaluated using the Statistical 
Parametric Mapping Version 8 (SPM8) mixed effects ANOVA on the Fisher-
transformed r value connectivity maps derived from the nucleus accumbens seed ROI; 
and  
(iii) 
impaired reward responsiveness as determined using mixed effects ANOVA on 
response bias scores.  
In addition, we will use a group mixed effects ANOVA to explore whether they will also differ 
from control participants with SCZ alone (G4) and control participants with CUD alone (G5, 
G6 and G7) on these measures.  
 

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Aim 2a and 2c (Group by Time effects on MID and BRC related to cannabis or dronabinol): 
Below, we describe the analyses involving dual diagnosis patients given cannabis (Group 1 -- 
G1); the same pattern of analyses will be carried out for the patients given dronabinol (Group 2 
-- G2). Similar analyses will also be carried out for participants with CUD alone (Groups 5, 6 
and 7 – G5, G6 and G7).  
 
The two sets of intervention effects (specific to SCZ-CUD and CUD alone) will be compared. 
To determine whether the dual diagnosis patients given cannabis (G1) will show differential 
changes in fMRI activation in specific ROIs within BRC and in RSC within the BRC between T1 
and T2, we will first conduct a Group (G1, G3, G4, G7, G8) by Time (T1, T2) mixed-model 
repeated measures ANOVA. Predicting a significant omnibus ANOVA, we will next examine 
planned contrasts to address specific hypotheses: To determine whether cannabis ameliorates 
BRC dysfunction, we will compare brain activation/connectivity in the patient group given 
cannabis (G1) to that of the control groups (SCZ-CUD placebo [G3]); (SCZ alone [G4]; CUD 
alone placebo [G7]; and normal controls [G8]) using a Group (G1, G3, G4, G7, G8) by Time (T1, 
T2) mixed-model ANOVA followed by pairwise comparisons. The inclusion of Group 4 in this 
analysis will allow us to examine whether any significant cannabis effect on BRC in Group 1 
(G1) is independent of any changes due to repeated testing specific to having a diagnosis of 
SCZ.  Lastly, although not a primary hypothesis of interest, to further explore any potential 
placebo effect on BRC, we will also conduct a comparison of G3, G4. G7 and G8.  
 
Aim 2b and 2c (Group by Time effects on RR related to cannabis or dronabinol): To explore 
whether the patients with SCZ-CUD who received cannabis (G1) will show differential 
changes in RR between T1 and T2 relative to G3, G4, G7 and G8, we will proceed as above for 
Aim 2a to assess response bias, and analogously for participants who received dronabinol 
(G2). Similar analyses will be used for Groups 5, 6, 7 and 8, with results compared to those 
obtained for patients with SCZ-CUD. 
 
Although not aims of the study, we will assess the relationship between THC plasma levels 
and changes in BRC activation/connectivity following cannabis (G1 or G5) and dronabinol (G2 
or G6) using covariance modeling in SPM8; we will conduct analyses to determine whether 
cannabis (G1 or G5) and dronabinol (G2 or G6) have comparable effects on fMRI BRC 
activation/connectivity using a Group (G1 or G5, G2 or G6) by Time (T1, T2) mixed-model 
ANOVA; and we will use cerebral blood flow values obtained from arterial spin labeling MRI 
as covariates in the ROI analyses of BOLD data to control for any artifactual changes in fMRI 
signal related to drug-induced influences on CBF. 
 
Aim 3 a, b (Group X Time effects of dronabinol on "high", liking, craving, mood, negative and 
positive symptoms, EPS and cognition in SCZ-CUD: These measures (other than cognition) 
will be taken in patients with SCZ-CUD (G2) prior to the fMRI scan and before dronabinol pill 
ingestion (Pre) and immediately after the MRI scan is completed (Post). We will conduct 
additional analyses to test the specific hypotheses that G2 patients will show: (a) improved 

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mood, reduced negative symptoms and EPS, and no significant change in psychotic symptoms 
from Pre to Post; and (b) a greater degree of change (from Pre to Post) in these measures than 
will those in G3, G4, G7, or G8. For cognitive measures, in which we will use assessments at T1 
and T2, we will first conduct a Group (G2, G3, G4, G7, G8) X Time (T1, T2) mixed-model 
repeated measures ANOVA.  
         
 
c) Justify the sample size, using the concepts of power, type I error, and effect size if applicable. If a 
formal protocol for the study exists, page references to the protocol are acceptable. 
  For Aim 1a (i), our pilot fMRI MID data comparing 12 healthy controls and 12 patients with 
SCZ-CUD yielded a Cohen's d of 1.10 during anticipation of reward for the accumbens ROI. 
For Aim 1a (ii), our pilot data on group differences in baseline RSC (12 SCZ-CUD; 12 controls), 
indicated effect sizes ranging from 0.84 to 1.28. For Aim 1a (iii), our pilot data on reward bias 
revealed a d of 0.77 for the group difference. Based on the above, we expect Aim 1a to be well 
powered (for 75 patients with SCZ-CUD and 25 normal controls) with effect sizes of d ≥ 0.7 
detectable with adequate power (≥ 80%). For Aim 1b, the fMRI/MID studies of Juckel et al. 
showed deficient accumbens response during the MID task in patients with 
SCZ (without CUD), 4, 5, 8 with d’s of 1.26 to 1.60, and 10 patients and 10 controls in each 
study, while the MID studies of CUD alone are inconclusive.11, 110 Moreover, there are no data 
available to permit estimation of effect sizes for RSC of the accumbens in patients with SCZ 
(without CUD) or those with CUD (without SCZ). For Aim 2a (i), our pilot data on the effects 
of smoked cannabis (N = 6) and dronabinol (N = 6) in SCZ-CUD on fMRI/MID indicated d's 
ranging from 0.78 to 2.41. For Aim 2a (ii) the effects of smoked cannabis and dronabinol in 
these same participants yielded effect sizes ranging from 0.83 to 1.0 for connectivity of the 
nucleus accumbens with other regions of the BRC. Thus, we expect that our group sample size 
should provide us with the ability to detect meaningful effects (d ≥ 0.7) for both cannabis and 
dronabinol. Smaller effects than this are not likely to be clinically relevant. Finally, for Aim 2c 
we expect limited power to explore the comparative effects of cannabis and dronabinol on 
patients with SCZ and CUD relative to those with CUD alone.         
 
 
8.  Data and Safety Monitoring:  
Describe plans for data and safety monitoring to ensure the safety of subjects and the quality of the data. As described in 
federal guidance “… a variety of types of monitoring may be anticipated depending on the nature, size, and complexity of the 
trial.  In many cases, the principal investigator would be expected to perform the monitoring function.” This plan should 
include monitoring to determine: 
 
The progress of the trial, including periodic assessments of data quality and timeliness, participant recruitment, accrual and 
retention, participant risk versus benefit, and other factors that can affect study outcome.  Monitoring should also consider 
factors external to the study when interpreting the data, such as scientific or therapeutic developments that may have an 
impact on the safety of the participants or the ethics of the study. 
 
Note:  This section does not request information related to sponsor study monitor visits.  This section requires a description 
of an adequate data and safety monitoring plan.  

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  The Dartmouth Department of Psychiatry has a Data Safety Monitoring Board (DSMB) to 
independently oversee clinical trials and other studies. The DSMB for this study will be composed of at 
least three people and will include (at minimum) a clinician knowledgeable about schizophrenia and 
substance use disorders, an investigator familiar with fMRI, and a biostatistician, all of whom will be 
independent of the study group. The group will follow the NIH policy for data and safety monitoring 
and guidelines as published on http://www.miaid.nih.gov/dmid/clinresearch/dsm.htm. Study data 
regarding participant enrollment, characteristics, symptoms, substance use, adverse events and serious 
adverse events will be submitted to the DSMB twice yearly for review and analysis. The DSMB will 
review study data to oversee the safety of study participants and conduct of the study. It will advise 
the PI (and the Departmental Research Committee) on continuation of the study and provide reports to 
the IRB regarding recruitment of appropriate participants and presence of adverse effects. 
     
 
9.  Genetics:   
Does any part of the study involve genetic analysis of biological specimens?  
 Yes   
 No 
If yes, respond to Genetics Attachment C    
 
  
 
 
10. Instruments:  
Describe each instrument, if any, used to collect data in this study. 
 
Attach copies of any questionnaires, surveys, or interview questions.  If the research involves interviews 
that could evolve as the research progresses, include a list of discussion topics and any “starter” 
questions for each topic that can reasonably be expected to be covered.  If a draft of a written 
questionnaire or survey is attached, it should be clearly labeled as such and a final version should be sent 
to CPHS for review before data collection begins. 
  Pre-screening: As part of our recruitment, a short, web-based survey will be used to 
prescreen people interested in participating in the study.  The survey will ask a series of 
questions targeting the most common and clearly defined criteria for inclusion (e.g., age, 
willingness to be abstinent during the study, current cannabis use).  The screening survey will 
provide feedback as to whether or not people may be eligible to participate and collect contact 
data on those appearing eligible.  The results of the survey will be for recruitment purposes 
and not a part of the study data.  
 
Diagnosis: We will do an all-source Structured Clinical Interview for DSM-IV-TR (SCID) 157 to 
ensure each participant meets the appropriate diagnostic criteria for his or her group.  Use of 
the DSM-IV will allow us to have a consistent measure across both the previous pilot study 
and this one (and the DSM-5 SCID is not yet available).  The SCID-II module for Antisocial 
Personality Disorder will be used to detect whether or not participants meet criteria for this 
disorder.  Research suggests that trauma may change reward circuitry.  We will therefore 
track trauma exposure using the PTSD Screening Questionnaire and use these data as 
covariates in our final analyses.                  
 

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Substance Use: We will use the Timeline Follow-Back (TLFB) calendar to establish use of 
cannabis or other substances following the recommended method of Sobell.173  
Psychiatric symptoms: We will use the PANSS (Positive and Negative Syndrome Scale)174  to 
assess psychiatric symptoms, as well as positive and negative symptoms. The Barkley Adult 
ADHD Rating Scale-IV (BAARS-IV; Barkley, 2011) will be administered during the Baseline 
Neuropsychiatric Testing visit to assess current symptoms of attention deficit. 
  
 
Neurological symptoms: Extrapyramidal system effects will be assessed with the Simpson-
Angus Scale (S-A),175 the Abnormal Involuntary Movements Scale (AIMS),176 and the Barnes 
Akathisia Scale.177  
 
Cannabis-related effects: We will employ a brief version of the visual analogue self-report scale 
(VAS) used by our consultant, Dr. Haney, in her studies of cannabis use.14, 178, 179 The VAS will 
be used to rate mood, "high" and "liking".  The Cannabis Withdrawal Assessment Scale will be 
utilized at each visit while participants are establishing abstinence from cannabis.  
 
Cannabis craving: The 12-item self-report Marijuana Craving Questionnaire (MCQ-12) will be 
used to rate craving for cannabis.180, 181 We will use the total score for our analyses.  
 
 
Intellectual Functioning: Study participants will complete the Wide Range Achievement Test – 
4 (WRAT–4) reading subtest183 at screening as an estimate of premorbid intellectual 
functioning. 
 
Baseline Neuropsychiatric Assessment: Intellectual assessment: Handedness will be measured 
using the Edinburgh Handedness Inventory (Oldfield, 1971). This 10 item questionnaire asks 
participants to rate the extent to which they prefer to use one hand or the other to complete a 
series of tasks. The Computerized Iowa Gambling Task (Bechara, 2007) task involves decision 
making under conditions of monetary reward and punishment.  It has been often used in 
studies of schizophrenia and of substance use disorders. Inhibitory control will be assessed 
using Stop Signal Task (Logan, Cowan, & Davis, 1984), which has been extensively studied in 
clinical populations.  The Barratt Impulsiveness Scale (BIS-11; Patton et al., 1995) will be used 
as a measure of impulsiveness.  
  
 
Brief Repeatable Cognitive Test Battery: Participants will complete a brief test battery to assess 
the effects of cannabis and dronabinol on cognitive functioning. This battery will include: the 
Hopkins Verbal Learning Test - Revised184 and the Brief Visuospatial Memory Test-Revised,185 
which each have six equivalent alternate forms; the Symbol Digit Modalities Test, which has 
four equivalent alternate forms;186, 187   the Delayed Discounting Questionnaire (Heerey et al., 

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2007) to measure impulsivity; the WAIS-III Letter Number Sequencing (Weschler, 1997) to 
assess verbal working memory which has been shown to be impaired in persons with 
schizophrenia; and the Continuous Performance Test - Identical Pairs Version (CPT-IP) 
(Cornblatt, Risch, Faris Friedman & Erlenmeyer-Kimling, 1998) to assess attention and 
working memory.     
 
Probabilistic Reward Task : Participants will be studied with the Probabilistic Reward Task of 
Pizzagalli and colleagues,93 which has adequate test-retest reliability93, 96 and has been used 
extensively to study RR in SCZ.73, 93, 95, 98 As suggested by the literature on RR, we will add the 
Perceived Stress Scale.189-191  
 
Assessment of THC and other substances: Dip stick analysis of urine will be performed  to 
assess cannabis and other substances; alcohol will be assessed with a breathalyzer. To further 
ensure abstinence for cannabis, we will also use an assay for urinary THC to help confirm 
continued abstinence. Plasma THC will be assayed by Gas Chromatography/Mass 
Spectroscopy- Selective Ion Monitoring (GC/MS/SIM) quantitation. Nicotine levels will be 
assessed at each scan day to control for possible effects of nicotine and nicotine withdrawal on 
the brain reward circuit. 
 
Safety Assessment - Participants in Groups 1-3 and Groups 5-7 will have a baseline medical 
history and physical assessment to rule out medical contraindications to administration of 
dronabinol or cannabis. The assessment will include blood pressure, electrocardiogram (EKG), 
complete blood count and blood chemistry screen. All women in the study will have a 
pregnancy test at screening and before the scan on each scan day.  Adverse events and 
medications that participants are receiving outside of the course of the study will be tracked 
and reviewed at each visit. 
Other: The Behavior Rating Inventory of Executive Functions - Adult version (BRIEF-A) will 
be administered to gauge subjective integrity of executive functions in everyday life over the 
past month (Roth, Isquith, Gioia, 2015).  This 75 item questionnaire takes about 10 minutes to 
complete.  Participants will complete the measure once at the T1 session. 
   
11. Deception.   
Will deception of participants, including withheld information, be used in this research?  
 Yes   
 No  
If yes, complete a-d. 
 
a) Describe the deception being used in this study: 
 The nature of the monetary incentive delay task and probabilistic reward task requires 
subjects to respond believing the speed of their response is linked to the money they 
earn.   However all participants will receive $35.00  for completing each of the two fMRI 
monetary incentive delay tasks and a total of up to $50 for completing the three 

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probabilistic reward tasks, regardless of their task performance (which is based on 
accuracy and speed) . The instructions participants are given for the task, however, do 
not indicate this, but rather only say that they can win money based on their 
performance.      
 
b) Explain why deception is necessary in this research: 
  We decided to fix the amount of winnings on each task, and thus deceive participants, 
so as to not disadvantage the participants with schizophrenia who tend to respond more 
slowly and with less accuracy than normal controls because of their illness (or related 
issues such as medications).  Participants will not be aware that everyone receives the 
same amounts because it is essential in the study of reward circuitry that they believe 
they are "winning" additional funds, and that their winnings are dependent upon 
performance.  This technique is used routinely by researchers across the world in order 
to study brain reward circuitry.  Use of the same technique allows researchers to 
compare results across studies.     
 
c) Describe the information provided to subjects when they decide to participate: 
  As stated above, the instructions participants are given for the task say that they can 
win money based on their performance.     
 
d) Describe how the subjects will be provided with additional pertinent information after 
participation (debriefing): 
  We will simply let participants know how much money they "won".  We cannot debrief 
participants and tell them that the earnings were fixed because we believe that 
participants may tell other participants and that this knowledge would then interfere 
with the consistent measurement of brain reward circuitry between patients.     
 
 
12. Enrollment: 
a) Estimated number of participants for duration of entire study: 
      
At Dartmouth or associated sites: Female:  100        Male:  300       
      
If Multi-center study: Estimated total number at all sites:  400       
b) Estimated age range of participants:  18-55       
 
 
13. Timetables:   
a) Indicate length of participant involvement in the study:  Approximately 4-6 weeks       
b) Estimate how long it will take to enroll enough participants to complete this study:  5 years     
 
 
14.  Risks:   
The purpose of this section is to determine if subjects will be placed "at risk," which in general means 

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exposed to the possibility of physical, psychological, social, economic, legal, dignitary or other harm as a 
consequence of any activity proposed in the research project.  
 
a) What is the overall risk classification of the research? 
 Minimal 
 Greater than minimal 
 Significant 
 Unknown  
 
 
Note: In the federal regulations on human subjects protection minimal risk means "The probability and magnitude of harm 
or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life 
or during the performance of routine physical or psychological examinations or tests." 
 
b) Describe any potential risks (physical, psychological, social, legal, economic, or other) and assess their 
likelihood and seriousness.  Describe the procedures for protecting against or minimizing these risks, 
including risks to confidentiality, and assess their likely effectiveness. Please list risks from most 
severe/likely to least severe/unlikely. 
  Overall Approach to Protecting Study Participants: The PI and the DSMB will monitor safety 
throughout the study. We will obtain careful informed consent and insure that each 
participant fully understands the study procedures and the fact that for participants with SCZ-
CUD both cannabis and dronabinol may cause a transient increase in symptoms and side 
effects.  Confidentiality will be maintained with the standard procedures described below. A 
participant's clinical status will be monitored throughout the protocol and care will be 
coordinated with each person's clinical treatment team. Study participants may discontinue a 
study procedure at any time if they are uncomfortable or the study procedures appear to be 
causing exacerbation of illness. 
 
Risk of potential exposure to COVID-19 
Due to the pandemic beginning in 2020, there is a risk of potential exposure to COVID-19.  For 
participant safety and safety of study staff we will follow all Dartmouth-Hitchcock procedures 
to reduce risk of infectious disease transmission.  As of April 2021, we will use the following 
procedures during all study visits, and procedures will be adjusted as recommended by 
Dartmouth-Hitchcock. 
 
 DH employees (potential participants and study staff) will complete any COVID-19 
risk screening requirements per DHMC policy (currently on-line screening or in-person 
with door screeners) prior to entering the building. 
 Non-DH employees will be screened at entrances staffed with door screeners. 
 Whether they participate in on-line or in-person screening, the participant and all study 
staff must meet all DH COVID-19 screening requirements in order to be allowed into 
the medical center.  If the participant/staff has symptoms or risk of exposure, research 
visits will not take place until the situation has resolved. 

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 Participants and all study staff will be required to wear a facial mask over their nose 
and mouth.  If the participant does not have one, they will be provided with one. 
Participants will be required to wear the mask at all times with the exception of while 
they are in the MRI scanner.  Study staff will also wear eye protection. 
 Surfaces and equipment will be cleaned per medical center policy 
 Study staff will practice frequent handwashing per DHMC guidelines. 
 Social distancing of a minimum of 6 feet will be maintained with the exception of 
procedures requiring closer contact such as obtaining vital signs, placing the IV and 
obtaining blood specimens, getting the participant positioned in the MRI scanner and 
during some of the neuropsychological testing. 
 If for any reason we feel it is unsafe for the participant or study staff to continue with 
the study visit we will cancel the visit and work to reschedule as soon as we feel it is 
safe to conduct the visit. 
 
 
 Risks from Cannabis and Dronabinol - Symptom Exacerbation:  In this study, the most 
prominent activity associated with risk is the administration of cannabis and dronabinol, 
particularly to Groups 1, 2 and 3 who have a diagnosis of SCZ and a co-occurring CUD.       
Multiple strategies will be used to protect patients with SCZ-CUD who are given cannabis or 
dronabinol (or double-blinded cannabis and placebo) from relapse of psychosis. First, patients 
will be under treatment for their psychosis during the study, and must be stable with a low 
level of symptoms in order to participate. Second, all participants who will be exposed to 
cannabis or dronabinol during the study will be current active cannabis users who are used to 
the effect of cannabis. Third, with our pilot work, we have established a safe dose of 
dronabinol (two 7.5 mg capsules) and of cannabis for the cigarette for these patients, which did 
not produce untoward effects. We will use these doses in this study. All participants given 
cannabis or dronabinol (or double-blinded placebo cannabis and dronabinol) will be 
monitored closely in the laboratory until it is determined by the MD that they are able to be 
safely discharged. If symptoms develop and do not remit, patients will be offered inpatient 
treatment, as appropriate. Moreover, for participants given cannabis, dronabinol or placebo, 
we will attempt to contact them both the day after T2 and one week later to assess their status. 
If additional check-ins or clinical interventions are needed, it will be coordinated by the study 
team.  In our pilot study with 15 patients in a similar protocol, none had problematic 
symptoms and no patients required additional medication or inpatient treatment. With the use 
of the strategies described here, study participation is unlikely to precipitate significant 
symptom exacerbations, but research staff, who have substantial clinical experience with this 
population, will be prepared to act immediately to treat patients and maintain safety if an 
exacerbation does occur. 
 
Risks from Cannabis and Dronabinol - Other: Known effects of dronabinol and cannabis are 
listed below.  These side effects occurred when people took dronabinol regularly.  They are 
also known to occur when people smoke cannabis.  We do not know how likely it is that these 

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side effects will occur if the medication is taken once as it will be in this study.  Participants 
will be monitored frequently in the lab all day on the days they take these drugs. 
 
Common side effects: A "high” feeling (e.g. laughing easily, feeling happy, having a 
heightened awareness) 
 
Occasional side effects (reported in 3-30% of people: Paranoia, confusion, nervousness, 
sleepiness, dizziness, stomach pain, nausea with or without vomiting, tachycardia, flushed 
face 
 
Rare side effects (reported in less than 3% of people): Red eyes, diarrhea and/or incontinence, 
depression, nightmares, trouble speaking, visual problems, ringing ears, low blood pressure 
 
Seizures have been reported in people taking dronabinol.  Patients with a history of a seizure 
disorder will be excluded from this study. 
 
Recruited patients with dual diagnosis and participants with CUD (without schizophrenia) 
will all be frequent cannabis users. Thus, we do not expect anything more than minimal effects 
from the modest dose of THC in the cannabis cigarettes or the two 7.5 mg dronabinol capsules.  
However, as with the potential of symptom exacerbation in the dual diagnosis patients 
(above), we will monitor all CUD patients until it is determined by an MD that they can be 
safely discharged and be prepared to act immediately to provide treatment and to maintain 
participant safety. Moreover, participants in Groups 1-3 and Groups 5-7 will have a baseline 
medical history and physical assessment to rule out medical contraindications to 
administration of dronabinol or cannabis. The assessment will include blood pressure, EKG, 
complete blood count and blood chemistry screen. All women in the study will have a 
pregnancy test as described in the section on assessments. 
 
Risk Related to Confidentiality: This research involves monitoring and treatment of patients 
who use cannabis, an illegal substance. Participants may engage in other illegal activities. 
Maintaining confidentiality is an area of utmost importance for this population. 
 
To minimize risk of divulging confidential information regarding substance use or other illegal 
activities as well as other study information, strict attention to confidentiality will be 
maintained throughout every aspect of this research with standard policies and procedures, 
and a Certificate of Confidentiality (provided by NIDA). All members of the research team 
will follow the procedures to protect confidentiality adhered to by research groups at 
Dartmouth per the Dartmouth Committee for the Protection of Human Subjects (CPHS).  
Interested participants will provide permission in the form of release of information for study 
personnel to contact treating clinicians to discuss appropriateness of the participant's 
participation in the study. Participant data will be coded to protect privacy. Each patient will 
be assigned a unique identification number. The list of participant names and identification 

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numbers will be kept in a locked file cabinet separate from the database. Access to the 
computerized data system is carefully protected by a secured password entry system. 
Participants will be made aware of the various parties who will have access to their data in the 
informed consent document. Access to participants' data will be restricted to project 
investigators and other study staff on a need to know basis. Patient information, if reported, 
will be reported as group data or anonymously in case reports. No patients will be 
individually identified. 
 
Risks from Research Assessments: The assessments being used in this study (i.e. measures of 
substance use, symptoms, measures of "high", mood, "liking", reward responsiveness, 
cognition, urine and blood assessments) may cause some discomfort, boredom, anxiety or 
fatigue. It is also possible, but not likely, that the SCZ participants may experience an increase 
in their underlying symptoms due to the process of research assessments.  
 
Participants will be advised that they can take a break, refuse to answer question(s), or end the 
study session if they become uncomfortable in any way. Research staff will involve a referral 
site clinician to provide consultation if a patient becomes more symptomatic during a study 
procedure. All participating mental health agencies have emergency services that can be 
accessed at any time if the participant’s regular clinicians are unavailable. Additionally,  
psychiatrists experienced in the treatment of this population, will be present or rapidly 
available via pager for emergency consultation at any time. 
 
Risks from Blood Draws:  
Drawing blood may involve some discomfort; the needle-stick can be slightly painful, and can 
cause bruising, a feeling of faintness, and in rare instances, infection at the site of the blood 
draw. Proper technique will be used by trained staff to minimize the likelihood of these 
problems.  A low dose of lidocaine delivered to the skin or subcutaneously will be offered to 
reduce the discomfort of placing the intravenous cannula.  When used in this fashion, the risks 
of lidocaine include: 
 
Common: Flushing, redness of skin, swelling of skin, warm skin 
 
Less common: Bruising, pain, itching, nausea, vomiting 
 
Serious allergic reactions can occur. This medication should not be used for persons with a 
history of allergy to lidocaine or related medications. 
 
Risks from the fMRI procedure: The scanner produces a loud banging noise and may be 
uncomfortable for people who have claustrophobic-like reactions in confined spaces. The long-
term risks of 2 MRI scans of the brain are unknown. 
 

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Participants will be screened for metallic implants or any magnetic devices on or in their 
bodies prior to inclusion in the study to help ensure safety when in the MRI scanner. 
Participants will be warned about the possible discomforts related to MRI scanning and will be 
advised regarding strategies for managing these discomforts. Participants may view the 
scanner and scanner room prior to participation to habituate to the environment. Rest breaks 
will be provided as needed. Guided relaxation exercises will be provided as needed should 
anxiety be elevated. Participants can terminate their participation should a strong reaction 
occur. 
 
Risks from Cannabis Withdrawal: Heavy cannabis users who discontinue use during the study 
may experience symptoms of cannabis withdrawal, involving nervousness, sleep disturbance, 
and appetite changes. Withdrawal from cannabis is not medically dangerous, and does not 
result in known long-term negative consequences. Since patients with schizophrenia tend to be 
light users of cannabis, we do not expect substantial cannabis withdrawal symptoms in our 
dual diagnosis participants. Some CUD (without SCZ) participants, if they are heavier users, 
may experience some withdrawal symptoms. 
 
Participants will be educated about cannabis withdrawal with a fact sheet that includes a brief 
list of coping strategies. If participants experience cannabis withdrawal, research staff will cue 
the participant to use coping strategies and, if needed, will link the patient with clinical 
support from their treatment team (for patients with SCZ-CUD) or from clinical staff at DHMC 
(for participants with CUD alone). 
 
Risks to Fetuses and Nursing Infants: Cannabis is known to be harmful to fetuses. Dronabinol 
is a pregnancy category C medication. The risks of brain fMRI for pregnant or nursing mothers 
to fetuses and to nursing babies are unknown. Thus, pregnant or nursing mothers will not be 
included in the study. 
 
A urine pregnancy test, paid for by the study will be given to all women at the initial 
assessment, and on the morning of each scan day (i.e., thus before administration of cannabis, 
dronabinol or placebo and before scanning). If a participant is pregnant at baseline or becomes 
pregnant, she will be informed immediately, referred to her psychiatrist and/or her primary 
care physician, and discharged from the study. She will not undergo scanning nor be given 
cannabis or dronabinol. 
 
Risks Related to Genetic Testing: The risks from genetic testing are mostly related to 
confidentiality and others (e.g. an insurer) learning a participant’s results. To protect them 
from this type of risk, test results will be kept private. Information about participants will be 
coded with a number, not their name.  Only the researchers in this study will be able to know 
the results of testing. The results of the genetic test will not be told to participants, treatment 
providers or other's outside of the study. The results of the test will not be included in 
participants' medical records.  

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Risks Related to the Eye Camera: The eye camera LED light emits in the infrared range of the 
spectrum. Because the eyes do not register infrared light, it is important when using any 
infrared source to ensure that exposure levels on the retina, lens, or cornea will not be large 
enough to cause damage (e.g., burns). The LED used in the device has a much lower radiation 
emission than the limits defined in the appropriate standards (U.S. ANSI IESNA 27 and 
international IEC 62471, which govern non-laser lamps and lamp systems and their effects on 
eyes and skin).  Specifically, at the deployment distance of 50mm or more from the eye, the 
intensity will be less than 4W/sr, and thus these LEDs belong to the "exempt group," 
considered to be of "no photobiological hazard". At a distance of 35mm or closer, the intensity 
would qualify as "low risk", but we will maintain the camera at a minimum of 50 mm using a 
fixed deployment on the head coil to ensure safety. 
  
 
15.  Risk/Benefit analysis:   
Describe why the risks to subjects are reasonable in relation to the anticipated benefits to participants 
and in relation to the importance of the knowledge that may reasonably be expected to result from the 
study. 
  Participation in this study is associated with a variety of possible risks, but none of them are 
severe.  We will obtain careful informed consent to insure that every potential participant fully 
understands all of the possible risks.  In addition, we will not include individuals who we 
believe would not be able to tolerate the study procedures.   
 
Those groups that will receive dronabinol or smoke cannabis already have a diagnosis of a 
CUD with recent use.  For Groups 1, 2 and 3, who have comorbid diagnoses of SCZ, the use of 
these substances is unlikely to precipitate symptoms or side effects that are new or unusual to 
the participant.  That was demonstrated quite clearly in the pilot study we completed.  For 
those persons with a CUD but not SCZ, we do not believe the use of this strength of cannabis 
or dose of dronabinol will be unusual for them or cause any untoward effects.  In the event 
that this is not the case, we have established intensive monitoring procedures that will allow 
us to detect instances in which a participant experiences adverse effects.  Overall, using these 
strategies, we believe the risks related to participation in this study are low.   
 
Data collected from this study will begin to improve knowledge regarding the biologic basis of 
cannabis use in patients with schizophrenia.  Since schizophrenia is a severe disorder, and the 
co-occurrence of cannabis use disorder in this population presents as a significant public 
health problem. Cannabis use disorder contributes to the morbidity of schizophrenia through 
increased relapse and hospitalizations, noncompliance with treatment, and poorer overall 
functioning. The literature suggests that cannabis use in patients with schizophrenia may be 
related to cannabis’ activation of brain reward circuitry, which may be dysfunctional in 
patients with schizophrenia. No medication treatments are currently available for the 
treatment of cannabis disorders, and the one medication that appears to decrease cannabis use 

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in patients with schizophrenia, clozapine, has side effects with severely restrict its use. The 
data gathered in this study will begin to expand knowledge regarding the biologic basis of 
cannabis use in schizophrenia, as well as to test whether dronabinol may correct the reward 
circuitry deficits thought to underlie this frequent, serious comorbidity. If data from this 
project suggest that dronabinol does improve reward circuitry impairments, it could become a 
candidate for study as a possible treatment for cannabis disorders in patients with 
schizophrenia. 
 
The overall risk from study participation is generally low as described above. We believe that a 
rigorous informed consent process, in combination with the procedures described above, are 
adequate to prevent potential risks and to mitigate potential negative impacts of the research. 
     
 
16.  Research Setting  
a) Is this a multi-center study?   
 Yes   
 No 
 
If yes:  Are you the lead investigator? 
 Yes   
 No 
If you are NOT the lead investigator: 
Name of lead investigator:         
Institution where the lead investigator is located:         
 
b) List all sites where research will take place and the CPHS at Dartmouth College is the reviewing IRB 
(e.g. DHMC Alliance Hospitals, DHMC Clinics, WRJ VAMC): 
 Participants with SCZ for the study will be recruited from DHMC and affiliated hospitals, 
community mental health centers, and DH affiliated clinics.  Recruitment sites participate in a 
clinical research network organized by the Dartmouth Psychopharmacology Research Group, 
of which Dr. Brunette is the Director.  These sites include DHMC, Dartmouth Affiliated 
Clinics, Mental Health Center of Greater Manchester, West Central Behavioral Health, 
Monadnock Family Services, Merry Meadows Farm, Clara Martin Center, Healthy 
Perspectives - Innovative Mental Health Services, Riverbend Community Mental Health 
Center, Greater Nashua Mental Health Center, Health Care and Rehabilitation Services of 
Southeastern Vermont,  Substance Abuse Treatment Center/ University of Vermont and 
Rutland Regional Medical Center.   All MRI scans and all cannabis, dronabinol, and placebo 
administrations will take place at DHMC and UVM .     
 
 
c)  If you are the lead investigator of a multi-center study, list all sites where research will take 
place and the CPHS at Dartmouth College is NOT the reviewing IRB: 
or check 
N/A 
 

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Note:  Each site taking part in the research should have appropriate institutional or IRB oversight.  A 
Site Agreement or Federalwide Assurance may be required.  The CPHS office can assist you with these 
arrangements.  
University of Vermont Medical Center under Dr. Michael Scott Mackey, as site PI. 
White River Junction Veterans Administration Medical Center under Dr.James Rustad, as site 
PI. 
 
 
d) Does the study involve sites outside of the United States and Canada?   
 Yes   
 No  
If yes, are arrangements for the international site(s) being made by a multinational pharmaceutical or 
device sponsor or a cooperative oncology working group?   
 Yes   
 No  
If no, please complete Attachment L. 
      
 
17. Adequacy of Resources to Protect Subjects: 
a) Investigator (including co-investigators) has sufficient time to conduct and complete the research.  
 Yes   
 No 
 
b) Adequately qualified (including experience, training, supervision, and familiarity with the protocol) 
staff are available for this research.  
 Yes   
 No. 
 
c) Describe availability of psychological, social, or medical services, which include counseling or social 
support services, that may be required as a consequence of research participation.  
 Study participants who have schizophrenia disorders will be engaged in treatment for their 
schizophrenia illness and will have access to their psychiatric prescriber and community 
mental health treatment team.  Additionally, Drs. Mary Brunette, or other psychiatrists, will be 
available should adverse events occur that require assessment and intervention.     
 
d) Describe psychological, social, or medical monitoring, ancillary care, equipment needed to protect 
participants (e.g. close proximity to resuscitation equipment or a plan for monitoring of emotional state 
during study procedures).  
 Intensive monitoring will occur throughout each Study Day as described in the protocol.     
 
e) Describe other resources needed for the protection of subjects in the conduct of this research (e.g. 
language translation services). 
 None     
 
f) Explain how the investigator has access to a population that would allow recruitment of the required 

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number of subjects. 
  Participants with schizophrenia or schizoaffective disorder (SCZ) will be recruited from the 
Dartmouth affiliated sites listed above, which treat more than 3000 such patients. Estimating 
that 33% of these participants have CUD, we expect to have a base of > 1000 participants from 
which to recruit. The most recent NH state data suggest that 7% of patients with SCZ are 
taking clozapine; thus, we expect that approximately 930 patients with CUD will be eligible for 
this study. We expect to exclude about 20% of the eligible sample because of previous head 
injury or other contraindications, leaving approximately 720 patients. Since our experience 
indicates that at least 50% of those eligible are willing to enter imaging studies that include a 
period of abstinence, we expect to have a sufficient number of participants to recruit  a 
sufficient number of participants so that we can  complete the study on 75 dual diagnosis 
participants (Groups 1, 2, and 3). There will also be sufficient patients for Group 4 (SCZ 
without CUD). Recruitment of those with CUD without SCZ (Groups 5, 6 and 7) and normal 
control participants (Group 8) will occur through advertising and the use of flyers. 
 
 
 
18.  Participant Population:   
Certain populations are considered vulnerable to coercion and undue influence.  These populations are 
provided with additional protections when participating in a research study. The populations include: 
 prisoners 
 
 
 
 
 
 human embryos 
 fetuses 
 elderly people 
 people with an cognitive disability (also see #24 below) 
 people with a disabling psychiatric illness 
 people who are economically disadvantaged persons 
 people who are illiterate 
 
Refer to:  
Students, Employees  Attachment D   
Illiterate Subjects 
Attachment E 
 
 
a)  List vulnerable groups:   
 
 
or check  
None 
 We are studying people with schizophrenia, who are typically disabled by their psychiatric 
illness and are often economically disadvantaged.    We do not anticipate recruiting Illiterate 
participants, but cannot rule it out.  If this occurs, we will follow the CPHS guidance (see 
Attachment E). Some persons who are employees of Dartmouth, DHMC or our recruitment 
sites may wish to participate in this study.    
b)  Describe additional protections:   
 
or check  
N/A  
 We will utilize all of the strategies we typically use in our studies of individuals with serious 
mental illness.  We will conduct a careful informed consent.  People who are unable to provide 
informed consent due to a lack of clear understanding of the potential risks (or for other 

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reasons) will not be included in the study.  We have a system of careful monitoring and 
backup treatments and supports to employ should a participant have difficulty, including a 24 
hour availability of clinicians and psychiatrists who are experienced in the treatment of 
persons with co-occurring schizophrenia and cannabis use disorder.   Because many 
participants do not have regular telephone service, thereby limiting their access to our 
emergency number, we will provide those participants who express the need for a telephone 
with a prepaid cellular phone (e.g. Tracfone) for use during the study.  This telephone would 
also be used for reminder calls and in case the doctor and participant agree that a telephone 
check-in is warranted.  To avoid exploiting persons who are economically disadvantaged, we 
are not making the stipend provided to participants unduly high.  It is similar to what was 
offered in our previous study. In terms of students and employees who wish to participate in 
this study, we are not specifically recruiting these populations but also would not deny them 
access to the study.  They would have the same careful protections to the confidentiality of 
their data as other participants and the consent forms clearly spell out the issues of who has 
access to study data.       
 
 
19.  Gender and Racial/Ethnic distribution:   
NIH guidelines state that research involving human participation should include minorities and both 
genders.  
Note:  If one gender or minorities are excluded or are inadequately represented in this research, particularly in proposed 
population-based studies, a clear and compelling rationale for exclusion or inadequate representation should be provided.  
 
Will eligibility for the study be based on gender, race, or ethnicity? 
 Yes   
 No 
If yes, explain: 
      
 
 
20. Pregnant Women:    
Are pregnant women eligible for enrollment into this study?  
 Yes   
 No 
If yes, respond to Research Involving Pregnant Women, Fetuses and Neonates:  Attachment M 
If no, explain and include a process to determine pregnancy status. If a pregnancy test is required, note 
who will pay: 
 As described elsewhere in this document, pregnancy tests paid for by the study will be 
conducted on all female participants.     
 
 
21. Fetuses and Neonates:   
Are fetuses and neonates participants in the research?    
 Yes   
 No  
If yes, respond to Research Involving Pregnant Women, Fetuses and Neonates:  Attachment M   
 

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22.  Children:   
Are children eligible for enrollment into this study? Under state law, a child is a person less than 18 
years old. 
 Yes   
 No  
If yes, respond to Children:  Attachment F 
If no, present an acceptable justification for the exclusion: 
 
Note:  NIH guidelines state that research involving human participation should include children unless there is appropriate 
justification for their exclusion.  The investigator should address the rationale for selecting or excluding a specific age range 
of children, or an explanation of the reasons for excluding children as participants in the research.  When children are 
included, the plan should also include a description of the expertise of the investigative team for dealing with children at the 
ages included, of the available facilities to accommodate the children, and a sufficient number of children to contribute 
meaningfully to the study analysis.  
 We have elected to exclude children (those under the age of 18) because schizophrenia in younger 
children is rare and the treatment of childhood-onset schizophrenia requires specialized 
management involving comprehensive social and family support services. Moreover, there may be 
increased risks of giving cannabis to young adolescent children (below the age of 18). 
 
 
23. Women of Child-Bearing Capability  
Are women of child-bearing capability eligible for enrollment into this study?   
 Yes   
 No 
If yes, describe potential harm to an unborn fetus from study activities and the process for determining 
pregnancy status if necessary. If a pregnancy test is required, note who will pay.  If there is potential 
harm to an unborn fetus, the investigator should review with each individual a plan to avoid pregnancy.  
If the investigator regards these contraceptive plans as inadequate, the individual should be advised on 
how to achieve adequate contraception or should be excluded from the study. 
  Cannabis is known to be harmful to fetuses. Dronabinol is a pregnancy category C 
medication. The risks of brain fMRI for pregnant or nursing mothers to fetuses and to nursing 
babies are unknown. Thus, pregnant or nursing mothers will not be included in the study. 
 
A urine pregnancy test, paid for by the study will be given to all women at the initial 
assessment, and on the morning of each scan day (i.e., thus before administration of cannabis, 
dronabinol or placebo and before scanning). If a participant is pregnant at baseline or becomes 
pregnant, she will be informed immediately, referred to her psychiatrist and/or her primary 
care physician, and discharged from the study. She will not undergo scanning nor be given 
cannabis or dronabinol. 
     
 
 
24.  Individuals With Impaired Decision-Making Capacity:   

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a) Will participants potentially lacking capacity to provide informed consent be eligible to enroll in this 
study?  
 Yes   
 No 
 
b) Is it likely study participants may lose their capacity to provide informed consent during the conduct 
of the study? 
 Yes   
 No 
 
If yes to a or b, respond to Research Involving Individuals with Impaired Decision-Making 
Capacity:  Attachment G    
 
 
25.  Recruitment:   
Describe how subjects will be recruited for participation in this study:   
Eligible participants may be identified from medical record information as a “preparatory to research” 
activity under the HIPAA Privacy Rule.  Protected health information obtained as a preparatory to 
research activity may not be removed by a researcher from DHMC, including on mobile electronic 
storage devices.  Contact with the identified participants, however, may not occur without prior CPHS 
approval of the recruitment plan for the study.  This plan should describe how initial contact with 
participants will be made and by whom.  Please note in general, individuals should not be contacted for 
recruitment into a research study by someone unknown to the individual. 
 
a) Will subjects be recruited by searching records (e.g., school records, medical records)?  
 Yes   
 No    
If yes, will this search include paper files?  
 Yes   
 No 
If yes, where will these paper files be located?  At the various recruitment locations       
 
If yes, will this search include electronic files?  
 Yes   
 No 
If yes, who maintains these electronic files?    The individual recruitment locations have 
their own electronic medical records    
 
 Dartmouth-Hitchcock Recruitment Procedure   
 
Under the “preparatory to research” activity provision in the HIPAA Privacy Rule, a 
study team member will screen medical records using key diagnostic codes to search for 
potentially eligible participants age 18 to 55 with a schizophrenia or schizoaffective 
disorder.  The team member will review the medical records to ascertain basic inclusion 
and exclusion criteria.  If a potential subject is identified, the team member will consult 
with the subject’s treatment provider to determine if they think the subject is stable and 
might be a good candidate for study participation.  If deemed appropriate the provider 
would discuss the study with the potential subject to determine their interest.  If 
interested the provider would get their permission to be contacted by the study team 

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and/or give them an approved handout describing the study with the study team’s 
contact information.  
      
 
b) Will databases be utilized?  
 Yes   
 No 
If yes, please specify types and locations of databases:       
 
c) Will fliers or brochures be posted, mailed or otherwise distributed?  
 Yes   
 No 
 
d) Will letters be sent to potential participants?  
 Yes   
 No   
If yes, please provide the letter(s) for CPHS review. 
 
e)  Will referral be utilized for recruitment?   
 Yes   
 No    
If yes, please be aware patients should first be informed about the study and agree to the contact before 
any referral.  
 
f)  Will any other method be employed?  
 Yes   
 No  
If yes, please specify, in detail, what those methods will be:  
 Normal  control and CUD without schizophrenia  participants (Groups 5-8) will be 
recruited not only through flyers, but also through advertisements on the radio, in 
newspapers, and on the internet..  Some internet based advertising will use sites such as 
Facebook and Google ads.  Viewer can click on the ad and will be directed to a brief 
description of the study and an online survey to determine if the person may qualify for 
the study.  (See section 10 for a description of the survey).  The description will also 
provide viewers with a telephone number that they can call if they want to find out more 
about the study or whether they might qualify without completing the survey online. 
 
Dual diagnosis participants and participants with schizophrenia without a CUD (Groups 
1-4 )will be recruited using the same methods as above but will also be recruited from 
local community mental health centers and other treatment providers.  Treatment  
providers will be given the eligibility criteria for the study.  They will be asked to contact 
those persons they treat who may be eligible and ask permission for the research team to 
contact the person.  Most potential participants are open to this but it can take a month 
or more for this to occur.  The reason for the delay is that some individuals in mental 
health care are only seen every two to four weeks and treatment providers can forget to 
ask about research.  To avoid the delay, we will use a form letter from the provider to the 
individual stating that it is believed that the person qualifies for a study and that the 

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provider would like to have the researcher contact them.  The participant has the option 
to call the provider and decline to be contacted by the researcher.   Because participants 
with schizophrenia often do not show up for scheduled visits/ information sessions to 
learn about the study prior to consent, those individuals in the groups with schizoprenia 
(with or without a CUD) who attend their scheduled appointment to learn about the 
study will receive a $25 gift card, regardless of whether or not they consent to participate 
in the study.    
 
g) Does the research plan include “finder fees” or incentives (bonus payment, gift certificates) offered to 
study personnel for enrollment of participants?   
 Yes   
 No    
Note:  As a rule, finder fees or incentives are not acceptable.  Please justify any offered incentives.  If incentives become 
available during the course of the study, please notify the CPHS. 
      
 
Attach copies of any proposed flyers, posters, pamphlets, print advertisements, and scripts for on-air 
advertisements or telephone calls.  All recruitment materials should be approved by CPHS prior to use. 
  
Note:  Advertising should not use terms such as “new treatment,” “new medication,” or “new drug” without explaining 
that the test article is investigational.  A phrase such as “receive new treatments” implies that research participants will be 
receiving newly marketed products of proven worth. Advertisements should not promise “free medical treatment,” when the 
intent is only to say participants will not be charged for taking part in the investigation.  The CPHS will determine if the 
promise of treatment without charge is an inappropriate inducement for study participation.  Advertisements may state that 
participants will be paid, but should not emphasize the payment or the amount to be paid.  The advertisement should include:  
the name and address of clinical investigator and research facility; the condition under study or the purpose of the research;  
in summary form, the criteria that will be used to determine eligibility for the study; a brief list of participation benefits, if 
any (e.g., a no-cost health examination); the time or other commitment required of the participants; and the location of the 
research activities; and the person or office from whom to obtain further information. 
 
26.  Consent Process:   
The Principal Investigator (PI) is responsible for ensuring all participants have provided informed 
consent to participate in this study unless the consent process is waived or altered by the CPHS.  The PI 
may authorize other appropriately trained individuals to obtain consent from participants. 
 
Please file the consent form in the medical record of each research participant if study participation may 
affect other medical treatment. 
 
Explain how informed consent to research participation will be obtained.  Please describe the consent 
process, including information about:  
 Who has been authorized by the PI to obtain consent 
 The time interval between providing information potential participants about a study and having 
the consent form signed 
 Any precautions taken to minimize the possibility of coercion or undue influence 

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 Plans for responding to a potential participant or a legally authorized representative who does not 
speak English, such as the use of a translator or a translated consent form 
 Any aids used to simplify scientific or technical information, like a diagram 
 Plans to accommodate the probable literacy level of potential participants 
 Our group has a procedure for the consent of participants into medication studies. It allows 
for only physicians and ARNPs to consent participants to be in studies.  Other staff may 
present a consent form to participants and review it with them, but a physician or ARNP must 
meet with the person (face-to-face or via telephone) to answer questions, and assess 
understanding and voluntariness prior to the participant signing the consent form. The 
physician or ARNP will also assess the competency to consent of each potential participant.  If 
an individual's capacity to consent is in doubt and the person does not have a guardian, the 
consent process will stop.  The physician or ARNP will consult with the individual's primary 
psychiatrist.  If in the opinion of the psychiatrist, the person cannot consent and the person 
lacks a guardian, the person will not be recruited.  If the treating psychiatrist believes that the 
diminished capacity is more of a transitory state, then the consent process will be tried again 
on another day. Potential participants are encouraged to read the consent form and ask 
questions.  They are further encouraged to solicit input from significant others and/or care 
providers, if appropriate. To minimize coercion, the consent form has language that clearly 
spells out that participation in the study is voluntary and refusal to participate will not affect a 
person's health/mental health care.   
 
Because we do not have foreign language version of all of the assessments, we do not 
anticipate consenting persons who do not speak English.  If literacy is a problem, our group 
follows the Dartmouth Committee for the Protection of Human Subjects procedure for 
consenting persons who cannot read or cannot read well (see Attachment E.)  Finally, our 
group makes a concerted effort to make the language in consent forms understandable to 
participants.     
 
 I intend to obtain consent for research participation but I am requesting a waiver for the use of a 
signed and dated consent form.  Please respond to the criteria listed in Attachment I and include an 
information sheet based on the CPHS template. 
 I am requesting an alteration of the consent process to exclude certain information that is ordinarily 
required.  A list of the essential elements of consent to research participation is available on the CPHS 
website: http://www.dartmouth.edu/~cphs/tosubmit/ConsentElements.html.  
Please respond to Attachment H. 
 I am requesting a waiver of the entire consent process and use of a consent form.  Please respond to 
Attachment H. 
Explain why any alteration or waiver to the consent process or form is necessary.   
      
 
 

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b) Authorization:  Explain how an authorization for research use of protected health information 
(PHI) will be obtained.  PHI is individually identifiable health information obtained from a health care 
provider or insurance plan.  In general, the HIPAA Privacy Rule permits the use or disclosure of PHI 
for research purposes only with an authorization from each participant whose PHI will be involved.  
Only when certain criteria are satisfied can the CPHS grant a waiver of authorization or of the use of a 
signed and dated authorization form.  A waiver of authorization is necessary for recruitment procedures 
when patient information is used to identify and contact potentially eligible research participants.  A 
single form may combine the essential information for both consent and an authorization.  The CPHS 
consent template contains this combination and is available on the CPHS website at 
www.dartmouth.edu/~cphs.  
 
Check all that apply: 
 This study does not involve PHI. 
 A single form combining an authorization with the consent form and based on the CPHS template is 
included with this application. 
 A separate authorization form is included with this application. 
 I am requesting a waiver of authorization for only the recruitment procedure.  Please respond to 
Attachment H. 
 I am requesting a waiver of signed and dated authorization.  Please respond to Attachment I. 
 I am requesting a waiver of authorization for the use or disclosure of PHI in this entire study.  
Please respond to Attachment H. 
 
In your explanation of the consent process above, please include information about obtaining 
authorization for the research use of PHI. 
 
 
27.  Privacy and Confidentiality:   
Describe the plans to protect the privacy of subjects and maintain the confidentiality of the data.  
 
Note:  Under certain circumstances, an invasion of privacy or breach of confidentiality may present a risk of serious harm to 
subjects (e.g., as when the research obtains information about subjects that would, if disclosed by the researcher, jeopardize 
jobs or lead to prosecution for criminal behavior).  Under other circumstances, an invasion of privacy or breach of 
confidentiality can be a moral wrong  
 
a) Will any study activities involve an interaction or reveal information for which protection of 
participant privacy is necessary? 
 Yes   
 No  
If yes, please identify the activities and describe the plan to protect the privacy of participants.  For 
example, a plan for protection of privacy might consist of conducting the assent process for an adolescent 
minor in a private setting, rather than in the presence of the minor’s parent. 
 Participants will be asked to provide a detailed account of their use of alcohol and drugs for 
the period that they are in the study.  Also people will be asked about past alcohol and drug 
use and its impact on their lives.  Participants will be tested for alcohol, marijuana and other 

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drugs of abuse.  Persons will be asked about their history of mental health symptoms.  Our 
plan to protect the privacy of participants is described below in section C. 
 
b) Will the data collected in the course of the study be considered sensitive, e.g., include information 
about a mental health disorder, HIV status, or SS#?   
 Yes   
 No  
If yes, provide the rationale for why these data are needed: 
 The aims of the study include the collection of data about substance use and psychiatric 
symptoms.     
 
If yes, could any of these data, if disclosed, damage financial standing, employability, insurability, or 
reputation? 
Yes   
No   
If yes, will a Certificate of Confidentiality be obtained?  
 Yes   
 No 
Any person engaged in research collecting information about illegal conduct from human research subjects may apply for a 
Certificate of Confidentiality.  NIH provides detailed instructions for investigators wishing to make an application at 
http://grants.nih.gov/grants/policy/coc/index.htm.   
 
c) Describe specific physical, administrative, and technical safeguards employed to secure data, e.g., 
limitation of access to data, use of locked file cabinets, protection of computer-based data systems.   
 Information gathered through interviews will be coded to a study number.  The name-
number code will be kept by the PI and interviewers in a locked file cabinet.  Coded interviews 
will be kept in separate locked cabinets in research offices at the offices of the 
Psychopharmacology Research Group (PRG) and the scanning laboratories at DHMC and 
UVM. 
Data will be managed according to usual procedures of the PRG and neuropsychology 
research groups and UVM.  These procedures include careful editing and coding of interviews 
and other research forms prior to data entry; locked storage of original data forms at the PRG; 
storage of scanning data on password protected computers, software controls on all data 
access; and regular backup of data files.  Neuropsychological testing data and imaging data 
sent to DHMC from UVM will be encrypted and sent securely 
We have obtained a certificate of confidentiality.  Additionally, the Geisel School of Medicine 
at Dartmouth's Department of Psychiatry is a HIPAA covered entity, so we follow those 
federal privacy regulations in addition to our current confidentiality safeguards.  
 
 All imaging study data are labeled with a unique study ID and the date of acquisition.  The 
link between participant information and the study ID is kept in a locked file cabinet, within a 
locked office, and will only be accessed by study personnel.  Coded data is recorded in a 
database, password protected on a secure server in the Brain Imaging Lab, Psychiatry.  Images 
are transferred to the Brain Imaging Laboratory from the Advanced Imaging Center at DHMC 
and archived using secure systems.  Images and scan readings will become part of each 

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participant's permanent medical record and this is clearly outlined in the consent form and 
discussed with each participant during the consent process     
 
d) Will data that identify individual subjects be published or in any way be disclosed to third parties 
other than project personnel?   
 Yes   
 No  If yes, please explain here and incorporate the information in consent form:  
      
 
 
28.  Responsibility for costs of injury or illness related to research: 
Will the sponsor or other funding agency be responsible for costs of injury or illness related to the 
research?    
 Yes   
 No 
 
If applicable, describe whether or not the sponsor will be responsible for investigational device removal if 
required: 
 NA     
 
If the sponsor or other funding agency will not be responsible for costs of injury or illness 
related to research, please complete: 
a)  The reasons why the sponsor or funding agency is not accepting responsibility for research-related 
injury. 
 NIH does not cover the cost of injury or illness.     
 
b)  Summary of risks as related to potential costs that could be incurred as a result of research-related 
injury or illness.   
 It is possible that a participant could have a severe psychiatric reaction to the drugs used in 
the study or to the scanning or other study procedures.  Should this occur, hospitalization 
could be required.  However, we believe this is extremely unlikely given our pilot work 
establishing a safe dose of cannabis and dronabinol for this study and since all participants 
who get study drug will be cannabis users, some schizophrenia patients will be taking 
antipsychotic medication already, and all will be required to be psychiatrically stable as 
indicated by outpatient treatment for the past month.  If a participant needs psychiatric 
hospitalization, it will be billed to their insurance.     
 
c)  Describe reasons for requesting that DHMC or Dartmouth College provide coverage for research-
related injury or illness, which is not standard policy.   
 We are not requesting this.     
 
 
29. Participant Remuneration: 

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Will participants be paid for their time, reimbursed for travel or meal expenses, or receive any sort of 
"gift" for participating in this study?  
 Yes   
 No 
If yes, please describe in detail: 
 
Note: Participant remuneration is not considered a benefit of being in a research study.  CPHS will consider the amount of 
payment in relation to the time needed and any inconvenience to participants.  Payment, reimbursement, or gifts should not 
be  in an amount that would be coercive to the participant population. 
 
If study is to be done at the VA, specific questions need to be answered if a participant is being paid "in excess of 
reimbursement for travel."  Please contact the CPHS office if you need more information. 
Participants with schizophrenia will receive a $25 gift card for attending the informational 
session to learn about the study.   
   
All participants in Groups 1-4 (SCZ-CUD and SCZ only) will be paid: 
 $25 for completing the Screening Visit  paid as a gift card on the day of the visit 
 $50 for the Neuropsych Baseline Visit paid as a check at the end of the study 
 $100 for T1 Scan day paid as a check at the end of the study 
 $35 will also be “won” on the T1 Test Day for the monetary incentive delay task paid as 
a check at the end of the study - NOTE: This amount is not disclosed to participants 
because it would invalidate the testing. 
 $200 for T2 Scan day paid as a check at the end of the study 
 $35 will also be “won” on the T2 Scan day for the Monetary Incentive Delay task paid 
as a check at the end of the study 
 Participants will "win" between $15-$20 for completing the Probabilistic Reward 
Task.    Over the three sessions, this would not total more than $50.  We do not state the 
exact amount in the consent because it invalidates the testing. 
Total = $495: $375 paid as stipends and $120 that is "won" 
 
 
 
All participants in Groups 5-7 (CUD only) will be paid: 
 $50 for completing the Screening Visit  paid as a gift card on the day of the visit 
 $50 for the Neuropsych Baseline Visit paid as a check at the end of the study 
 $400 for T1 Scan day paid as a check at the end of the study 
 $35 will also be “won” on the T1 Test Day for the monetary incentive delay task paid as 
a check at the end of the study 
 $500 for T2 Scan day paid as a check at the end of the study 
 $35 will also be “won” on the T2 Scan day for the Monetary Incentive Delay task paid 
as a check at the end of the study 
 Participants will "win" between $15-$20 for completing the Probabilistic Reward 
Task.    Over the three sessions, this would not total more than $50.   
Total = $1,120:  $1,00 paid as stipends and $120 that is "won" 

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All participants in Group 8 (Healthy Control) will be paid: 
 $50 for completing the Screening Visit  paid as a gift card on the day of the visit 
 $50 for the Neuropsych Baseline Visit paid as a check at the end of the study 
 $200 for T1 Scan day paid as a check at the end of the study 
 $35 will also be “won” on the T1 Test Day for the monetary incentive delay task paid as 
a check at the end of the study 
 $200 for T2 Scan day paid as a check at the end of the study 
 $35 will also be “won” on the T2 Scan day for the Monetary Incentive Delay task paid 
as a check at the end of the study 
 Participants will "win" between $15-$20 for completing the Probabilistic Reward 
Task.    Over the three sessions, this would not total more than $50.   
Total = $620:  $500 paid as stipends and $120 that is "won" 
 
 
In addition, all but Groups 4 and 8 can earn money for being abstinent from alcohol or 
drugs.   
 $90 - A $30 gift card each for confirmed abstinence at Neuropsych Baseline Visit, T1 
and T2 
 $360 - Participants need to demonstrate two weeks of abstinence prior to the first 
scan (T1) plus another three visits between T1 and T2.  They will go to a local clinic 
for a visit up to 3 times a week.  They will be paid: 
o $10 cash for attending the visit 
o $30 gift card for confirmed abstinence 
We anticipate nine of these visits, though the actual number may fluctuate. 
Estimated total for abstinence = $450 
 
 
The study provides transportation for study visits to participants through a taxi service.  This 
is especially helpful for participants with SCZ who often lack transportation.  For those 
persons who provide their own transportation, the study provides the following 
reimbursement:     
  
A $25 gas card for each visit for people coming from 25-49 miles away.  
  
A $50 gas card for each visit for people coming from 50 miles away or beyond. 
 
IMPORTANT: Participants cannot drive themselves to appointments in which they may 
receive dronabinol or smoke a marijuana cigarette. They must either have someone else drive 
or take the taxi provided by the study.    
 
Those participants who choose to have the study provide them with a prepaid cellular 
telephone will be allowed to keep the cell phone and any unused minutes at the end of the 
study. The phones will not have a contract. 

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30. Use of Drug or Biological Agent:   
Respond to items below or check 
 No drug or biological agent involved.  
 
List the drugs and biologic agents to be used in this study:  dronabinol, marijuana     
 
Is each drug or biological agent approved by the FDA for the specific indication for which it is used in 
this study?   
Drug or Biologic Agent:  dronabinol     
 Yes   
 No 
Drug or Biologic Agent:  marijuana     
 Yes   
 No 
 
If no, respond to a and b for each drug or biologic agent used for an unapproved indication:  
 
a) Briefly discuss the plan for the storage, dispensing, handling, and disposal of investigational and 
FDA-approved drugs, devices, and biologics. When these activities are being done by the investigator, 
include a description of the procedures for inventory control and documentation. 
 
DHMC Investigational Pharmacy is managing all study drugs.   
 Yes  
 No 
If No please describe management plan below. 
      
 
b) Check and respond to one of the following statements for each drug or biologic agent:  
 If this study is being done under an Investigational New Drug (IND) application to the FDA please 
provide:  IND # (Investigational New Drug):  #  106130      and specify who holds the IND#:  Mary F 
Brunette, MDOR 
 If a drug or biologic agent or the combination of drugs or agents is not FDA approved for the 
indication for which it is used in this study, but an IND # has not been obtained, please complete 
Attachment J. 
 
 
31.  Placebo vs. Standard Care:   
Does any part of the study involve use of a placebo or procedures that are inconsistent with the standard 
of care at DHMC?   
 Yes   
 No 
If yes, respond to Placebo:  Attachment B 
 
 
32.  Medical Device:  
Respond to items below or check 
 No devices involved. 
 
List the devices to be used in this study:       

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Is each device approved by the FDA for this indication?    
Device:       
 
 Yes   
 No 
Device:       
 
 Yes   
 No 
If no or if FDA approval is pending, respond to a, b, and c for each device used for an unapproved 
indication. 
a) Is the device provided free of charge by the sponsor?    
 Yes   
 No 
b) Where are the devices used in the study stored?  Who controls their use? 
c) Respond to (1), (2), (3), or (4) 
(1) If this study is being done under an Investigational Device Exemption (IDE) from the FDA 
please provide:  IDE#: #      or check here if the IDE is pending: 
 
Also check the FDA Device HCFA Reimbursement Category: 
 
     
 A     
 B2     
 B3 
Please note: CPHS will not approve a study before an IDE # has been received. OR 
(2) If 510(k) notification for a device has been sent to FDA check here 
 and either:  
provide a copy of the documentation verifying 510(k) clearance, or check here if 510(k) clearance 
is pending 
. OR 
(3) If a device is exempt from IDE requirements, check here 
 and provide a copy of a letter 
from the FDA or sponsor stating that the device is exempt from IDE requirements under 
812.2(c). OR  
(4) If you are requesting a nonsignificant risk determination for a device from CPHS, please 
check here 
 and complete Attachment A. 
 
Please note: The CPHS may approve, disapprove, or require modifications in a protocol that has been 
approved or cleared by the FDA.  
 
 
33.  Conflict of Interest Review: 
Dartmouth College, Dartmouth-Hitchcock Clinic, Mary Hitchcock Memorial Hospital, and the 
Hitchcock Foundation have adopted a policy on Conflict of Interest that applies to each study reviewed 
by the CPHS.  Copies of the policy are available on the CPHS web site at 
http://www.dartmouth.edu/~cphs/policies/. 
 
Instructions: To assist institutional review of the proposed research for conflicts of interest, please 
respond to the questions below as applicable to this study.  Definitions of terms are available at the end 
of this section. 
Regarding only this proposed research study, does any investigator or other individual 
among the research staff, including certain family members, hold a financial or other outside 
interest that would reasonably appear to affect or be affected by the proposed study that: 
a. Consists only of compensation for services or equity in a publicly held entity worth less 
than $5000 when combined in the prior 12 months or anticipated during the next 12 
months? 

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  No or not applicable.  Please answer the next question. 
  Yes.  Please add an appropriate disclosure to the "Funding" section of the consent form 
for this study. 
b. Consists of i) compensation for services or equity in publicly held company worth $5000 
or more when combined in the prior 12 months or anticipated during the next 12 months, 
or ii) any equity in a privately held entity, iii) intellectual property rights, or iv) another 
outside interest, which may present a conflict?  The latter interests listed here are limited to 
those held or received over the prior 12 months and those anticipated in the next 12 
months. 
  No or not applicable. 
  Yes.  Please follow the instructions below. 
 
c. Consists of reimbursed or sponsored travel from a single entity worth $5000 or more that 
was received over the prior 12 months and is anticipated in the next 12 months? 
  No or not applicable. 
  Yes.  Please follow the instructions below. 
 
If you have answered "No" to the three questions above, no further information or action is needed. 
If you have answered "Yes" to question #33b or #33c, then please identify each individual holding the 
outside interest  
  Robert M. Roth, PhD is an author of the BRIEF-A, a questionnaire measure that will be used in the 
project.  He receives royalties from the publisher who holds the copyright (Psychological Assessment 
Resources, Inc; PAR, Inc).  Dr. Roth will provide the BRIEF-A gratis to the project from the copies 
he receives for free for research annually from the publisher. 
     
Each individual listed above should complete a CPHS Conflict of Interest Disclosure Form.  The 
CPHS Conflict of Interest Disclosure Form is available on the CPHS website at the following url: 
http://www.dartmouth.edu/~cphs/tosubmit/forms/ 
 
Please send an electronic copy of the completed disclosure form to CPHS.Tasks@dartmouth.edu or a 
paper copy to the CPHS office at Hinman box #6254.  These copies should be clearly identified as 
containing confidential information. 
 
Definitions: 
“Conflict of interest” occurs when an individual's outside interests, financial or otherwise, 
might reasonably lead an independent observer to question whether the individual's actions or 
decisions in connection with a study are influenced by the outside interests. 
Conflicting interests do not include: 
 
 Salary from Dartmouth College, Dartmouth-Hitchcock Clinic, Mary Hitchcock 
Memorial Hospital, and the Hitchcock Foundation or income from consulting done on 
behalf of one of these entities; 

v.4.30.2021 
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 Income from seminars, lectures, teaching engagements, or service on advisory 
committees or review panels sponsored by: 
o A federal, state, or local governmental agency,  
o A U.S. institution of higher education,  
o An academic teaching hospital,  
o A medical center, or  
o A research institute that is affiliated with a U.S. institution of higher education; 
o Income from mutual funds or other retirement accounts where the holder does not 
directly control the investment decisions; 
o Copyrights in books, primary literature, or presentations.  This exclusion does not 
apply to income resulting from such copyrights. 
 
“Investigator or research staff” means the project director or principal investigator and any 
other person, including a student, research support staff member, consultant, or collaborator 
who is responsible for the design, conduct, or reporting of research involving human subjects.  
For the purposes of conflict of interest review, this term includes spouses, domestic partners, 
and dependent children of investigators and research staff. 
 
"Publicly held entity" means a company that has stock publicly traded on a stock exchange. 

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Attachment B 
Placebo or Procedures that are Inconsistent with the Standard of Care  
 
Consider the ethical implications of using a placebo or procedures that are inconsistent with the 
standard of care in this study.  Specifically, explain what "standard of care" therapy is for this 
participant population and how the use of placebo therapy may affect risks for participants. Also discuss: 
a) the safety and efficacy of other available therapies (if any), 
b) the maximum total length of time a participant may receive placebo on study, 
c) the greatest potential harm that may come to a participant as a result of not receiving effective therapy  
(immediate or delayed onset), and 
d) safeguards for the participants receiving placebo. 
 
Required comment from the local research team specifically addressing a-d above and in 
addition to any justification included in the study protocol.  Information copied directly from 
the protocol is not acceptable in this section: 
Placebo is being used in this study, but not as a treatment, because this is not a treatment 
study.  All individuals in this study, who are diagnosed with schizophrenia, are in active 
treatment for their symptoms throughout the study.  Placebo is given to those participants 
with SCZ-CUD and those with CUD only on a single occasion to maintain the blinding of the 
study and to serve as a control condition.  Participants are to receive one of the following: 
• 
Two 7.5mg dronabinol capsules and a placebo marijuana cigarette 
• 
Placebo capsules and an active marijuana cigarette 
• 
Placebo capsules and a placebo marijuana cigarette 
 
a) 
Safety and efficacy of other therapies – The placebo is not being used to replace another 
therapy, therefore this question does not apply. 
b) 
Maximum amount of time a participant may receive placebo – One day 
c) 
Greatest potential harm from not receiving treatment – This does not apply because this 
is not a treatment study.  All SCZ-CUD participants are receiving treatment during the study.  
CUD only participants are not receiving treatment, but they have not been receiving any 
treatment and are not seeking treatment.   
d) 
Safeguards for persons receiving placebo – This question does not apply.  While there 
are a multitude of safeguards, they are in place to protect people from the potential harms 
from receiving dronabinol or marijuana.    
 
 
 

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Attachment C 
Genetic Research  
 
For research studies involving genetic testing the CPHS describes below two categories of studies to 
assist its further review.  The researcher should determine if the research falls into category A or B as 
described below. If the research falls into category A. indicate by checking below and add comments as 
appropriate to this research project. 
If the research falls into category B. please respond to questions that follow.  
 
Respond to A or B: 
 
 A. The study is looking for an association between a genotype or a biomarker and a specific disease 
or condition, but at this point it is not clear if the genetic marker has predictive value. The uncertainty 
regarding the predictive value of the genetic marker is such that studies in this category will not involve 
referral of participants to genetic counseling. 
 
Comment: 
Participants will have the option of donating a genetics sample for analysis to explore the 
relation of genetic markers to brain function and structure.  Participants will also have the 
option to have their blood and/or genetics specimen banked for future research.  Because 
this genetics research is exploratory and will not likely provide a meaningful result for 
individual participants, they  will not be given the results of the genetic testing. If new 
information develops during the study such that results of the analysis would be meaningful 
to participants, then we would approach the IRB at that time to discuss the proper course of 
action. Additional information is provided on page 15 of the Study Plan. 
 
 
 B. The study is based on the premise that a link between a genotype or a biomarker and a specific 
disease or condition is clinically useful in predicting the development of that specific disease or 
condition.  
 
Respond to the items below: 
1.  Are clear guidelines established for disclosure of information, including interim or inconclusive 
research results, to the participants?   
 
2.  Will participants be told what genetic information (and its meaning) they may receive at a certain 
point in the research?   
 
3.  Will family members be protected against disclosure of medical or other personal information 
about themselves to other family members?   
 
4.  Will participants be given the option not to receive information?   
 
5.  Will limits on protections be clearly communicated to participants, including advance consent to 
disclosures about health risks to family members? 

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6.  Are the possible psychological and social risks of genetic research included in the consent 
process?   
 
7.  Will genetic counseling be provided, both as part of the consent process and when 
communicating test or other research results to participants? 
 
8.  Will participants be informed about the possibility of important incidental genetic findings such 
as paternity and heritable conditions other than the one(s) under the study? 
 
9.  Will the study data be protected from disclosure to third parties, such as employers and 
insurance companies?  How? 
 
10.  Will participants be informed about the potential consequences of a third party, such as 
employer or insurance company, becoming aware of the study findings? 
 
11.  Will the data be stored in a secure manner?  How?   
 
12.  Will the data be coded?  Who holds the key to the code? 
 
13.  Is a request for a certificate of confidentiality necessary? 
Yes    
No  
If No, why not? 
 
14.  Does the investigator plan to disclose research findings to participants or their physicians for 
clinical use?  Describe the clinical significance of the findings to participants. 
 
15. Is the possibility of disclosure of study findings to participants discussed during the consent 
process with prospective participants? 
 
16.  How will the biospecimens be stored?   
 
17.  Will biospecimens be made available for future use by participants?  by other investigators?  for 
new studies? 
 
18.  What will happen to data and biospecimens in the event of withdrawal from the study? 
 
19.  How will the privacy of participants be protected when study results are published?   
 
20.  If research involves family members:  
 
20a. How will family members be recruited for study participation? 
20b. Will information be obtained from the medical records of family members?   
 
In general, the consent process and form should include the following information: 
•  they will receive only the genetic information the investigator feels is clinically significant and reliable, or no 
genetic information will be provided;  
•  at what point in the study they will receive genetic information; 
•  they may find out things about themselves or their family that they did not really want to know, or that they 
may be uncomfortable knowing; 
•  information about themselves may be learned by others in their family; 
•  any effect on their insurability; 

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•  actions taken as a result of participation may expose participants to risks (e.g. submitting insurance claim forms 
for the costs of genetic counseling); 
•  available protections for the confidentiality of study data; 
•  what the consequences of withdrawal from the study are; and 
•  costs to them that may be associated with participation (including, for example, the cost of genetic or 
psychological counseling). 

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Attachment D 
Employees and Students   
 
One of the primary responsibilities of the CPHS is to ensure that a participant’s decision to participate 
in research will be voluntary and that consent will be sought “only under circumstances that provide the 
prospective subject... sufficient opportunity to consider whether to participate and that minimize the 
possibility of coercion or undue influence.”  Students and employees may be vulnerable to “subtle 
inducements to participate”. 
 
The researcher who plans to recruit either population must define clearly the participants to be 
enrolled and the rationale for their participation.  In addition, the mode and timing of recruitment must 
be explained. 
 
Another special consideration for employee and student populations is the issue of confidentiality of 
research data. Depending on the nature of the research and the data collected, a break of confidentiality 
could affect a person’s employment, career path, educational plans, or social relationship with the 
hospital/academic community.   Therefore, the researcher should document carefully the methods to 
protect the subjects’ identity and research data (e.g., coding, storage of research files, limits of 
accessibility to research data, etc.). 
 
Comment: 
 
 We are not specifically recruiting employees or students of Dartmouth College, Geisel School of 
Medicine or DHMC, but anticipate that some people who are employees and/or students will 
respond to advertisements for this study and if appropraite will be entered into the study.  
Because of the nature of this study, there are already a fairly large number of precautions in 
place to protect the privacy of individuals.  These would also apply to students and employees.  
The specifics of this and the limits are clearly spelled out in both the study plan and consent 
form.  
 
 
 
Please Note: Studies enrolling Dartmouth Medical School students must be reviewed by the Medical 
Education Institutional Review Committee (MEIRC).   
Check here if you plan to enroll Dartmouth Medical School Students. 
Contact Greg Ogrinc MD for more information about MEIRC review. 
 
 

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Attachment E 
Illiterate Subjects  
 
Subjects who are unable to read should not be excluded from research on the grounds of illiteracy. If a 
subject is unable to read or if a legally acceptable representative is unable to read, an impartial witness 
should be present during the entire informed consent discussion.  After the written consent form and 
any other written information to be provided to subjects is read and explained to the subject or the 
subject's legally acceptable representative, and after the subject or the subject's legally acceptable 
representative has orally consented to the subject's participation in the trial, and, if capable of doing so, 
has signed and personally dated the consent form, the witness should sign and personally date the 
consent form.  By signing the consent form, the witness attests that the information in the consent form 
and any other written information was accurately explained to, and apparently understood by, the 
subject or the subject's legally acceptable representative, and that informed consent was freely given by 
the subject or the subject's legally acceptable representative. 
 
Comment: 
We do not anticipate recruiting Illiterate participants, but cannot rule it out.  If this occurs, we 
will follow the above guidance. 
 
 
 

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Attachment G 
Research Involving Individuals With Impaired Decision-Making Capacity  
 
Introductory Information:  
When a subject lacks capacity to give informed consent, the investigator should obtain written 
permission from a legally authorized representative prior to enrolling the subject in a research study.  
Federal Regulations define legally authorized representative as an "individual or judicial or other body 
authorized under applicable law to consent on behalf of a prospective subject to the subject's 
participation in the procedure(s) involved in the research" (45CFR46.102(c)).  Neither Federal 
Regulations nor New Hampshire State Law provide specific information about who may or may not 
qualify as a legally authorized representative in a research setting.  For the purposes of this policy 
statement, the options of defining a legally authorized representative include:  
 
a) Durable power of attorney for health care (DPAHC),  
b) Court appointed legal guardian 
c) Next-of-kin.  
 
A strict interpretation of NH state law does not provide for the use of next-of-kin as a surrogate decision 
maker for investigational activity. The argument for allowing next-of-kin to consent to participation in 
research activity for an individual who lacks capacity to consent is that, without such an option, it is 
often impractical or impossible to conduct important medical research on conditions where results with 
the best current therapy are suboptimal. When investigational therapy represents the best treatment 
option or when risks to the subject are small in relation to the potential benefit of research to society, a 
policy which creates a major obstacle to the conduct of important research activity is ethically unsound.  
 
With the above issues in mind, the Dartmouth CPHS has established the following policy for research 
studies that may involve adult subjects who lack capacity to give informed consent to participation in a 
research study. Please carefully review all items. 
 
Submission requirements: 
When initially submitting a protocol for review by the CPHS, the investigator will inform the CPHS in 
the appropriate section of the CPHS Study Plan (item #18) if the study may involve subjects who lack 
capacity to give informed consent to participate in the study being proposed. 
 
In addition, when a study may involve subjects who lack capacity to give informed consent, the 
investigator will use the form provided below to inform the CPHS of the requested options to provide 
permission for an individual who lacks capacity to participate in the research study and respond to 
specific CPHS questions. 
 
For all requests: 
Even with the permission of a DPAHC, or court appointed legal guardian, the CPHS will not permit a 
subject who lacks capacity to give informed consent to participate in a research study that offers little 
chance of DIRECT BENEFIT to the research subject over what they could receive outside the research 
setting and involves a meaningful increase in the risk of harm or discomfort, regardless of the potential 
gain to future subjects or society in general.  
Please complete a) and b): 
a) Does participating in this study offer the subject a chance of direct benefit over what they could 
receive outside the research setting? 
 

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We will allow individuals with legal guardians who meet eligibility criteria for Groups 1-3 - 
Participants with SCZ-CUD and Group 4 - Control participants with SCZ to participate in this 
study.  Persons who have a legal guardian but do not have schizophrenia (Groups 5-8) would 
not qualify for this study.   
For persons in the SCZ-CUD group, there is a direct benefit because there is really no 
place from which they could receive the contingency management program that is used 
to help people to abstain while in this study. For control participants with SCZ (but not 
CUD), there is no direct benefit.   
b) Is there an increase in the risk of harm or discomfort for the subject over what they would 
experience outside the research setting? 
 
 
No - The MRI, blood draws and other testing are routine non-invasive medical procedures 
that many people experience.  Participants in the SCZ-CUD group may be exposed to 
THC through a capsule or by smoking it on a single instance, but persons meeting the 
criteria for these groups take this (through marijauana use) on their own on a regular 
basis. 
 
 
 
When there is a meaningful chance of DIRECT BENEFIT to the research subject over what they could 
receive outside the research setting, the CPHS will make a judgment decision about who may consent to 
participation in the study.  The options include: DPAHC, court appointed legal guardian, and a 
properly motivated next-of-kin.  
 
Please indicate the option(s) requested to allow for consent if a subject is incompetent to provide 
consent:    
Durable power of attorney for health care (DPAHC) 
 YES 
NO  
Court appointed legal guardian 
 
 
 
 YES 
NO 
Next-of-kin.   
 
 
 
 
 
 YES 
NO 
 
If a study requests the use of Next-of-Kin as the legally authorized representative,  Please complete a)  
through e)  below:    
 
a) Could the subject receive the same management that they will receive in the research study outside 
the setting of a research protocol? 
 
 
      
 
 
 b) Will participation in the study increase the risk of harm or discomfort compared to what is expected 
with the management that the subject will receive if they do not participate in the research study?  
 
 
      
 
 

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c) Will participating in the study increase the chance that the subject will experience a favorable 
outcome compared to what is expected with the management that the subject will receive if they do not 
participate in the research study?  
 
 
      
 
 
d) What is the magnitude of the benefit that future patients, or society in general, may experience as a 
result of the subject participating in this study?  
 
 
      
 
 
e) The process of appointing a legal guardian may take several months. Would this type of delay 
compromise patient care?  
 
 
      
 
 
The CPHS will use the responses to the items a) – e) when discussing the option of allowing Next-of-Kin 
to enroll subjects into a research study.   
 
Signature section of the consent form:  
Below is the signature line to use when individuals lacking decision-making capacity may be enrolled 
into a research study.  As described above, use of the next-of-kin option requires special CPHS 
approval: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Participant Signature and Date 
 
 
 
 
 
Printed Name 
 
If participant lacks capacity to provide informed consent, sign below as appropriate: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Durable 
Power of Attorney for Health Care and Date  
Printed Name 
 
 
or  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
Court Appointed Legal Guardian and Date  
 
Printed Name 
 
 
or 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Next-of-kin and Date  
 
 
 
 
Printed Name 
 
 

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Decision by the CPHS:   
 
The CPHS decision will be relayed to the investigator via the CPHS approval letter.