Clinical trial NCT03008005
Conditions: PostTraumatic Stress Disorder
Sponsor: Wayne State University
Start date: 2017-06-01; Completion date: 2019-12-31
Enrollment: 46 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The goal of this study is to look at how a type of drug called cannabinoids are related to the processing of fear signals, the experience of emotions and fear, and the pattern of activity in the brain that is involved in these processes and how this relates to the development of post-traumatic stress disorder (PTSD). PTSD is an anxiety disorder that occurs after experiencing a traumatic event(s) and is characterized by unwanted memories of the trauma(s) through flashbacks or nightmares, avoidance of situations that remind the person of the event, difficulty experiencing emotions, loss of interest in activities the person used to enjoy, and increased arousal, such as difficulty falling asleep or staying asleep, anger and hypervigilance. The information gained from this study could lead to the development of new treatments for persons who suffer from anxiety or fear-based disorders.

Detailed description:
The total time that for each participant involved in this study is 5 visits, as outlined below:

Visit 1: Questionnaires, Screening, and Orientation: During this visit the potential participant will learn about the study procedures, sign the informed consent documents, and fill out a packet of forms that ask about his or her race and ethnic background, use of drugs and alcohol and physical and mental health.

Visit 2: Behavioral Tests: During this visit the participant will complete several computer tasks, and the study staff will be measuring reaction time and psychophysiological measures.The tasks that the participant will perform will show three different images and an aversive stimulus (e.g. loud burst of noise or animated snake) may follow one image most of the time, while the other images may never be followed by the aversive cue. The participant will need to try to predict whether the aversive cue will occur or not based on which image is shown and will be asked to repeatedly rate on a scale how likely it is that he or she thinks an aversive cue will occur after each image. Lastly, during the session the participant will also be asked to report his or her level of anxiety on a scale from 0 to 100.

Visit 3: Behavioral Tests with Drug or Placebo and Magnetic Resonance (MR) scan: For safety reasons participant will not be allowed to take any drugs for at least 24 hours before this visit, and should not use marijuana for at least 2 weeks before. Participants will be required to pass a urine drug test (and pregnancy test for women) and breathalyzer test before being allowed to continue with this visit. The participant will also not be allowed to drive himself or herself home from this visit, so he or she should arrange a friend or family member to pick him or her up or a taxi can be called by our research staff.

The participant will view the same images he or she did on the previous day (Visit 2), and may experience the same aversive stimulus as during Visit 2. The participant will again be asked to rate how much he or she expects to experience the aversive stimulus after each image and he or she will also be asked to report his or her level of anxiety on a scale from 0 to 100. However, about 2 hours before the task begins, the participant will be asked to swallow a capsule containing either a marijuana-like drug (Dronabinol) or a placebo (sugar pill). Dronabinol is a Food \& Drug Administration (FDA) approved drug and the doses (5mg or 10mg; one time) are unlikely to have any effects that last beyond the duration of the study visit. About every 30 minutes after taking the pill, the participant will fill out some questionnaires about mood and how he or she is feeling at the moment.

Visit 4: Behavioral Tests and MR scan: This visit will be very similar to Visit 2. Participants will participate in the same type of task inside the MR scanner, while the study staff measures reaction time and psychophysiological responding and brain activation. Participants will view the same images he or she did previously, and may experience the same aversive stimulus as during Visit 2. Participants will again be asked to rate how much they expect to experience the aversive stimulus after each image and will also be asked to report their level of anxiety on a scale from 0 to 100.

Visit 5: Behavioral Tests and MR scan: This visit will occur approximately 1 week after Visit 4 and will have the same procedure. Participants will participate in the same type of task inside the MR scanner, while the study staff measures reaction time and psychophysiological responding and brain activation. Participants will again be asked to rate how much they expect to experience the aversive stimulus after each image and will also be asked to report their level of anxiety on a scale from 0 to 100.

Arms: arm 1: In a randomized, double-blind, placebo-controlled, between-subjects design, we will administer a one-time oral dose of dronabinol (5mg or 10mg) or placebo (PBO) approximately two hours prior to MR scanning and task performance in 78 patients with PTSD.

One-third of the participants will receive 5mg dronabinol (n=26) , one-third of the participants will receive 10mg dronabinol (n=26), and the remaining one-third of the participants will receive placebo (n=26). arm 2: In a randomized, double-blind, placebo-controlled, between-subjects design, we will administer a one-time oral dose of dronabinol (5mg or 10mg) or placebo (PBO) approximately two hours prior to MR scanning and task performance in 78 patients with PTSD.

One-third of the participants will receive 5mg dronabinol (n=26) , one-third of the participants will receive 10mg dronabinol (n=26), and the remaining one-third of the participants will receive placebo (n=26). arm 3: In a randomized, double-blind, placebo-controlled, between-subjects design, we will administer a one-time oral dose of dronabinol (5mg or 10mg) or placebo (PBO) approximately two hours prior to MR scanning and task performance in 78 patients with PTSD.

One-third of the participants will receive 5mg dronabinol (n=26) , one-third of the participants will receive 10mg dronabinol (n=26), and the remaining one-third of the participants will receive placebo (n=26).
Interventions: intervention 1: Placebo Oral Capsule intervention 2: Dronabinol Cap 5 milligrams (MG) intervention 3: Dronabinol Cap 10 milligrams (MG)
Intervention descriptions: intervention 1: Placebo is administered only once (approximately 120 min prior to MR scanning in Visit 3) by the oral route and contains only dextrose in opaque capsules. intervention 2: Dronabinol (5mg) is administered only once (approximately 120 min prior to MR scanning in Visit 3) by the oral route and is placed in an opaque capsule with dextrose filler. intervention 3: Dronabinol (10mg) is administered only once (approximately 120 min prior to MR scanning in Visit 3) by the oral route and is placed in an opaque capsule with dextrose filler.

Protocol documents:
Prot_SAP_000.pdf: 
Protocol Title: Effects of THC on Retention of Memory for Fear Extinction Learning In PTSD: R61 Study 
 
Principal Investigator: Christine Rabinak, PhD 
 
IRB # 015017MP4F 
 
Version #11 
Version Date: 2/17/21 
1
RESEARCH PLAN 
A. SIGNIFICANCE 
A.1. Problem to be addressed. An estimated 7% to 12% of people exposed to a traumatic event will develop 
Posttraumatic Stress Disorder (PTSD)1,2, a stress-induced illness characterized by excessive, inappropriate fear 
responses (e.g., hypervigilance, flashbacks)3. The burden of PTSD on this population and on society is great, 
given those with the disorder are at increased risk for suicidality4, experience loss of productivity5, require more 
health care resources6, are more likely to develop medical illness7, and have dysfunction in occupational8, 
interpersonal8-11, and parental/family domains12,13. PTSD symptoms include impairment in fear extinction, as 
memories of an aversive experience are strongly held in PTSD well after the trauma has occurred. Additionally, 
PTSD is due in part to decreased activation in the ventromedial prefrontal cortex (vmPFC) and hippocampus 
(HPC), brain regions involved in fear extinction and recall of extinction learning (i.e., extinction retention)14-28. 
Consequently, a pharmacological agent that restores vmPFC-HPC function has the potential to reduce PTSD 
symptoms in the meditext of treatment that encompasses fear extinction. 
Prolonged Exposure (PE) therapy, a first-line psychotherapy for PTSD29, utilizes extinction learning principles. 
It aims to generate new, safe memories by repeatedly exposing the patient to feared objects, memories, images, 
and situations to integrate disconfirming/corrective information that will diminish trauma-related fears30. This 
cognitive processing may be a critical part of extinction retention over time in PE. Thus, effective exposures are 
crucial for treatment success. The beneficial effects of exposure therapy have been shown to derive from 
neurophysiological processes typical of fear extinction. Specifically, significant post-therapy increases in PFC 
activity in conjunction with decreases in amygdala (AMYG) activity31. Even though PE produces clinically 
meaningful improvements for many PTSD patients there is still substantial room for improvement. Many patients 
prematurely discontinue PE (e.g., 13-39%;32-35). In those that do show improvements in PTSD symptoms 60-
72% of patients continue to meet criteria for PTSD after completing PE36-40, which includes repeated exposures 
to trauma memories (imaginal exposure) and avoided situations (in vivo exposure) and practice exposures (e.g., 
listen to tapes of imaginal exposure, carry out in vivo exposure) outside of PE sessions as “homework”. PTSD 
remains a difficult-to-treat disorder, thus, a medication that enhances the neural and neurochemical substrates 
of extinction and recall of extinction learning could solve this challenge and improve PTSD treatment outcomes41-
43. 
Exciting new evidence from studies in rodent models of fear suggests that activation of the cannabinoid (CB) 
system specifically within the AMYG, vmPFC, and HPC may regulate fear extinction and recall of extinction 
learning. For instance, drugs that block CB type 1 (CB1) receptors or genetic deletion of CB1 receptors within 
these structures prevent recall of extinction learning, whereas activation of these same receptors, via agonists, 
such as Δ9-tetrahydrocannabinol (THC), can promote recall of extinction learning44-54. In addition, drugs that 
increase endogenous CB (eCB) levels during fear extinction not only enhance recall of extinction learning, but 
also impair the return of extinguished fear in rats (i.e., prevent spontaneous recovery of fear)44. Recently, PI 
Rabinak showed that administration of dronabinol (synthetic THC) prior to fear extinction facilitated the 
subsequent recall of extinction learning in healthy humans using a similar behavioral design as proposed in the 
current R61 project55. Together, rodent and human data indicate that THC modulates neural correlates of fear 
extinction and its recall, therefore, a critical next step is to examine the efficacy of THC to facilitate recall of 
extinction learning through activation of the fear extinction circuitry in individuals with PTSD. In the proposed 
project we will test fear extinction circuitry as a pharmacological target for THC’s actions in PTSD.  
A.2. What neural circuits mediate fear extinction? Convergent evidence from rat and human work has 
revealed that discrete, yet anatomically and functionally interconnected brain structures are critical for fear 
extinction and recall of extinction learning (i.e., AMYG, vmPFC, HPC)14-28,56-59. During fear acquisition, sensory 
information about the conditioned stimulus (CS) and the aversive unconditioned stimulus (US) converge in the 
AMYG and become associated (i.e., yielding the fear memory) and produce conditioned responses of fear 
(CRs)18,56. In functional magnetic resonance imaging (fMRI) studies AMYG activation has been correlated with 
physiological fear responses (e.g., skin conductance response [SCR]) during conditioning in human participants 
[LaBar et al60: r = 0.88, p < 0.03 ; Phelps et al20: r = 0.64, p < 0.05; Phelps et al61: r = 0.59, p < 0.05]. Notably, 
the AMYG also seems to be involved in extinction learning19,57,58. Prefrontal brain regions that interconnect with 
the AMYG, particularly the vmPFC, are important for the recall of extinction learning and consequent attenuation 
of fear CRs perhaps by inhibiting AMYG output neurons20-25,59. In humans, vmPFC activation during recall of 


Protocol Title: Effects of THC on Retention of Memory for Fear Extinction Learning In PTSD: R61 Study 
 
Principal Investigator: Christine Rabinak, PhD 
 
IRB # 015017MP4F 
 
Version #11 
Version Date: 2/17/21 
2
extinction learning and vmPFC thickness both correlate with magnitude of extinction recall [activation: Milad et 
al26: r = 0.66, p < 0.01; thickness: Milad et al62: r = 0.52, p < 0.03; Hartley et al: r = 0.83, p < 0.003] . In addition, 
the magnitude of task-dependent functional coupling between the AMYG and vmPFC has been shown to be 
negatively correlated with self-reported intensity of negative affect during regulation of negative affect63,64. 
Similarly, HPC activation is associated with successful recall of extinction learning26,65 and is positively correlated 
with vmPFC activation during extinction recall in humans [Milad et al26: r = 0.94, p < 0.0001]. Interestingly, 
increased AMYG-HPC functional connectivity has been attributed to the persistence of memories for emotionally 
arousing events in humans66-70. These lines of convergent evidence suggest activation in these brain regions 
and how they interact with one another are quantifiable brain-based indices of fear extinction and recall of 
extinction learning in humans. 
A.3. What brain regions are involved in the pathophysiology of PTSD? Dysfunction in fear circuitry has been 
a consistent finding in PTSD neuroimaging studies and plays a role in maintaining trauma memories. Using a 
Pavlovian fear conditioning paradigm, Milad  and colleagues showed a PTSD group exhibited reduced vmPFC 
and HPC activity, along with greater psychophysiological reactivity (SCR, a commonly used index of arousal) 
when attempting to recall extinction learning (i.e., 24 hr post-extinction learning). Thus, signifying impaired 
retrieval in extinction learning to the previously extinguished conditioned stimulus (CS+E) compared to trauma-
exposed controls without PTSD (TEC)71. Similarly, PTSD patients show impaired extinction recall with increased 
SCRs and AMYG activity to the CS+ (i.e. CS that was paired with US)72. Of note, the relevance of testing recall 
of extinction learning pertains to the phenomenon of spontaneous recovery in which previously extinguished 
fears diminish over time73. Other neuroimaging studies of emotion processing have shown the AMYG, also 
crucial to generating fear reactions74, is hyperactive in PTSD in response to trauma-related imagery75,76, combat-
related sounds or smells77-79, trauma-related photographs or words80-83, and fearful facial expressions84-87. With 
regard to regulation of emotions, our group has shown prefrontal dysfunction in PTSD in dorsolateral prefrontal 
cortex (dlPFC) and medial prefrontal cortex (mPFC)88, regions crucially involved in regulating emotion particularly 
during willful emotional regulation of negative affect evoked by aversive stimuli25. Beyond emotion processing 
and regulation, exaggerated AMYG reactivity observed in PTSD has been posited to be at least partly due to 
insufficient top-down regulation from the vmPFC, consequently leading to hyperarousal and deficits in extinction 
recall as well as inability to suppress attention and responses to trauma-related stimuli89-92. For example, 
exaggerated AMYG reactivity is negatively correlated with responses in the dorsal and vmPFC among individuals 
with PTSD76,85. Although less commonly implicated, abnormal HPC function and diminished HPC volumes in 
PTSD patients have been associated with deficits in contextual processing, as well as memory impairments and 
neuroendocrine dysregulation76,93-98. Evidence of aberrant activation in fear circuitry in humans with PTSD 
indicates a mechanism that directly impacts PE success, since treatment relies on activation of fears89,99-105. 
A.4. Can THC enhance recall of extinction learning? As mentioned previously rodent 
models of fear suggests activation of the CB system within the AMYG, vmPFC, and HPC 
may regulate fear extinction and recall of extinction learning and impair the return of 
extinguished fear4948-58. In line with these findings PI Rabinak et al.55 demonstrated (using 
procedures similar to this proposed R61 project) that an acute oral dose of THC administered 
prior to fear extinction facilitates recall of extinction learning in healthy humans. Participants 
who received placebo (PBO) during fear extinction exhibited, as expected, spontaneous 
recovery of fear to the CS+E, whereas THC (7.5mg) attenuated spontaneous recovery of 
fear during a recall test of extinction learning (Fig 1). THC did not affect within-session fear 
extinction, but only influenced the ability to successfully recall extinction learning when 
compared to PBO, suggesting THC affects the ability to maintain and/or 
successfully retrieve extinction memories. These findings are consistent with 
pre-clinical studies in rats in which CB activation and/or enhancement can facilitate recall of extinction 
learning45,47,49,50,52,53,106 and provide the first evidence that pharmacological enhancement of recall of extinction 
learning is feasible in humans using CB system modulators.  
A.5. What neural correlates of fear extinction and recall of extinction learning are a target of CBs? In the 
brain, eCBs from the postsynaptic cell diffuse in a retrograde fashion to activate presynaptic CB1 receptors, 
densely localized within AMYG, vmPFC, and HPC107-110, which then inhibit presynaptic release of 
neurotransmitters47,111. It has been hypothesized that during fear extinction, eCB activation of CB1 receptors in 
Fig. 1: THC reduces fear recovery 
during extinction recall; Rabinak et al.55 
Mean Difference SCR (CS+E – CS+U [µS1/2]) 


Protocol Title: Effects of THC on Retention of Memory for Fear Extinction Learning In PTSD: R61 Study 
 
Principal Investigator: Christine Rabinak, PhD 
 
IRB # 015017MP4F 
 
Version #11 
Version Date: 2/17/21 
3
the AMYG decreases activity in local gamma-aminobutyric acid (GABA) 
networks, which leads to disinhibition of principal neurons and to 
extinction of fear CRs47,51. Interestingly, intra-basolateral AMYG infusion 
of CB1 agonists enhances recall of extinction learning (via effects on 
memory consolidation)112.  On the other hand, activation of CB1 
receptors within the vmPFC during fear extinction induces neuronal 
plasticity within the vmPFC, and subsequently increases inhibition of 
brain areas involved in the expression of conditioned fear responses 
(e.g. AMYG)49. In addition, HPC CB1 receptor activation enhances 
glutamatergic neurotransmission, which may support long-term storage 
of fear extinction (via memory consolidation)46.  
Studies in PI Rabinak’s lab using fMRI found that oral THC (vs. PBO) 
modulates mPFC-AMYG activation and connectivity during emotional 
processing110. Although not directly related to fear extinction, these data 
show that THC effects on brain response to threat can be localized to 
fear-related AMYG-mPFC circuitry. PI Rabinak also investigated CB 
effects on the underlying neural circuitry involved in healthy 
volunteers’ recall of extinction learning; the fMRI results suggest THC 
administration during fear extinction subsequently increases vmPFC and HPC activation to the CS+E vs. non-
extinguished conditioned stimulus (CS+U) during a recall test of extinction learning relative to PBO113 (Fig. 2). 
Collectively, these exciting findings suggest that activating CB1 receptors within select neural circuitry can 
enhance efficacy of fear extinction and recall of extinction learning. These findings lead to our proposed 
translational investigation in patients with PTSD, who exhibit impaired recall of extinction learning and associated 
aberrant vmPFC-HPC function. 
A.6. Can cannabinoids facilitate fear extinction in PTSD? As noted, extinction 
retention deficits and vmPFC-HPC dysfunction have been observed in patients 
with PTSD, and enhancing CB transmission helps extinction recall. Thus, the CB 
system, which modulates brain activity in regions involved in recall of extinction 
learning, is a promising mechanism for improving learning that occurs in therapy 
and may increase the efficacy and durability of PE in treating PTSD (e.g., 
shortening treatment while strengthening and prolonging gains). Preliminary data 
from PI Rabinak’s K01 suggests an acute dose of THC (7.5mg) given prior to fear 
extinction in PTSD participants facilitates recall of extinction learning to a CS+E 
(Fig. 3). Therefore, the primary goal of the proposed project is to test the 
hypotheses that (1) administration of an exogenous CB1 agonist will ‘rescue’ 
deficits in recall of extinction learning in PTSD patients and (2) these effects will 
be mediated by increased activation of vmPFC and/or HPC. 
B. INNOVATION 
This project is innovative in several ways. First, it is translational as the aims, predictions, and study design 
are propelled by compelling preclinical and clinical neuroscience findings showing that the CB system regulates 
recall of extinction learning. Second, it is interdisciplinary – strategically combining multiple lines of 
investigation—psychopharmacology, neuroimaging, psychophysiology, and a psychosocial intervention trial 
(often carried out separately). Third, it tests multiple layers of ‘target engagement’ including behavioral and neural 
correlates (recall of extinction learning). Studies using other “cognitive enhancers”, such as D-cycloserine, have 
reported mixed results regarding their efficacy in facilitating exposure therapy114,115. However, recent evidence 
suggests that dose and dose timing differences are largely responsible for these mixed findings115,116. 
Additionally, there are a number of different pharmacological pathways to access the circuits that underlie fear 
extinction and specific classes of compounds, like THC, may be superior to others in their ability to facilitate fear 
extinction117. Dose and dose timing will be evaluated in the R61 phase  
C. APPROACH 
Fig. 2: THC increases vmPFC and HPC activation during 
recall of extinction learning recall; Rabinak et al.113 
Fig. 3: THC facilitates recall of 
extinction learning in PTSD 
HPC 
HPC 


Protocol Title: Effects of THC on Retention of Memory for Fear Extinction Learning In PTSD: R61 Study 
 
Principal Investigator: Christine Rabinak, PhD 
 
IRB # 015017MP4F 
 
Version #11 
Version Date: 2/17/21 
4
C.1. Preliminary Studies. The data here establish the capacity of the research team 
to carry out: 1) fMRI studies of fear extinction and THC challenge in humans; and 2) 
extinction studies in PTSD. 
Impaired Extinction Recall and Dysfunctional Activation of vmPFC and HPC during 
Extinction Recall in PTSD 
Milad and colleagues have developed a fear conditioning-extinction paradigm in 
which PTSD patients (vs. trauma-exposed non-PTSD controls) show less activation 
in vmPFC and HPC and increased arousal (i.e., increased SCRs) during extinction 
recall to the CS+E vs. CS+U71. Similarly, PI Rabinak has pilot data showing fear 
recovery (increased SCR to the CS+E=CS+U) in PTSD patients (n=14) compared to 
healthy controls (HCs; n=15) during an extinction recall test 24 hr after extinction 
learning (Fig. 4).  
THC Facilitates Recall of Extinction Learning via Increased Recruitment of the vmPFC-HPC 
We have validated that our Pavlovian fear conditioning paradigm 
is 
effective 
in 
the 
context 
of 
acute 
pharmacological 
manipulation55,113 (Figs. 1, 2, 5, & 6). PI Rabinak demonstrated that 
THC facilitated retention of extinguished fear responses and 
prevented spontaneous recovery of fear in healthy humans55 (Fig. 
1). In a separate fMRI study using a similar design as the one 
proposed, PI Rabinak showed that THC (vs. PBO) during fear 
extinction subsequently increases vmPFC-HPC activation to the 
CS+E (vs. the CS+U) during recall of extinction memory113 (Fig. 2). 
Additionally, preliminary data suggest 
THC 
administration 
during 
fear 
extinction 
subsequently 
increases 
vmPFC-HPC 
functional 
coupling 
(psycho-physiological interaction; PPI) 
to the CS+E (vs. CS+U) during recall of 
extinction memory (vs. PBO; Fig. 5).  
We have also demonstrated THC 
facilitates extinction processes in health 
participants (THC n=18, PBO n=22) as 
signified by less SCR (Fig. 6A) and 
greater bilateral HPC activation during 
fear extinction (“EXT”) and recall of extinction learning 24 hr (“REC1”) and one-week (“REC2”) post-extinction 
learning (Fig. 6B and C). 
 
C.2. Overall Study Design: The R61 study will employ a randomized, double-blind, PBO-controlled, between-
subjects design, coupling a standard Pavlovian fear conditioning paradigm during fMRI with an acute 
pharmacological challenge using oral dronabinol (THC) or PBO prior to fear extinction in PTSD patients and test 
recall of extinction learning 24 hr (proximal memory) and 1 week later (distal memory) when spontaneous 
recovery is expected to be robust. 78 PTSD participants will be randomized to 1 of 3 conditions: single doses of 
5mg or 10mg of THC, or PBO, using covariate adaptive randomization118-122, in which a new participant is 
sequentially allocated to a treatment condition by taking into account baseline characteristics (e.g., CAPS-5, age, 
sex, race) and previous assignments of participants123, with 26 PTSD participants per condition. However, 
because randomization does not guarantee comparability across groups, the groups will be compared to ensure 
reasonable similarity in the distributions of their baseline characteristics. The imbalance in covariate levels will 
be measured by a 2 goodness-of-fit test (for categorical covariates) or t-test (for quantitative covariates. 
Variables with significant group differences (p<0.05) will be included as covariates in primary analyses. 
Additionally, 26 healthy trauma-exposed controls (TEC; demographically matched) will be included and tested 
at comparable time points to separate the impact of trauma from the impact of PTSD. The TEC group will not 
receive THC, any drug-related monitoring, or undergo blood draws but will otherwise complete all phases of the 
Fig. 4: SCR in healthy controls 
and PTSD during recall of 
extinction learning  
Fig. 5: THC increases vmPFC-HPC functional 
connectivity at extinction recall 
Fig. 6: Effects of THC and PBO on SCR and HPC response during fear acquisition, fear extinction, 
and recall post 24 hr and 1 week after extinction learning.  
vmPFC ‘seed’ PPI: THC > PBO 
CS+E > CS+U 
X = -30
X = 30 
HPC 


Protocol Title: Effects of THC on Retention of Memory for Fear Extinction Learning In PTSD: R61 Study 
 
Principal Investigator: Christine Rabinak, PhD 
 
IRB # 015017MP4F 
 
Version #11 
Version Date: 2/17/21 
5
experiment. With the conservative anticipation that about 25% will fail to complete all parts of the study, we 
estimate about 20 PTSD subjects in each condition (60 PTSD participants in total) and 20 TEC participants in 
total. Participants will be recruited from the Detroit community and mental health clinics (see ‘Protection of 
Human Participants’). 
Key inclusion criteria: All participants must be age 18-60, able to consent to the study, generally medically 
and neurologically healthy, and endorse exposure to a Criterion A stressor (defined by clinician-administered 
PTSD scale for DSM-5; CAPS-5). In addition, PTSD candidates must have significant PTSD severity as indicated 
by a clinician-administered PTSD scale for DSM-5 (CAPS-5) diagnosis and/or score of ≥ 25 regardless of trauma 
type as effect size of PE has been shown to be similar across trauma types (i.e., combat/terror, childhood sexual 
abuse, rape, mixed124). TECs must be free of any history of PTSD symptoms (CAPS-5 score < 25 and no 
diagnosis). Key exclusion criteria: Participants in either group with the following are excluded from the study: 
a) clinically significant medical or neurologic condition; b) MRI contraindications (metal objects in body or 
claustrophobia); c) positive urine pregnancy test or self-reported current pregnancy identified during screening 
procedures; d) pervasive development disorder history; e) traumatic brain injury (TBI) with current cognitive 
impairment related to TBI; f) exclusively left-handedness; g) current severe alcohol or substance use; h) risk of 
harm to self or others that requires immediate intervention; i) lack of fluency in English; j) current or past diagnosis 
of bipolar, schizophrenia, or psychotic disorder; or k) presence of contraindications, current or past allergic or 
adverse reaction, or known sensitivity to cannabinoid-like substances. In addition, PTSD participants with the 
following will be excluded: a) comorbid mood or anxiety disorder that is primary to PTSD (i.e. when treatment is 
indicated for symptoms beyond PTSD such as major depressive disorder, which does not involved exposure to 
fears125); b) concomitant treatment with medication that has level 1 evidence indicating severe drug-drug 
interactions with dronabinol that is taken daily. (see c‘Protection of Human Participants’). TEC’s with current 
diagnoses of any obsessive-compulsive, trauma/stressor-related, depressive, or anxiety disorder will be 
excluded. 
C.2.1. Pavlovian Fear Conditioning Paradigm: This fMRI protocol uses an event-related design developed and 
validated in Dr. Rabinak’s lab113 (Fig. 5A). During fear conditioning (Context A, ‘garden’), two conditioned stimuli 
(CS+s: e.g. blue and red messenger bags) will be paired with the unconditioned stimulus (US: animated snake 
striking at participant when bag is opened; Fig. 5B) at a partial reinforcement rate of 60%. One CS+ will be 
extinguished during the subsequent extinction phase (CS+E; blue) whereas the other will not (CS+U; red). A 
third CS (e.g. yellow messenger bag) will be presented during conditioning but never paired with the US (CS-; 
empty bag when opened). The US will co-terminate with the CS presentation. Approximately, twenty-four hours 
after fear acquisition, but no more than 1 week later, participants will undergo extinction learning. Based on the 
known time course of THC’s peak subjective effects and peak plasma levels of THC55,110,126-128, we will begin 
extinction learning  ≈120 min after ingestion of either THC or PBO capsule. During extinction learning (Context 
B, ‘art gallery’), participants will receive of the CS+E (no snake when bag is opened) and CS-. To assess 
extinction retention, we will conduct a proximal extinction recall test approximately 24 hr after extinction learning, 
but no more than 1 week later, (Extinction Recall Visit 4 and distal extinction recall test approximately 1 week 
after the 
first 
B 
A 
Fig. 5: A) Schematic of experimental paradigm; B) Snake US 


Protocol Title: Effects of THC on Retention of Memory for Fear Extinction Learning In PTSD: R61 Study 
 
Principal Investigator: Christine Rabinak, PhD 
 
IRB # 015017MP4F 
 
Version #11 
Version Date: 2/17/21 
6
extinction recall test, but no more than 3 weeks later (Extinction Recall Visit 5), in which participants will be 
presented with the CS+E, CS+U, and CS- (no snake) in Context B. Contrasting CS+E and CS+U during 
extinction recall in Context B will allow us to assess physiological and brain responses specific to recall of 
extinction learning and independent from recall of fear acquisition. To test for contextual renewal of fear (context 
shift from the extinction context [B] to the conditioning context [A]), we will conduct a proximal fear renewal test 
approximately 24 hr after extinction learning, but no more than 1 week later (Fear Renewal Visit 4) and a distal 
fear renewal test approximately 1 week later, but no more than 3 weeks later (Fear Renewal Visit 5), in which 
participants will be presented with the CS+E, CS+U, and CS- (no snake) in Context A. Stimulus parameters will 
be similar to those conducted in our previous studies113. During all sessions, our primary measures of conditioned 
fear will be SCR magnitude and US expectancy ratings for each CS trial. Extinction Learning (Visit 3) and 
Extinction Recall/Fear Renewal Visits 4 & 5 will be conducted in the MRI scanner with simultaneous recording 
of SCR and US expectancy ratings, except in the event a participant is unable to be scanned, in which case 
these visits will be conducted outside the scanner in the PI’s research laboratory. Fear acquisition (Visit 2) will 
be conducted outside of the scanner in the PI’s research laboratory. During all sessions, our primary measures 
of conditioned fear will be SCR magnitude and US expectancy ratings for each CS trial129. 
 
Genotyping: DNA extraction and genotyping of the rs324420 variant will be completed in Dr. Burghardt’s 
laboratory (see letter). If the participants signs the DNA consent form, DNA will be extracted from buccal swabs 
using Quiagen buccal DNA kits. 
    C.2.2. Psychological Measures: Along with standardized assessments of symptom severity and mood/ 
emotional state (see ‘Protection of Human Participants’), participants will complete measures at multiple time 
points (e.g., before and after fear extinction), of perceived success (e.g., reduction Subjective Units of Distress 
Scale; “SUDS”130) in addition to measures that evaluate temporal changes in mood/anxiety level, such as, the 
state subscale of the Spielberger Trait/State Anxiety Inventory131. Subjective drug effects will be conducted 
throughout the extinction session (Visit 3), when THC/PBO is ingested (see ‘Protection of Human 
Participants’).  
C.2.3. THC Concentration: Plasma concentrations of THC, 11-OH-THC (THC’s active metabolite), and THC-
COOH (THC’s inactive metabolite) will be quantified in PTSD participants at 9 time points: 1) before receiving 
THC or PBO on Visit 3; 2) at approximately 30 min intervals after receiving THC or PBO on Visit 3 (i.e., at 30, 
60, & 90 min), immediately before going in the MRI scanner, soon after coming out of the MRI scanner; and once 
before the end of the visit; 3) before recall of extinction learning on Visit 4; and 4) before recall of extinction 
learning approximately a week later (but no more than 3 weeks later; Visit 5). Blood will be obtained via 
venipuncture using a 22 or 23g straight needle or a 20-22g shielded IV catheter (MRI compatible) which is 
appropriate for a longer indwelling time. At each blood draw time point approximately 3mL of blood will be drawn 
from a vein in the participant’s arm or hand by a certified phlebotomist on the research team. Blood concentration 
levels will be determined using ultra performance liquid chromatography tandem mass spectrometry 
(UPLC/MS/MS)132. Based on previous studies we expect peak plasma THC concentration will occur ≈120 min 
post-administration55,110,126-128; therefore, we will use these samples to confirm timing of peak concentration levels 
and if necessary adjust the timing between ingestion of THC/PBO and fear extinction to coincide with peak levels. 
In the event that we are unable to obtain adequate blood samples from a participant this will be noted in the 
participant file and all other study procedures will proceed. 
C.2.4. fMRI: MR scanning at WSU will be performed on a 3.0 Tesla Siemens Magnetom Verio System using 
an industry-leading 32-channel head-coil for superior image quality. We will use a multi-band EPI sequence 
[similar to: TR = 2000ms; TE = 30ms; Flip = 73°; 128x128 matrix; FOV = 256 mm; 66 slices; 2.0 x 2.0 x 2.0 mm 
voxels], which we are currently using in PI Rabinak’s K01 project. A high-resolution structural image will provide 
precise anatomical localization. Whole-brain fMRI blood oxygen-level dependent (BOLD)-related signal 
measures will be acquired to measure task- and drug-related effects and to minimize susceptibility artifact (signal 
loss) at the medial temporal lobe (including the AMYG and the vmPFC)133-135. 
C.2.5. General Statistical Approach: All analyses will use a conventional alpha level of 0.05 and all tests will 
be two-tailed. To evaluate the main effects, Analysis of Variance will be used for neuroimaging (i.e., BOLD 
percent signal change (PSC)) and peripheral measures of fear (e.g., SCR, US expectancy, SUDS, 
psychological/mood measures). We will also include covariates such as gender and childhood trauma/adversity 


Protocol Title: Effects of THC on Retention of Memory for Fear Extinction Learning In PTSD: R61 Study 
 
Principal Investigator: Christine Rabinak, PhD 
 
IRB # 015017MP4F 
 
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Version Date: 2/17/21 
7
if found unbalanced and correlated (r>0.03) with the outcome variable (e.g., MANCOVA, ANCOVA). If significant, 
multivariate analysis will be followed by univariate analysis, which if significant, will be followed-up with simple 
effects analysis (e.g., independent t-tests, paired t-tests). In addition to omnibus tests, planned comparisons will 
be used to test specific hypotheses such as THC dose (vs. PBO) on fear extinction in PTSD, as well as 
comparisons between THC doses; if there is no significant difference between THC doses we will examine 
potential positive trends with increasing dose. To evaluate relationships, Pearson correlations will be used along 
with scatterplots to examine the nature of the relationships. Hochberg step-down multiplicity adjustment will be 
used to control for all multiple comparisons136. Confidence intervals and effect sizes will be also be calculated. 
C.2.6. fMRI Analysis: Functional data will be processed and analyzed using conventional methods (GLM, 
event-related design, random effects) with Statistical Parametric Mapping (SPM8; Wellcome Department of 
Cognitive Neurology, London; www.fil.ion.ucl.ac.uk/spm)137-140, as described in our pharmacological fMRI 
studies110,113 and fear conditioning studies113,141,142. Analysis will implement 2 complementary approaches127: 1) 
a hypothesis-driven anatomically-focused region of interest (ROI)-based analysis; and 2) exploratory whole-brain 
voxel-wise analysis. Based on our hypotheses, our two main ROIs are vmPFC and HPC; the AMYG, or at least 
different sub-regions within AMYG, are involved in fear acquisition20,60,61 and extinction19, and thus we identify 
the AMYG as another a priori ROI. These ROIs will be based on anatomical landmarks from human atlases143-
145. In addition, vmPFC, HPC, and AMYG activation reported by Milad et al.71 will be used to create a 5-mm 
radius spherical ROI around peak coordinates to examine data in this study for replication. Extracted BOLD 
percent signal change (PSC) from each ROI, confined to anatomically-based masks, will be subjected to a 
repeated measures group (PTSD-5mg, PTSD-10mg, PTSD-PBO, TEC) x stimulus (CS+E, CS+U) MANCOVA 
controlling for potential confounds (e.g., childhood trauma/adversity) during Extinction Recall. Statistical tests to 
directly test group and drug effects are described below (‘Summary of Planned Analyses to Test Specific 
Hypotheses’). For the second approach (whole-brain, voxel-wise), we will employ ANCOVA across the entire 
brain in an exploratory search to generate hypotheses for subsequent study. Statistical maps for the whole brain 
analysis will be created using a threshold of p < 0.001 with a cluster threshold of at least 10 voxels. Within the 
ROIs, a small volume threshold (p < 0.05, corrected for multiple comparisons) will be used. 
Context-dependent renewal of fear could also affect the efficacy of PE therapy. Therefore, we will also test 
whether THC induces generalization of extinction across extinction recall (ABB) and renewal (ABA) contexts. 
We will conduct the same statistical tests on extracted PSC from each ROI, confined to anatomically-based 
masks, during the Fear Renewal test, as described above for the Extinction Recall test.  
We will also examine correlations between BOLD responses in the AMYG, vmPFC, and HPC and the extinction 
retention index (see below) during Extinction Recall and Fear Renewal tests. In addition, we will implement a 
generalized psychophysiological interaction analyses (PPI)64,146,147 to measure task-dependent functional 
connectivity among the AMYG, vmPFC, and HPC.  Separate connectivity analyses will be performed with each 
group condition (PTSD-5mg, PTSD-10mg, PTSD-PBO, and TEC), using AMYG, vmPFC, and HPC as the seed 
regions followed by between-group connectivity analyses to assess the effect of THC on functional coupling of 
the vmPFC, AMYG and HPC during Extinction Recall and Fear Renewal. 
C.2.7. Skin Conductance Response (SCR): Assessment of fear learning will be change in SCR magnitude. 
The SCR signal will be amplified and recorded with a BIOPAC Systems SCR module connected to a PC. All 
data will be continuously sampled at 1000 Hz. AcqKnowledge software (BIOPAC Systems) will be used for off-
line analysis. Analysis: SCR for each CS trial will be calculated as described by Consultant Milad142. Extinction 
recall will be assessed by comparing the mean differential response during the first 4 trials of the CS+E vs. the 
first 4 trials of the CS+U as described below (‘Summary of Planned Analyses to Test Specific Hypotheses’). In 
addition, we will use the “extinction retention index” (ETI) as described by Consultant Milad142 to measure the 
magnitude of extinction retention. The ETI adjusts the SCR during extinction recall for differences in CR 
magnitude during fear acquisition100. Analyses for psychophysiological and behavioral data will be conducted by 
ANOVA models as above. We will also conduct Pearson correlations between psychophysiological and 
behavioral data to examine relationships. 
C.2.8. Behavioral: We will obtain subjective US expectancy ratings (US expectancy) and level of distress 
(SUDS), a proxy of fear extinction, to the CS+E vs. the CS+U129.  
C.2.9. Summary of Planned Analyses to Test Specific Hypotheses: 


Protocol Title: Effects of THC on Retention of Memory for Fear Extinction Learning In PTSD: R61 Study 
 
Principal Investigator: Christine Rabinak, PhD 
 
IRB # 015017MP4F 
 
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Specific Aim 1 (R61 Primary Target Engagement): Assess effects of THC on recall of extinction learning 
and vmPFC and/or HPC activation in PTSD patients in a dose-finding study. Hypothesis 1A: Relative to 
PBO, THC will dose-dependently increase vmPFC and/or HPC activation to a CS+E (vs. CS+U) during proximal 
(24 hr post-extinction learning) and/or distal (1 week post-extinction learning) recall of extinction learning in 
PTSD. PCS (CS+E vs. CS+U) with ROIs (vmPFC, HPC) will be submitted to MANCOVA with Group (PTSD-
5mg, PTSD-10mg, PTSD-PBO, TEC) as between-subjects factor and Recall (24 hr, 1 week) as within-subject 
factor, controlling for potential confounds. In addition to omnibus tests, planned comparisons will examine dose 
of THC on prefrontal-limbic engagement during recall of extinction learning in PTSD relative to PBO, and 
comparisons between THC doses; if there is no significant difference between THC doses we will examine 
potential positive trends with increasing dose. Similar analyses will be conducted using other variables of interest 
such as psychological measures, mood state, and drug effects. Hypothesis 1B: Relative to PBO, THC will dose-
dependently decrease peripheral measures of extinction recall (“extinction recall index” (ETI), US expectancy, 
SUDS) to the CS+E during a proximal and/or a distal test of extinction learning recall in PTSD. These data will 
be submitted to MANCOVA with Group (PTSD-5mg, PTSD-10mg, PTSD-PBO, TEC) as between-subjects factor 
and Recall (24 hr, 1 week) as within-subject factor, controlling for potential confounds. Analyses will be 
comparable to that used to examine BOLD activation (Hypothesis 1A). Hypothesis 1C: vmPFC and/or HPC 
activation will correspond with extinction recall success (i.e. higher ETI, lower US expectancy, lower SUDS). 
Pearson correlation analyses will be used to correlate measures of BOLD activation (PSC) and peripheral 
measures (e.g., SCR, ETI, US expectancy) to the CS+E vs. CS+U within and across the two contexts/recall and 
renewal tests. 
R61 Power Analysis: We have conducted several power calculations in our previously published work used to 
determine the sample sizes proposed here. First, we have consistently found that an n of 14-16 healthy controls 
and an n of 14-16 PTSD patients provide adequate power to observe: 1) SCR differences and AMYG, vmPFC, 
HPC signal differences between groups during fear extinction and/or extinction recall; and 2) THC’s effects on 
ETI and AMYG, vmPFC, and HPC activation in healthy controls. Similarly, normalization of corticolimbic 
responsivity to affective stimuli has been observed following exposure-based therapy in an n of 14 anxious 
patients148 and following administration of a serotonin selective reuptake inhibitor (SSRI) with an n of 21 anxious 
patients149. Given that the effect sizes tested within- and between-groups in previous fMRI studies have ranged 
between moderate to large (Cohen d = 0.7 - 1.5) with the anticipated cohort of 20 participants per group (PTSD-
5mg, PTSD-10mg, PTSD-PBO, TEC), who complete the entire protocol with usable fMRI and SCR data, will 
confer >80% power to detect an effect size 0.72 or higher after necessary multiplicity adjustment. 
  


Protocol Title: Effects of THC on Retention of Memory for Fear Extinction Learning In PTSD: R61 Study 
 
Principal Investigator: Christine Rabinak, PhD 
 
IRB # 015017MP4F 
 
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PROTECTION OF HUMAN PARTICIPANTS 
 
This Human Participants Research meets the definition of a clinical trial. 
 
1. Risks to Human Participants 
 
a. Human Participants Involvement, Characteristics, and Design 
 
Involvement of Human Participants:   
 
The total time commitment estimated per participant is 8.5-13 hr across all study visits.  This is broken down 
below: 
Visit 1: Screening & Study Entry: Approximately 3 hours for participants, unless a participant has already 
completed any of the screening assessments as part of another separate study. In this case, if the overlapping 
screening assessments were completed no more than 1 month prior to Visit 1 and the participant has signed 
HIPPA Authorization allowing us to access this prior data, Visit 1 will be approximately 1.5 hr.  
Note: Due to the length and rigor of this initial screening process, it may sometimes be necessary for 
participants to complete screening measures across more than one visit (e.g., schedule conflicts). All screening 
measures will be completed within 2 weeks of the consent date. 
Visit 2: Fear Acquisition:  Approximately 1 hr for all participants. Participants are considered enrolled in the 
study once they have begun Visit 2 (if enrolled in PTSD group, participant will be randomized). Visit 2 will occur 
within 6 months of Visit 1. If more than 6 months have passed, we will re-do Visit 1 before the participant is 
able to complete visits 2 – 5. 
Visit 3: Fear Extinction:  Approximately 5 hr for those receiving a capsule (PTSD groups) or approximately 3 
hours for those not receiving a capsule (TEC group) 
Visit 4: Fear Extinction Recall and Fear Renewal Test (approximately 24 hr after extinction, but no more than 
1 week later): Approximately 1.5 hr  
Visit 5: Fear Extinction Recall, Fear Renewal Test, & Debriefing (approximately 1 week after extinction, but no 
more than 3 weeks later): Approximately 1.5 hr 
 
Nature of Participant Population: Participants of both genders will be included in the study and the age range 
of participants will be from 18-60. Persons below 18 or above 60 are excluded because beyond this range age 
may influence response to the drugs. Furthermore, the relatively small age range is intended to reduce variation 
in performance on the behavioral task. There are no enrollment restrictions based upon race or ethnic origin. 
Candidates will undergo a structured clinical psychiatric interview150 and complete questionnaires related to their 
general physical health, current medications, with a detailed section on current and lifetime drug and alcohol 
use. This study will not involve vulnerable populations. 
 
The number of participants expected to participate is 104: 78 trauma-exposed participants with PTSD and 26 
trauma-exposed participants without PTSD (TEC; demographically matched). There will be 3 experimental 
groups: PTSD participants will be assigned to 5mg of THC (n=26), 10mg of THC (n=26), or a placebo (PBO) 
(n=26). The 26 TEC participants will not receive THC or PBO. With the conservative anticipation 25% will fail to 
complete all parts of the study, we estimate 20 PTSD participants in each condition (60 PTSD participants in 
total) and 20 TEC participants will complete the study for a total of 80 participants. Participants will be recruited 
from the Detroit community and mental health clinics. We will enroll up to 175 participants to guarantee enough 
viable data and to account for participant drop out. 
 
Recruitment 
Participants will be recruited from several sources including flyers and webpage advertisements on Academica. 
In addition, we will also recruit patients seeking treatment at the Trauma Recovery Center of Southeast Michigan, 
Wayne State University (WSU) Physicians Group, North Central Health Center in Detroit, Detroit Wayne Mental 
Health Authority, St. John Providence Eastwood Clinics, WSU Psychology Clinic, WSU Clinical Research Center 


Protocol Title: Effects of THC on Retention of Memory for Fear Extinction Learning In PTSD: R61 Study 
 
Principal Investigator: Christine Rabinak, PhD 
 
IRB # 015017MP4F 
 
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in Detroit. Current staff in the Departments of Psychiatry and Psychology and related clinical departments at 
WSU will be informed about the study to pass along the information (in flyer format) to their participants. In 
addition, individuals who participate in the study may earn additional compensation for referring other people to 
the study. Once a participant contacts the project coordinator/research assistant at WSU, they will explain the 
study to the participant and schedule the participant to come in for a screening and orientation session (Visit 1) 
at the Eugene Applebaum College of Pharmacy and Health Science (EACPHS) building. 
 
Retention 
Strategies for participant retention will be discussed regularly in weekly research meetings, and will be practiced 
for optimized retention such as contact with the PI and her research team during the study, phone 
reminders/confirmation of visits, established contact with the study coordinator, arrangements for transportation 
(as needed) at each visit, reimbursement for parking/travel at each visit and for time and effort. Also, office hours 
are flexible (e.g., 7am-7pm during the week with weekend availability). Based on these strategies, we anticipate 
that drop-out will be minimized to less than 25% of the sample. 
 
Inclusion Criteria  
Inclusion criteria across all groups will be: (a) generally medically and neurologically healthy, including no 
evidence of intellectual disability or serious cognitive impairment that would interfere with task performance; (b) 
between the ages of 18-60; (c) willing and able to give informed consent; (d) exposure to Criterion A stressor as 
defined by the CAPS-5 and identified by the LEC-5, regardless of type of trauma (e.g., civilian or combat). 
Inclusion criteria for the PTSD group will be: (a) significant PTSD severity as indicated by a clinician-administered 
PTSD scale for DSM-5 (CAPS-5) diagnosis and/or score (see below) of ≥ 25 of at least the past month prior to 
study entry (primary PTSD will be identified as the patient’s primary concern). Inclusion criteria for the TEC group 
will be: (a) absence of any history of PTSD symptoms (CAPS-5 < 25 and/or no diagnosis), related to any type of 
trauma. 
 
Exclusion Criteria  
Exclusion criteria across groups will be: (a) exclusively left-handed (i.e., score of -100.00 on Handedness 
Questionnaire); (b) risk of harm to self or others that requires immediate intervention; (c) presence of 
contraindications, current or past allergic or adverse reaction, or known sensitivity to cannabinoid-like substances 
(dronabinol/marijuana/cannabis/THC, cannabinoid oil, sesame oil, gelatin, glycerin, and titanium dioxide); (d) 
lack of fluency in English; (e) currently pregnant (positive pregnancy test or self-report), planning pregnancy, or 
lactating (women); (f) traumatic brain injury (as defined by The American Congress of Rehabilitation as a person 
who has had a traumatically induced physiological disruption of brain function (i.e., the head being struck, the 
head striking an object, and/or the brain undergoing an acceleration/deceleration movement (i.e., whiplash) 
without direct external trauma to the head), as manifested by at least one of the following: any loss of 
consciousness; any loss of memory for events immediately before or after the injury; any alteration in mental 
status at the time of the incident; or focal neurological deficits that may or may not be transient); (g) inability to 
tolerate small, enclosed spaces without anxiety (e.g. claustrophobia), as determined by self-report; (h) presence 
of ferrous-containing metals within the body (e.g., aneurysm clips, shrapnel/retained particles); (i) current or past 
diagnosis of any bipolar or related disorder or schizophrenia spectrum and other psychotic disorder as 
determined by the MINI 7.0.2; (j) current severe alcohol or substance use as determined by the MINI 7.0.2; (k) 
history of pervasive developmental disorder (e.g., Autism, Asperger syndrome). Exclusion criteria for the PTSD 
group will be: (a) current diagnosis of a mood, anxiety, or other disorder that is more clinically salient than PTSD 
(e.g., MDD, OCD, Panic, GAD); (b) concomitant treatments with medication known to have level 1 evidence for 
severe drug- drug interactions with dronabinol that are taken daily. Exclusion criteria for the TEC group will be: (a) 
current diagnosis of any obsessive-compulsive and related disorders or trauma- and stressor-related disorders 
as determined by the MINI 7.0.2 for DSM-5; (b) current diagnosis of any depressive disorder as determined by 
the MINI 7.0.2 and a score > 22 (indicating very severe depression) on the Hamilton Depression Scale (HAM-
D); (c) current diagnosis of any anxiety disorder as determined by the MINI 7.0.2 and a score > 24 (indicating 
moderate to severe anxiety) on the Hamilton Anxiety Scale (HAM-A). 
 


Protocol Title: Effects of THC on Retention of Memory for Fear Extinction Learning In PTSD: R61 Study 
 
Principal Investigator: Christine Rabinak, PhD 
 
IRB # 015017MP4F 
 
Version #11 
Version Date: 2/17/21 
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Termination Criteria  
Participants may be terminated for any of the following: (a) participant request to exit or withdraw consent; (b) 
development of risk of harm to self or others that requires immediate intervention; (c) alcohol, drug, medication 
use that would interfere with dronabinol or has level 1 evidence for severe drug-drug interaction with dronabinol; 
(d) development of a systemic, medical, neurologic, or psychiatric illness requiring treatment that would exclude 
participation; (e) clinical deterioration (see below); (f) non-compliance with study protocol requirements. We will 
make every effort to ensure that the sessions are accessible (i.e., scheduling sessions during evening and 
weekend hours). We will attempt to schedule Visits 2-4 on consecutive days, but in the event that this is not 
possible we will allow no more than 1 week between Visits 2 & 3 and Visits 3 & 4 and no more than 3 weeks 
between Visits 4 & 5. Of note, if there is more than 1 week between Visit 2 & 3, we will re-do Visit 2 and proceed 
with the rest of the visits as normal. But once a participant completes Visit 3, Visits 4 & 5 need to be completed 
within the above timeframe otherwise participation will be terminated. We will make every effort to ensure that 
appointments are accessible (i.e., scheduling an appointment during evening and weekend hours). 
 
Medical and Neurological Health Determination 
All health information collected in the pre-screening and baseline interview (Visit 1) will be reviewed by the PI or 
Co-I Kilgore, who will indicate whether the participant is medically and neurologically healthy enough to continue 
in the study. These determinations may be made in person, over the phone, or via e-mail, and will be documented 
using a Medical Review form. 
 
Emergent Suicidal or Homicidal Risk  
The clinician or research staff may remove a participant from the clinical trial if the PI thinks that the participant 
is at imminent suicidal or homicidal risk. The presence of suicidal ideation is evaluated at the initial assessment. 
Endorsement of suicidal or homicidal ideation will be addressed in session. If the patient is deemed to have 
specific suicidal or homicidal ideation, the PI, Co-I Kilgore, or Co-I Tancer will be immediately notified and the 
participant will meet with the PI and/or Co-Is Kilgore and/or Tancer, or other licensed social 
worker/psychologist/psychiatrist covering for the PI or Co-Is on the premises, and the police will be alerted. 
 
 
Vulnerable Populations 
This study will include women of child-bearing potential and college students. However, we will conduct urine 
pregnancy tests at the screening visit (Visit 1) and at the beginning of Visit 3 to make sure that women are not 
pregnant. Of note, if the participant is unable to provide a urine sample at Visit 1 (e.g., currently menstruating), 
we will conduct a urine pregnancy test at the beginning of visit 2.  We will also conduct pregnancy tests if the 
study staff and/or participant have reason to believe they may be pregnant. In addition, participation of college 
students in this study is completely voluntary, as it is for all participants, and will not be required by any course. 
 
Study Group Assignment 
Individuals with PTSD will be randomized to a THC or PBO condition. In our previous studies we have shown 
that 7.5mg of THC facilitates extinction recall and modulates prefrontal and hippocampal activation in healthy 
humans volunteers55,113. Moreover, PI Rabinak has preliminary data to suggest that 7.5mg of THC may facilitate 
extinction recall in PTSD, but it is not known whether this is the MED. This is an initial step in translation to be 
tested in the R61 phase. Therefore, we will have a low 5mg condition and a high 10mg condition should 5mg be 
too low to detect effects. Of note, a 10mg dose of THC does not typically produce anxiety151 or strong negative 
effects on cognition152. We aim to identify the MED that facilitates recall of extinction learning. Dronabinol is 
administered only by the oral route and will be placed in opaque capsules with dextrose filler. Placebo capsules 
will be identical in appearance but will contain only dextrose. All capsules will be administered to participants in 
double-blind conditions and participants assigned to receive dronabinol (two-thirds of the PTSD participants) will 
only receive dronabinol on one occasion.  
 
Study medication, dronabinol or PBO, will be dispensed to participants by PI Rabinak, who possesses a 
Schedule II-V controlled substance research license through the State of Michigan and the DEA and has 
experience in the use of dronabinol and PBO in human participant research. A registered pharmacist will handle 


Protocol Title: Effects of THC on Retention of Memory for Fear Extinction Learning In PTSD: R61 Study 
 
Principal Investigator: Christine Rabinak, PhD 
 
IRB # 015017MP4F 
 
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Version Date: 2/17/21 
12
the overencapsulation of the required dronabinol and creation of the matching placebo. Dr. Rabinak will store 
the capsules in her office, room 2136 in the Eugene Applebaum College of Pharmacy, in a locked refrigerated 
safe. She holds current controlled substance licenses from the State of Michigan and Drug Enforcement 
Administration allowing her to order, store, and dispense dronabinol from her office. 
 
Dr Rabinak will randomize participants to the study groups: 5 mg dronabinol, 10 mg dronabinol, or placebo. She 
will dispense one pill from the appropriate container labeled by the pharmacist and put the pill into a separate 
pill bottle. This new pill bottle will be labeled with the participant specific ID. Dr. Rabinak will be responsible for 
appropriate documentation of drug orders, inventory, subject-specific drug order forms, dispensing, and disposal 
records.  Research staff associated with the study will give the drug or PBO to participants, and Co-I Paul Kilgore, 
M.D., a board-certified and licensed physician, or Co-I Manuel Tancer, M.D., a board-certified and licenses 
psychiatrist, or their physician designate, will be present on-site and/or available by pager/phone.  
 
b. Sources of Materials 
 
Primary Diagnostic Assessments (Table 1) 
(1) Mini International Neuropsychiatric Interview Version 6.0.0 (MINI): The MINI is a structured interview for 
general diagnostic assessment providing an assessment of major psychiatric diagnoses; (2) Clinician-
Administered PTSD Scale for DSM-5 (CAPS-5)154, a validated, gold-standard clinician interview measure of 
PTSD severity. WSU clinical research staff members will conduct diagnostic interviews using MINI/CAPS 
instruments. While most interviews will be conducted by one rater, inter-rater reliability will be examined to ensure 
good reliability (Kappa at least 0.6)155.  
Table 1: R61 Assessment Schedule 
 
 
FMRI 
THC 
or 
PBO 
 
Screening, 
Informed 
Consent, & 
Study Entry 
Fear 
Acquisition 
Fear 
Extinction 
Extinction 
Recall Test 
1 
Extinction 
Recall Test 
2 
MINI 
 
 
 
 
 
CAPS-5 
 
 
 
 
 
Standard Health Questionnaire 
 
 
 
 
 
Ethnicity/Race Form 
 
 
 
 
 
MRI Safety Form 
 
 
 
 
 
Gender Identity Questionnaire 
 
 
 
 
 
Concomitant Medication Form 
 
 
 
 
 
Handedness Questionnaire 
 
 
 
 
 
Connor-Davidson Resilience Scale 
 
 
 
 
 
Posttraumatic Growth Inventory 
 
 
 
 
 
LEC-5 
 
 
 
 
 
PCL-5 
 
 
 
 
 
PSQI 
 
 
 
 
 
STAI** 
 
 
 
 
 
HAM-D 
 
 
 
 
 
HAM-A 
 
 
 
 
 
BDI-II 
 
 
 
 
 
C-SSRS 
 
 
 
 
 
WHODAS 2.0 
 
 
 
 
 
CTQ 
 
 
 
 
 
ERQ 
 
 
 
 
 
ACQ 
 
 
 
 
 
US Expectancy 
 
 
 
 
 
SUDS 
 
 
 
 
 
VAS** 
 
 
 
 
 
DEQ** 
 
 
 
 
 


Protocol Title: Effects of THC on Retention of Memory for Fear Extinction Learning In PTSD: R61 Study 
 
Principal Investigator: Christine Rabinak, PhD 
 
IRB # 015017MP4F 
 
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Secondary Measures (Table 1) 
(1) Standard Health Questionnaire; (2) 
Ethnicity/Racial Category Form; (3) 
MRI Safety Form; (4) Gender Identity 
Questionnaire; (5) Concomitant Medication Form. This form will be reviewed and updated (if applicable) by the 
participant at each study visit; (6) Handedness Questionnaire; (7) Connor-Davidson Resilience Scale (CD-RISC); 
(8) Posttraumatic Growth Inventory (PTGI); (9) Life Events Checklist for DSM-5 (LEC-5)156: The LEC-5 is  a self-
report measure designed to screen for potentially traumatic events in a person’s lifetime; (10) PTSD Checklist 
for DSM-5 (PCL-5)157: The PCL-5 is a 20-item self-report measure that assesses the 20 DSM-5 symptoms of 
PTSD. It is used for monitoring symptom change during and after treatment, screening individuals with PTSD, 
and for making a provisional PTSD diagnosis; (11) Pittsburgh Sleep Quality Index (PSQI)158: The PSQI is a self-
rated questionnaire which assess sleep quality and disturbances over a 1-month time interval; (12) Spielberger 
State-Trait Anxiety Inventory (STAI)159: The STAI is a measure of trait and state anxiety; (13) Hamilton 
Depression Scale (HAM-D)160: The HAM-D is used to determine a patient’s level of depression before, during, 
and after treatment; (14) Hamilton Anxiety Scale (HAM-A)161: The HAM-A is a questionnaire used by clinicians 
to rate the severity of a patient’s anxiety; (15) Beck Depression Inventory (BDI-II)162-165: The BDI-II is self-report 
questionnaire used to measure severity of depression; (16) Columbia-Suicide Severity Rating Scale (C-
SSRS)166 is a standardized 8 point clinician-administered suicidal rating system designed to track suicidal 
adverse events across a treatment trial and covering the wide spectrum of suicidality; (17) World Health 
Organization Disability Assessment Schedule 2.0 (WHODAS 2.0)167: This is an assessment of global functioning 
and impairment; (18) Childhood Trauma Questionnaire (CTQ)168,169: The CTQ is a 28-item self-report measure 
that provides brief, reliable, and valid screening for histories of abuse and neglect. It inquiries about five types of 
maltreatment—emotional, physical and sexual abuse and emotional and physical neglect. (19) Emotion 
Regulation Questionnaire (ERQ)170: The ERQ is designed to assess individual differences in the habitual use of 
two emotion regulation strategies: cognitive reappraisal and expressive suppression; (20) Attentional Control 
Questionnaire (ACQ)171: The ACQ is a self-report questionnaire designed to measure individual differences to 
major components of attention: attention focusing and attention shifting. The ability to regulate emotions and 
focus on the task at hand (e.g., attend to fear-cues) is expected to factor into PE therapy; therefore, the ERQ 
and ACQ are for exploratory purposes. 
 
Additional Secondary Measures (Table 1) 
In addition to standardized assessments of symptom severity and mood/emotional state, the following measures 
will be completed at various time points within a session (e.g., before, during, and after) on days in which fear 
acquisition and/or fear extinction and extinction recall/fear renewal tests occurs: (1) US expectancy; (2) 
Subjective Units of Distress Scale (0=absolutely calm; 100=worst distress), frequently used in exposure-based 
therapy, which will provide a measure of subjective fear.  
 
THC/PBO Day Measures (Table 1) 
The following standardized assessments will be collected throughout the session when THC/PBO is ingested to 
assess mood states and subjective drug effects. These questionnaires are sensitive to the effects of a variety of 
psychoactive drugs on affective state/mood and drug liking172,173: (1) Visual Analog Scales (VAS): This 
questionnaire consists of visual analog scales used to describe current medication effects. This particular form 
consists of twenty 100-mm horizontal lines each labeled with an adjective (“clear- headed,” "anxious," 
“stimulated,”  “tired,”  “calm,”  "drowsy,"  “peaceful,”  "nervous,"  "hungry,"  "energetic," “uneasy,” “relaxed,” “alert,” 
“content,” “focused,” “dreamy,” “restless,” “nauseous” “worn out,” and “jittery”). The left end of each line is labeled 
"not at all" and the right "extremely." Participants are instructed to place a mark on each line indicating how they 
feel at the moment; (2) Drug Effects Questionnaire (DEQ)174: This questionnaire assesses the extent to which 
participants “feel any substance effect(s),” “feel high,” “like the effects,” “dislike the effects,” and “want more of 
the substance” using 100 mm visual analog scales. The left end of each line is labeled “not at all” and the right 
“extremely.” Participants are instructed to place a mark on each line indicating how they feel at that moment; (3) 
Addiction Research Center Inventory (ARCI)175,176: The 53-item ARCI is a true-false questionnaire with five 
ARCI** 
 
 
 
 
 
ESQ** 
 
 
 
 
 
Blood Draw Safety Questionnaire** 
 
 
 
 
 
Debriefing Interview 
 
 
 
 
 
**These measures are NOT completed by the TEC group at Visit 3, as they do not ingest THC/PBO


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empirically derived scales that are sensitive to the effects of a variety of classes of abused drugs.  The scales 
are the MBG (Morphine-Benzedrine Group), a general measure of drug-induced euphoria; the A (Amphetamine) 
scale, a measure specific for dose-related effects of d-amphetamine; the BG (Benzedrine Group), an 
amphetamine scale consisting mainly of items relating to intellectual efficiency and energy; the PCAG 
(Pentobarbital-Chlorpromazine Group), a measure of sedation; the LSD (Lysergic Acid), a measure of dysphoria 
and somatic symptoms; and the M scale, a measure of marijuana’s effects; (4) Spielberger State-Trait Anxiety 
Inventory (STAI)131 (state subscale): This state subscale is used to assess the level of state (current/in the 
moment) anxiety in an individual; (5) At completion of drug session, participants will complete the End of Session 
Questionnaire (ESQ) which asks them to indicate the extent to which they think they felt a drug effect, the extent 
to which they think they received THC or PBO, and to rate how much they “liked its effects.” They will be also 
asked to comment on any unusual effects they experienced, and whether they would take the substance again. 
In addition, physiologic measures (heart rate, blood pressure) will be collected at regular intervals throughout 
the drug session. (6) The Blood Draw Safety Questionnaire will be completed by the participant at the beginning 
of the THC/PBO session (Visit 3) and reviewed prior to blood collection at all subsequent visits. 
 
These psychological and physiological measures are collected 1) before receiving THC or PBO on Visit 3; 2) at 
approximately 30 min intervals after receiving THC or PBO on Visit 3 (i.e., at 30, 60, & 90 min), immediately 
before going in the MRI scanner, soon after coming out of the MRI scanner; and once before the end of the visit 
unless otherwise specified (ESQ will be collected only at the end of the drug session; DEQ will also be collected 
before recall of extinction learning on Visits 4 & 5). Because the effects of the drugs may have a lingering effect, 
measures of the effects of the drug (DEQ) and review of adverse events will also be collected for exploratory 
purposes at two additional times: approximately 8 hr after drug administration. 
 
Debriefing Session Measures  
At the final extinction memory recall session (Visit 5), a short Debriefing Interview will be conducted with the 
participant. The participant will be asked about what they remember from each session and to provide feedback 
about their experience in the study. The study aims and measures will be explained in detail to the participant 
and any questions they have will be answered. 
 
All of the questionnaires that will be administered to participants are standardized questionnaires that have been 
extensively used in research and are valid and reliable. 
 
Psychophysiological  
Skin conductance recordings (SCR) will be collected, if able, during fear acquisition, fear extinction, and 
extinction memory recall sessions (i.e., Visits 2-5). 
 
FMRI Data  
FMRI data will be collected, if able, during the fear extinction learning and extinction memory recall and fear 
renewal sessions (i.e., Visits 3-5). 
 
c. Potential Risks 
 
Diagnostic/Assessment Procedures 
The diagnostic interviews (and questionnaires) are time consuming and may be boring to some individuals. 
These are, however, necessary to determine eligibility for the study. In addition, questions about alcohol/drug 
use, interpersonal relationships, abuse/trauma history, and questions related to history of suicidal and/or 
homicidal behavior may be considered sensitive by some participants. The collection of such data poses a 
potential risk of loss of confidentiality around sensitive information such as psychiatric status, history of 
substance abuse, etc. Participants will also be informed in the consent document that confidentiality will be 
limited in cases where the participant reveals intentions to harm themselves or others, and the investigator feels 
that the proper authorities may need to be notified to prevent the occurrence of harm to the participant, or others. 


Protocol Title: Effects of THC on Retention of Memory for Fear Extinction Learning In PTSD: R61 Study 
 
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Experienced mental health workers will conduct interviews and will maintain confidentiality. All data from 
interviews and questionnaires will be numbered to conceal the identity of the participant. 
 
Other Tasks 
The virtual snake presented during the fear conditioning procedure will be uncomfortable and aversive and 
participants will not know that the virtual snake will only be presented during the first session of the experiment 
and on several but not all trials. Study staff will be present during all tasks and participants may communicate 
with them always, including when the participant is in the MRI scanner. A medical clinician on this study (e.g. 
physician) will be available during all behavioral tasks to evaluate and recommend treatment for the emergence 
of any anxiety/panic attack, elevated levels of anxiety, changes in vital signs (heart rate and/or blood pressure), 
or emotional discomfort. 
 
Blood Draws 
Foreseeable risk or discomforts associated with the blood draw include the potential for pain, bruising, or infection 
at the blood draw site. This is rare and usually temporary. Occasionally nausea, lightheadedness, or fainting 
may occur. 
 
Magnetic Resonance Imaging 
Magnetic resonance imaging is non-invasive, widely used, and safe. The potential risks such as static magnetic 
field, radio-frequency field, magnetic field gradients, and acoustic noise are rarely dangerous or life threatening.  
Additional minor and/or rare risks include: (a) discomfort or anxiety from being in the confined space of the MRI 
scanner; (b) fast imaging sequences, such as those employed in this study, have the potential to induce 
peripheral nerve stimulation (PNS). PNS can be described as a light touching sensation on the skin surface and 
may cause mild discomfort, but is not harmful to the participant; (c) risks of hearing damage due to loud noises 
produced by the scanner; (d) risk that the magnetic resonance image will reveal a minor or significant lesion in 
the brain, e. g. a tumor, previously unknown to the participant, and requiring additional follow-up; (e) risk of injury 
from objects accelerated by the strong magnetic field of the magnet, striking the participant; or metallic 
substances on the skin or foreign bodies implanted deliberately or accidentally in the participant that acquire 
kinetic or thermal energy from the magnetic or radiofrequency emissions of the MRI, causing tissue injury to the 
participant; (f) sometimes, participants report a temporary, slight dizziness or light-headedness when they come 
out of the scanner; (g) potential risk for pregnant women: According to the NIMH Council Workgroup on MRI 
Research and Practices (September, 2005), “there is no known risk of MR brain scanning of a pregnant woman 
to the developing fetus for scanning at 4T or less, and no known mechanism of potential risks under normal 
operating procedures.” Nevertheless, participants should be warned about potential risks not yet discovered. 
 
Discovery and disclosure of incidental finding or abnormality on MRI scans: During the formal consent process, 
all participants will be informed about the potential risks of discovering an incidental finding or abnormality on 
their MRI scan. If an abnormality is found in a participant’s MRI scan, the PI may ask a radiologist at the MR 
Facility will review the scan data and provide recommendation to the PI if the incidental finding or abnormality is 
something the participant should follow-up with their primary care physician about. If follow-up is recommended, 
the PI will contact the participant. The decision as to whether to proceed with further examination and/or 
treatment lies solely with the participant and his/her primary care physician. 
 
Dronabinol   
Dronabinol is associated with some adverse experiences (incidence 1%-10%) including: asthenia, increases in 
heart rate, palpitations, facial flush, sensory impairment, headache, nausea, vomiting, dry mouth, changes in 
appetite, easy laughing, euphoria, restlessness, panic attacks, anxiety/nervousness, paranoid reaction, 
confusion, dizziness, drowsiness, and impairment in coordination. A board-certified psychiatrist and/or physician 
associated with the study (Co-I Kilgore or Co-I Tancer) or his/her physician designate, will be available during all 
behavioral tasks and pharmacological challenge days to evaluate and recommend further evaluation and 
treatment for the emergence of any adverse events/side effects. 
 


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Participants taking medications that have level 1 evidence indicating severe drug-drug interaction with dronabinol 
daily will be excluded. Also, we will exclude participants with a known sensitivity to the active drug or capsule 
excipients, including cannabinoid oil, sesame oil, gelatin, glycerin, and titanium dioxide.  Pregnant participants 
will be excluded from participation because there is insufficient data to assure safety of the fetus during 
dronabinol exposure, as well as during MR scanning.  In addition, nursing mothers will be excluded from the 
study because dronabinol is concentrated in and secreted in human breast milk and is absorbed by the nursing 
baby (for reference see: http://www.fda.gov/ohrms/dockets/05n0479/05N-0479-emc0004-04.pdf). 
 
Marinol®/dronabinol is one of the psychoactive compounds present in cannabis, and is abusable and controlled 
[Schedule III (CIII)] under the Controlled Substances Act. Both psychological and physiological dependence 
have been noted in healthy individuals receiving dronabinol, but addiction is uncommon and has only been seen 
after prolonged high dose administration. Although any exposure to dronabinol may entail some risk for 
development of problems of abuse, this is highly unlikely177. There is no evidence that participation in controlled 
laboratory studies such as these increases the risk for developing substance use problems172,173,178, including 
those conducted in laboratories (with 20+ years of experience) from which the current protocol is based110,127,128. 
In fact, in an open label study in patients with AIDS who received dronabinol for up to five months, no abuse, 
diversion or systematic change in personality or social functioning were observed despite the inclusion of a 
substantial number of patients with a history of drug abuse. There are low social, legal or psychological risks 
associated with ingestion of dronabinol as a volunteer in this research study.  Because the participants are 
physically healthy volunteers there are no alternative treatments. Participants will be fully debriefed following the 
study. During debriefing, any questions participants may have will be answered with the exception of which drug 
they received. In order to maintain integrity of the data collected, blinding needs to be maintained. 
 
2. Adequacy of Protection Against Risks 
 
a. Recruitment and Informed Consent 
 
Recruitment 
Participants will be recruited from several sources including referrals, flyers and webpage advertisements on 
Academica. In addition, we will also recruit patients seeking treatment at the Trauma Recovery Center of 
Southeast Michigan, Wayne State University (WSU) Physicians Group, North Central Health Center in Detroit, 
Detroit Wayne Mental Health Authority, St. John Providence Eastwood Clinics, WSU Psychology Clinic, and 
WSU Clinical Research Center. Current staff in the Departments of Psychiatry and Psychology and related 
clinical departments at WSU will be informed about the study to pass along the information (in flyer format) to 
their participants. Once a participant contacts the project coordinator/research assistant, they will explain the 
study to the participant and schedule the participant to come in for a screening and orientation session (Visit 1) 
at the Eugene Applebaum College of Pharmacy and Health Science (EACPHS) building. A waiver of signed 
consent will be requested for the phone or online screen to save a high number of ineligible participants from 
coming in for the initial assessment session (Visit 1). Information collected in the pre-screening will be used at 
Visit 1 to determine eligibility.  During the initial assessment (Visit 1), the participant will be provided with the 
informed consent form, along with an oral presentation of the material in the consent form by a research staff 
member. Only after signing the consent form will the participant be evaluated for participation in the study. 
 
Informed Consent 
During the initial assessment (Visit 1), the nature of the research project will be described to participants. A 
written summary, in lay terms, of the research project will be provided to the participants in the written informed 
consent document that the participants will review. The consent document will inform the participants of the 
voluntary nature of the study procedures, the purpose of the study, the procedures to be followed, the duration 
of the study, the risks associated with MR scanning, and exposure to dronabinol and to behavioral tasks, as well 
as the potential benefits to the community at large. Participants will agree in the consent not to take other drugs 
for 24 hours before and 12 hours following each session and not to operate any machinery requiring 
concentration for 12 hours following the session in which the drug may be administered. Women will agree that 


Protocol Title: Effects of THC on Retention of Memory for Fear Extinction Learning In PTSD: R61 Study 
 
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they are not pregnant and not planning to become pregnant and not nursing. Women will be informed that we 
will administer a urine pregnancy test at Visit 1. Participants will be informed that blood alcohol levels and urine 
samples to test for pregnancy and drugs will be obtained on Visit 3 prior to receiving the drug. Written informed 
consent will be obtained by the PI or designated research staff and the participant will receive a copy of the 
signed consent form. Participants will be informed that they can discontinue participation at any time without 
penalty. 
 
b. Protection Against Risk 
 
General Considerations 
To protect against, or minimize any possible risks, we adhere to the following procedures: (a) participants will be 
carefully screened to exclude those who are physically, neurologically, or psychiatrically at risk (see above); (b) 
studies are conducted in laboratory areas (Eugene Applebaum College of Pharmacy & Health Sciences Building 
and the Magnetic Resonance Research Facility at WSU) located nearby a hospital, where emergency assistance 
can be obtained; (c) a radiological technician and member of the research team are present during all fMRI 
sessions; (d) heart rate (HR) and blood pressure (BP) will be monitored regularly during the fMRI sessions; (e) 
a member of the research team and Co-I Kilgore, a board-certified physician, or Co-I Tancer, a board-certified 
psychiatrist, or their physician designate will be available on-site or by pager/phone at all pharmacological 
challenge sessions; (f) participants will agree not to take any other drugs for 24 hours before and 12 hours 
following the drug session (Visit 3), and compliance will be monitored by breathalyzer and urine tests conducted 
at the beginning of Visit 3, prior to drug administration; (g) participants are instructed not to drive and should 
arrange alternate transportation through a family member/friend or a taxi will be arranged to take them home; 
(h) a complete medical history, review of medications and physical symptoms/signs will be performed prior to 
entry into this study; (i) participants will be informed that they may withdraw by informing the investigators or 
research staff when they are present at the time of the study or by using one of the phone numbers/locations 
provided on the consent form. Withdrawal from the study after the clinical and fMRI/psychophysiological data 
has been collected is also possible through contacting the investigators or research staff using one of the phone 
number/locations provided on the consent form. Effective screening should exclude participants who would be 
placed at greater risk. All the testing will be done in the presence of appropriately trained research staff and in a 
facility specifically designed, equipped, and functioning to support these types of studies. Participants are free 
to drop out of the study at any time without cost or penalty. Participants will be informed that they do not have to 
participate if any procedure or questionnaire causes them discomfort. 
 
Confidentiality 
All data from participants are marked with a research identifier number only and kept in locked cabinets. No data 
will have participant names on them, except for consent forms, which are stored separately from other 
questionnaires in a locked file cabinet.  Paper records are kept in locked file drawers in a locked room, to which 
only authorized research personnel have access. Confidentiality of participant records is assured by assigning 
each 
participant 
with 
a 
research 
identifier 
number/code, 
and 
such 
data, 
as 
well 
as 
behavioral/fMRI/psychophysiological data, are stored in password-protected computer files, such as encrypted 
Microsoft Excel files, (except for a single tracking file) on a password and firewall-protected private lab server as 
well as in an Electronic Data Capture system (Castor). Data that may be reported in scientific journals will not 
include any information that identifies any person as a participant in this study.   
 
Clinical Evaluation/Participant Materials 
The interview forms, paper and pencil questionnaires, and the laboratory assessment forms will be labeled with 
a participant code (not participant name) that is not readily identifiable to non-study staff. These forms will be 
kept in a locked cabinet or a private, password and firewall-protected server, where only approved study staff 
can have access. All information obtained during this study is strictly confidential, except when there is either a 
danger to self or others. Members of the research teams will not divulge any information about interviews or 
other tests to non-study staff personnel. Data that may be reported in scientific journals will not include any 
information that identifies any person as a participant in this study.   


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Limits of Confidentiality on Clinical Information 
Confidentiality is limited, however, where there is either a danger to self or others. If the participant is discovered 
to be acutely homicidal or suicidal during the evaluation period the police will be alerted. 
 
Suicide Risk 
If a participant endorses current (e.g., within the past month) suicidal ideation on the C-SSRS (e.g., a score of 
yes for question 4 and/or 5 from the suicidal ideation section of the C-SSRS), the PI and/or Co-I Kilgore, and/or 
Co-I Tancer will immediately be notified and the participant may meet with the PI and/or Co-I Kilgore and/or Co-
I Tancer, or other licensed social worker/psychologist/psychiatrist covering for the PI on the premises, and the 
police may be alerted. Determinations about level of risk and appropriate actions to be taken will be made by the 
PI and/or Co-I Kilgore together with the research staff member who conducted the suicidality assessment. In all 
cases, the research staff and/or the PI will follow up with the participant and provide mental health 
resources/referrals as needed. The PI may remove a participant from the protocol if the research team thinks 
that the participant is at imminent suicidal risk and may be a danger to himself/herself.   
 
Confidentiality of Breathalyzer/Drug & Pregnancy Tests Prior to Scans or Assessment 
The results of the breath alcohol test and urine drug and pregnancy tests performed at the beginning of Visit 3 
(and Visit 1 for pregnancy test) will remain confidential. The only individuals who will have knowledge of the 
results of these tests are research staff directly working on the project. The breath alcohol and urine tests will be 
performed at the beginning of the visit. If the participant produces a positive pregnancy test at either Visit 1 or 
Visit 3 or reports becoming pregnant at any time during which they are active in the study, they will be withdrawn 
from the study at that time. At the beginning of Visit 3, if the participant (a) fails the alcohol breathalyzer test 
and/or (b) fails the urine drug test without any current medication use (e.g., non-illicit) which explains the positive 
result, the session will end at that time and the remaining visits will be rescheduled. Visits 3-5 will be rescheduled 
such that Visit 3 occurs within 1 week of Visit 2, otherwise the participant will need to re-do Visit 2. If the 
participant cannot be rescheduled or fails the urine drug test for a second time (i.e., at their rescheduled Visit 3) 
they will be withdrawn from the study. In the event of failed drug screen, follow-up questions will be asked to 
determine whether the result can be explained by a daily medication and not illicit drug use. This information will 
be stored in a secure computer database that uses participant codes (rather than names) as identifiers. 
 
Other Tasks 
Participants are re-assured that they can withdraw from the study at any time if they do not wish to experience 
the virtual snake.  All participants will be informed that they are able to take a break at any time during any of the 
behavioral tasks. 
 
Dronabinol 
Participants are made aware of the side effects common to dronabinol in the informed consent document and 
again during their initial screening visit. Participants will be monitored for side effects at the pharmacological 
challenge visits.  Participants are reassured that they can withdraw from the study at any time.  
 
Magnetic Resonance Imaging 
To minimize the risk of discomfort and anxiety, and to make the participant as comfortable as possible, we will 
use custom pads and pillows. The participant can communicate with the machine operator via an intercom and 
may trigger an audible alarm at any time. Before the participant rolls into the core of the magnet, he or she is 
always reminded that they are free to stop the study at any time if they become uncomfortable. If they were to 
experience an anxious reaction, the study would be halted, and study staff would monitor the participant for 
further/worsening anxiety symptoms. The participant would have the option to meet with the PI or another study 
psychiatrist, psychologist, or social worker. Participants often find that once outside of the scanner, they 
experience immediate relief of any anxiety and discomfort. If the study team has any doubts about the relief of 
anxiety, follow-up telephone calls would be made later that day or 1-3 days after the session to confirm the 
transient nature of their reaction. 


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The MRI machine is operated within FDA guidelines so the potential for inducing peripheral nerve stimulation 
(e.g., experiencing twitching sensation) is low. 
 
All participants are required to wear foam earplugs to reduce the risk of hearing damage.  
 
In the event of an anomalous finding on the MRI, the PI would contact the participant and explain that the 
participant should contact their primary care provider to obtain a clinical MRI scan (see plan below for more 
details).  
 
The MRI suite is kept clear of all objects that could be picked up by the magnetic field. MRI personnel are trained 
in safety procedures, which include training around the materials that cannot be brought into the scanner room. 
The technician administering the scan is trained to review each participant’s MRI safety form to assess suitability 
of the participant to enter the MR environment. Additionally, participants are screened at multiple points. An initial 
phone screening is done, in which the MRI is explained and participants are excluded from participation if they 
have contraindications to an MRI scan. On the day of the scan (Visit 3), the participant completes an MRI safety 
screening form, which is reviewed by study personnel, as well as the MRI technician. Participants are prompted 
at two points to remove all metallic objects, soon after they arrive at the MRI center. Participants are given 
instructions to empty their pockets, remove jewelry, watches, wallets, and they are shown a storage box where 
belongings can be safely stored. Immediately before entering the scanner room, they are prompted again to 
ensure that they have removed any items that might interfere with the scan or interact with the magnetic field. 
 
To minimize risks of dizziness or light-headedness, participants are carefully eased out of the scanner, and a 
technician guides the participant as they arise from the scanner bed, instructing them to rise slowly, ensuring 
that they have adequate balance. 
 
Participants are informed that pregnancy is a contraindication to receiving a research MRI scan. At the initial 
phone screening, female participants are asked about pregnancy or the possibility of pregnancy. When the 
participant is consented for the study, language in the informed consent document mentions this exclusion, 
again. All women of child bearing age will be given a urine pregnancy test at the screening visit (Visit 1) and 
beginning of Visit 3 prior to drug administration. Women with a positive pregnancy test will not be permitted to 
continue in the study.  
 
If a woman is found to be pregnant, the study coordinator will assess the impact of this surprise finding upon the 
participant. If the participant is particularly distressed, the PI may be notified and will meet with the participant to 
counsel her about the surprise of this unexpected, stressful news. 
  
Incidental findings arising from assessment: Incidental findings discovered during a research scan have the 
potential to raise significant anxiety in participants, while the nature of a research scan seriously limits the 
usefulness of the scan for resolving an incidental finding. At the first level, it is critical to make all participants 
aware of this risk. The following language will be used to warn participants during the informed consent process: 
 
“There is the potential that a magnetic resonance image may reveal an abnormality that is already in your body, 
such as a cyst or tumor. Many such abnormalities are not clinically significant, but you may need or want to 
investigate them further. Such a finding might require additional studies, and maybe even treatment, which would 
not be paid for by the investigators, the sponsor, or Wayne State University.” 
 
Another important consideration is to make participants aware that they are receiving a research scan, which 
cannot be used to assess the clinical significance of any finding. The informed consent document will contain 
language stating the following:  
 


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"The types of scans we will use are not very sensitive to many abnormalities. The scanning procedures used for 
this study cannot be used make medical diagnoses from the scan. That is, even if there is an abnormality in your 
body, it is likely that it would not be discovered by the people who inspect the images. Therefore, it is likely that 
any abnormality that you may currently have will not be revealed by the images obtained in this experiment. If 
you have any current health concerns, you should consult your doctor." 
 
Standard operating procedure at Wayne State University’s imaging center does not entail reading of research 
MRI scans by neuroradiologists. Nevertheless, the experienced technicians and investigators collecting research 
data do encounter anomalous incidental findings, such as the presence of a large cyst or tumor, and may consult 
with a radiologist to determine if follow-up should be recommended to the participant. The following protocol is 
in place to handle these events.  
 
Discovery of a finding: Incidental findings that arise during assessment, such as an abnormal finding in the MRI, 
will be brought to the immediate attention of the PI.  
 
Gathering additional information: The PI will review the finding, and seek consultation as appropriate.  
 
Informing the participant: If the PI is available while the participant is being scanned, and can assess the finding 
and decide about informing the participant, this will be done immediately. If the PI is not available for a face-to-
face meeting with the participant, study staff are instructed to complete as much of the protocol as is reasonable, 
without revealing the existence of an anomaly. The intention here is to control the circumstances by which the 
participant is informed of the anomaly, making sure that the PI is the person who talks to the participant, can 
answer questions and gauge the emotional reaction of the participant to the news. The participant will be 
informed by the PI, personally, either through a phone call or a face-to-face meeting. While a face-to-face 
meeting is preferred, this may not be immediately convenient for the participant, and the PI must weigh the 
relative benefits of the more personal setting versus anxiety engendered by anticipating a meeting to discuss 
something the participant did not expect to hear. 
 
Informing the participant’s health care provider: If follow-up is recommended, the PI will contact the participant. 
The decision as to whether to proceed with further examination and/or treatment lies solely with the participant 
and his/her primary care physician. The PI nor study staff will contact the participant’s primary care provider 
about the incidental finding. 
 
3. Potential Benefit of the Proposed Research to Human Participants and Others 
 
There will be no direct benefit to participants for participation in this study, other than they will be compensated 
for their time for participation in this study. There will be no costs to participants associated with participation in 
this study other than transient discomfort.  
 
4. Importance of the Knowledge to be Gained 
 
This R61 study will provide the most directly translational and critical test of THC effects in PTSD, advancing our 
understanding of the neurobiology of extinction learning, and potentially hastening the development of novel 
pharmacological modulators of the cannabinoid system to maximize the efficacy of exposure therapy for PTSD. 
The risks involved in this study are minimal when compared to the benefits gained. 
 
5. Data and Safety Monitoring Plan 
 
Protocol deviations will be defined as noncompliance with the research protocol that does not increase risk or 
decrease benefit and/or affect the integrity of the data. Protocol deviations may result from the action of the 
participant, research staff, or MR Facility and MR staff. All protocol deviations will be documented on a 
participant-specific Protocol Deviation Form and will explain any deviation from the approved protocol. Protocol 


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deviations will be reported to the IRB and NIMH PO by the PI with the continuing review and annual progress 
report, respectively. 
 
Adverse Events (AEs) are defined as any untoward or unfavorable medical occurrence in a human participant, 
including any abnormal sign (for example, abnormal MRI finding), symptom, or disease, temporally associated 
with the participant’s participation in the research, whether or not considered related to the participant’s 
participation in the research. Study personnel will ask each participant about the presence/absence of adverse 
events (AEs) at every study visit and document AE presence/absence. AEs will be documented in a participant-
specific AE log, which will include documentation of the following information: a) grading the AE as mild, 
moderate, or severe; b) determining how likely the AE is related to the participant’s participation in the study 
procedures; c) action taken regarding study participation; d) outcome of the AE; e) whether the AE was expected 
or unexpected (not listed as a potential side effect/risk in the protocol); and f) whether the AE is determined to 
be a serious adverse event (SAE). 
 
A serious adverse event (SAE) is any severe adverse experience occurring during the study that: (a) results in 
death, (b) is life-threatening (e.g., suicidality, homicidality), (c) results in hospitalization or prolongation of existing 
hospitalization, (d) results in persistent or significant disability, (e) is a congenital anomaly or birth defect, or (f) 
any other AE that, based on appropriate medical judgment, may jeopardize the subject’s health and may require 
medical or surgical intervention to prevent one of the other outcomes listed in this definition. Moderate AEs are 
defined as any non-serious event which causes discomfort and requires treatment, but does not pose any 
significant or permanent risk of harm to the participant or require in-patient hospitalization, including social or 
psychological trauma causing moderate or temporary distress, significant embarrassment, stigmatization of 
individual or community/ group, disruption of familial/social relationships or nontrivial emotional distress. 
Moderate AEs will include evaluation in the emergency room not leading to hospitalization. Mild is defined as 
any non-serious event of less than moderate severity. All SAEs and unexpected AEs will be reported to the PI 
or Co-Is Kilgore or Tancer as soon as possible within 24 hours of the study staff becoming aware of the S/AE. 
The PI or Co-I’s Tancer or Kilgore will determine whether participation in the study should be altered or 
terminated for the safety of the participant. 
 
All unexpected problems, defined as any incident, experience, or outcome that is unexpected, related or 
possibly related to participation in the research, and suggest that the research places participants are greater 
risk of harm than was previously known or recognized will be reported by the PI to the IRB and NIMH PO 
as soon as possible, but within 5 business days of the PI becoming aware of the AE. For all AEs and SAEs that 
are deemed expected and/or unrelated to the study, a summary will be submitted by the PI to the NIMH PO with 
the annual progress report.  
 
Documentation of protocol deviations will begin at Visit 1 and documentation of AEs will begin once a participant 
begins Visit 3 and will be collected/documented until the participant completes the study procedures (at the end 
of Visit 5) or is withdraw from the study (by self or my research staff). 
 
Weekly meetings of the research staff of this study will be conducted that will include review of accrual, 
consenting procedures, protocol adherence, AEs, and quality control of all data obtained from the study in the 
previous weeks. Minutes of these meetings will be recorded, signed by the PI, and archived in a Regulatory 
Folder on the lab server. In addition, to participant-specific protocol deviation forms, protocol deviation will also 
be documented in a study-wide deviations log to facilitate monitoring and reporting to regulatory authorities. 
Similarly, AEs will be also documented in a study-wide AE log, which will be used to facilitate safety monitoring 
and identify AE trends across subjects, as well as overall AE reporting to the IRB and NIMH.  
 
We will conduct a preliminary analysis during the early stages of data collection (once 10% of the THC group 
has completed the study) to assess the efficacy and safety of the 5mg and 10mg doses and submit an 
amendment to adjust the dosing as needed (e.g. if 10mg shows significant improvement over 5mg, a further 


Protocol Title: Effects of THC on Retention of Memory for Fear Extinction Learning In PTSD: R61 Study 
 
Principal Investigator: Christine Rabinak, PhD 
 
IRB # 015017MP4F 
 
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increase in dosing [15mg] would be worthwhile). Our efficacy and safety metrics are based on the following 
criteria:  
1) a. At least a medium effect size (Cohen’s d ≥ 0.05) between THC and PBO conditions in BOLD responses 
in a priori ROIs (vmPFC and/or HPC) and/or peripheral measures (SCR, US expectancy, SUDS) during recall 
of extinction learning; or 
    b. Relationship between change in BOLD responses in a priori ROIs (vmPFC and/or HPC) and/or change 
in peripheral measures (SCR, US expectancy, SUDS) during recall of extinction learning in THC (vs. PBO) is 
of at least a medium effect size (r ≥ 0.30). 
2) There will be no adverse events of more than mild severity that are rated as possibly, probably, or definitely 
related to acute administration of THC (more than PBO) in PTSD participants. 
 
We will apply O’Brien-Fleming179  type monitoring bounds as guidelines for the decisions regarding continuation 
or early termination of the trial. In addition to efficacy comparisons, frequency of AEs along with formal statistical 
comparisons of the frequency of AEs will be performed. 
 
Reporting responsibility 
The PI will have ultimate responsibility for event reporting. Monitoring will occur by the research team, who will 
then bring all AEs to the attention of the PI. Co-Is Kilgore or Tancer will be consulted for evaluation and gradation 
of AEs. The PI and the study manager/coordinator will be responsible for overseeing data integrity, safety 
monitoring, and reporting of adverse events. 
 
Training in Fair, Responsible, and Ethical Conduct of Research 
The PI and the research team have undergone training in fair and ethical conduct of research in general and on 
human participants. The PI and the research team have taken HIPAA training mandated by WSU. An additional 
consent form consistent with the HIPAA 2003 rules will be used to educate the research participants and obtain 
informed consent regarding safeguards for the privacy and security of health information. 
 
6. ClinicalTrails.gov Requirements 
 
This project includes an applicable clinical trial, which will require registration in ClinicalTrials.gov. The 
responsible party is the principal investigator of this project: Christine Rabinak, Ph.D. 
 
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Protocol Title: Effects of THC on Retention of Memory for Fear Extinction Learning In PTSD: R61 Study 
 
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