Clinical trial NCT03732248
Conditions: Alcohol Use Disorder Alcohol Dependence
Sponsor: Medical University of South Carolina
Start date: 2018-07-12; Completion date: 2020-01-20
Enrollment: 21 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to examine the effects of rapamycin (sirolimus) versus a placebo, an inactive substance, on responses to alcohol cues in individuals with alcohol use disorder. Rapamycin (sirolimus) is a FDA-approved antibiotic and immunosuppressive drug that is currently used to (a) prevent organ transplant recipients from rejecting their transplants (b) treat cardiovascular diseases, and (c) treat some forms of cancer. Rapamycin (sirolimus) is not FDA-approved to treat alcohol use disorder. The use of rapamycin (sirolimus) in this study is investigational, meaning that the study medication is not a proven treatment for alcohol use disorder. The study will examine the medication's use as a potential treatment for alcohol use disorder, as well as how safe and tolerable it is to take.

Detailed description:

Arms: arm 1: Rapamycin (sirolimus) is administered in three 5mg oral capsules. This administration happens once during the first visit. arm 2: Placebo is administered in three 5mg oral capsules. This administration happens once during the first visit.
Interventions: intervention 1: Rapamycin intervention 2: Placebo
Intervention descriptions: intervention 1: Immunosuppressive drug intervention 2: Inert drug

Protocol documents:
Prot_SAP_000.pdf: 
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Cover Page 
 
 
Study Short Title:  Altering memories that increase risk of relapse in alcohol use disorders  
(Pro00073523 ) 
 
   NCT03732248 
 
 4/29/2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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A. Statement of Problem/Background: 
The role of basic associative learning processes in addiction has been well established in both theory and 
research1-8. In alcohol use disorders (AUD), numerous pairings between alcohol-related cues (e.g., sight and 
smell of preferred beverage) and the reinforcing effects of alcohol can result in cues acquiring the ability to elicit 
a range of conditioned responses, most importantly craving and physiological reactivity/arousal. Since craving 
has been shown to be powerfully associated with relapse9-14, it is clear that craving remains a major obstacle to 
successful abstinence. While some current pharmacotherapies for AUDs have craving dampening properties15, 
it appears that individual differences greatly influence their efficacy16-18. Thus, the treatment of AUDs could be 
significantly advanced by increasing medication alternatives to address this important obstacle to abstinence. 
To this end, the medication to be tested in this pilot study specifically targets the memory processes that support 
cue-elicited craving.      
New learning is said to become stable in memory via the process of consolidation19-23. Reconsolidation refers 
to a process in which retrieval of consolidated memories begets a period of instability during which the memories 
can either be strengthened or otherwise altered and then are restabilized in long-term storage24-30. Generally, 
reconsolidation begins with memory retrieval, which is initiated by the presentation of cues that elicit target 
memories. There is a large body of basic neuroscience research27,31,32 demonstrating that reconsolidation of 
memories for both appetitively- and aversively-motivated learning can be pharmacologically disrupted, leading 
to a decrement in, or near eradication of, behavior supported by the original learning. By contrast, a small body 
of human fear conditioning studies, using the -adrenergic antagonist propranolol as the disrupting agent, has 
yielded findings that parallel those of the animal literature33-37. Translational studies targeting clinical anxiety and 
addictive disorders are also few in number and have focused almost exclusively on propranolol as a disruptive 
agent. In the case of anxiety disorders, three published reports have yielded suggestive evidence of attenuated 
trauma-related memory in PTSD, as indicated by decreased emotional responsiveness and PTSD 
symptomatology38-40. Our research group was the first to study propranolol’s effects on memories for important 
addiction related-learning. In that study of cocaine dependent individuals, we found a single administration of 
propranolol following memory retrieval (via cocaine cue presentation) resulted in attenuated cocaine craving and 
physiological reactivity during a test performed the following day41. Recently, a study42 involving nicotine 
dependent smokers failed to find any effect of propranolol on smoking cue-elicited reconsolidation (i.e., no effect 
on physiological and emotional reactivity to smoking cues presented in a test the following day). These 
contrasting findings tentatively suggest that a single disrupting agent may not have uniform effects across all 
addictive disorders and that reconsolidation disruption in substance users might be more profitably pursued with 
a pharmacological agent other than propranolol.   
Identification of an alternative disrupting agent can be guided by the existing basic neuroscience literature. 
Specifically, one prototypical agent that has been used in animal studies to demonstrate disruption of 
reconsolidation (DoR) is the protein synthesis inhibitor, anisomycin26,43-45. The robust DoR effects observed 
with anisomycin have not been replicated in humans because of concerns about toxicity46. However, there are 
three emerging lines of evidence suggesting that the FDA-approved, protein synthesis inhibitor rapamycin 
(sirolimus) may be as effective a disrupting agent as anisomycin. First, animal studies employing fear 
conditioning procedures have reported that either systemic or intra-amygdalar injection of rapamycin can 
substantially disrupt reconsolidation of contextual and discrete cue fear memory47-49. Second, it has been shown 
that systemic rapamycin administration following re-exposure to a drug-paired environment results in lasting (14 
days) decrements in morphine-, cocaine- and alcohol-reinforced place preferences, which could not be 
reinstated with priming drug injections50. Additionally, a recent Nature Neuroscience report showed that either 
systemic or intra-amygdalar administration of rapamycin after retrieval of alcohol-related memories substantially 
impaired relapse to alcohol self-administration for up to 14 days; these effects were similar to those observed 
when anisomycin served as the DoR agent51. Lastly, a clinical study employing Vietnam era and post-Vietnam 
era war veterans has provided the first evidence that a 15-mg dose of rapamycin vs. placebo administered 
contiguously with recall (retrieval) of war-related trauma resulted in reduced PTSD symptom score at a 1-month 
follow-up assessment, albeit only in the post-Vietnam era war veterans and not at 3-month follow-up52. 
Importantly, the authors of the study reported that no adverse medical outcomes or side-effects occurred during 
the course of the study. Collectively, these studies indicate that systemic rapamycin (sirolimus) (i) can effectively 
disrupt memories for both fear-based and a broad range of drug-reinforced learning and that this effect may be 
long lasting and comparable to anisomycin-induced DoR, and (ii) may be able to attenuate clinically important 
memories in the absence of side-effects.  
While rapamycin’s exact mechanism of action is unknown, it is likely that it achieves DoR by inhibiting the 
mammalian target of rapamycin (mTOR) kinase, which regulates phosphorylation of a large number of 
intracellular targets responsible for protein synthesis and translation53-57. Since rapamycin is a safe medication 
with minimal side effects, there are no obstacles to initiating research with human participants. Accordingly, the 


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proposed research will evaluate the novel hypothesis that the strategic administration of rapamycin (sirolimus) 
can disrupt reconsolidation of memories for cue-elicited craving in AUD drinkers. 
B. Primary Hypotheses to be Tested: 
Primary aim and hypothesis: 
Aim: Preliminarily evaluate (a) the safety and tolerability of a single 15 mg dose of rapamycin (sirolimus), and 
(b) the effects of post-retrieval rapamycin vs. placebo on craving and cue reactivity assessed 1 day and 10 
days following a medicated Retrieval session. 
Hypothesis: Side effects/adverse events will be low and indistinguishable among the rapamycin vs. placebo 
groups. Compared to placebo treated AUD individuals, rapamycin-treated AUD individuals will evidence less 
craving, emotion/arousal and physiological reactivity to alcohol cues presented during the (a) Test session 
(24-hr. post) and (b) Follow-up session (10 days post). 
Secondary aim and hypothesis: 
Aim: Evaluate the effects of post-retrieval rapamycin vs. placebo on drinking behavior occurring during the 
10-day follow-up period. 
Hypothesis: Compared to placebo-treated controls, rapamycin-treated AUD individuals may evidence 
changes in drinking behavior during follow-up (approximately 9 days) as indicated on multiple measures 
including total number of standard drinks consumed over the 10-day follow-up period, mean number of 
standard drinks consumed per drinking day, % days drinking, time to first drink. 
C. Research Plan: 
i. Overview:  
The proposed study will employ treatment-seeking AUD individuals who will be randomly assigned to receive 
either 15 mg of rapamycin (sirolimus) or placebo (group n’s=9) immediately after the first of two alcohol cue 
exposure sessions scheduled to occur on consecutive days. The first session will serve as a Retrieval session 
during which alcohol (e.g., sight, smell and handling of preferred alcoholic beverage) cue exposure will elicit 
retrieval and reconsolidation of alcohol-related memories; the second session will be a Test session to examine 
the potential modulatory role of rapamycin on the reconsolidation of memories putatively elicited during the 
retrieval session. Participants will be required to refrain from drinking the day before their first laboratory (i.e., 
Retrieval) session and will remain abstinent from drinking until the completion of the second laboratory (i.e., Test) 
session. It is posited that changes in reactivity during the test session will reflect medication effects on memory 
reconsolidation that occurred following cue exposure in the Retrieval session. Subjective responses (i.e., 
craving) and physiological (heart rate & skin conductance) reactivity will be obtained before, during and after cue 
presentations in both sessions. The durability of any observed treatment effects will be assessed in a Follow-
up session performed 10 days following completion of the initial Test session. Treatment effects on self-report 
measures of drinking behavior during the 10 days preceding the Follow-up session will also be assessed.                    
ii. Participants, Sample Size and Recruitment:  
A total of 18 treatment seeking AUD men and women (9 per group), aged 18 or older, will be randomized 
into two groups. Participants must meet DSM-V criteria for AUD, drink  30 standard drinks per week, be willing 
to make an abstinence attempt, and comply with reinforced abstinence requirements for the three laboratory 
sessions described below. Participants must (i) not have another substance use disorder (other than nicotine), 
(ii) willing to use appropriate birth control methods (females) during study participation, (iii) remain abstinent from 
alcohol and all non-prescription drugs for a full day prior to medication administration and testing sessions, (iv) 
not be undergoing other medication treatment for AUD (e.g., naltrexone), and (v) not be taking medications that 
may interact with the study medication or alter responding on any study measure. 
Sample Size. This pilot study is designed to yield an estimate of variance by calculating a 95% confidence 
interval for the pilot-derived squared sample standard deviation as well as estimates of mean responses and 
their differences. These estimates will be used to determine the necessary sample size needed to conduct a fully 
powered follow-up study (NIH R mechanism such as R21, R34, RO1). 
Recruitment. Participants will be primarily recruited using the local online media (e.g., Craigslist), a 
recruitment strategy that has been very successful in our previous and ongoing studies. We will also recruit from 
the Medical University of South Carolina’s (MUSC) Center for Drug and Alcohol Programs (CDAP).  Additionally, 
we will be adding television advertisements as a form of recruitment.  
iii. Screening, Consent, Baseline Cue Reactivity and General/Abstinence Assessment: 
Screening, Consent, Baseline Cue Reactivity. A brief phone screening will preliminarily assess participant 
suitability via inclusion/exclusion criteria. Qualifying individuals will be scheduled for an in-person assessment 
session; they will be requested to remain abstinent from alcohol and other drug use beginning the day before 
this session. Upon arrival at MUSC, participants will undergo an IRB-approved informed consent procedure. 
After consent, all female participants will undergo a pregnancy test to confirm a negative test result.  Any female 


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participant with a positive pregnancy test result will be immediately excluded from the study.  Then, participants 
will undergo a baseline cue reactivity (BCR) assessment. The purpose of this assessment is to ensure that 
participants exhibit expected levels of responsive to alcohol cues (a necessary precondition for inclusion in this 
study). During the BCR assessment, participants will be shown two sets of three neutral picture cues on a video 
monitor (e.g. picture of a residential lawn, a telephone), followed by two sets of three alcohol picture cues related 
to their preferred alcoholic beverage (beer, liquor, or wine), and then finally two more sets of three neutral picture 
cues. Participants will score each set of cues on a scale from 0-100 indicating craving for alcohol. After each set 
of picture cues, participants will also be asked to provide an estimate of their desire for their favorite alcoholic 
beverage on a scale of 0-100. Inclusion in the study will occur if participants provide a mean craving rating of at 
least 30 during the alcohol picture cues, which must also be higher than the mean craving rating in response to 
the neutral picture cues. Those who do not qualify for inclusion will (1) receive $25 compensation for their time, 
(2) be provided the opportunity to receive treatment referral, and (3) be discontinued from further participation.  
In the event that a participant experiences elevated craving at the end of the baseline session (i.e., report a 
post-session craving score ≥ 20% above baseline), they will be asked to remain in the SCTR Research Nexus 
until their craving subsides. A member of the research staff will be available to discuss management of 
craving/urges. This procedure will be used in all subsequent sessions as well.  
 General/Abstinence Assessment: Participants whose craving responses qualify them for inclusion in the 
study will undergo a general assessment of alcohol and other substance use and general psychiatric functioning. 
They will be administered the Mini-International Neuropsychiatric Interview for DSM-V (Version 7.0.0) or MINI58-
62, which is a measure of psychiatric functioning. The Timeline Follow-Back (TLFB; a calendar-based instrument 
with specific probes to obtain detailed information about substance use)63 will be used to assess alcohol and 
other substance use during the three month period preceding study involvement. Participants will also undergo 
a general health screening.  Then, MUSC SCTR Research nexus nursing staff will provide additional services 
including vitals, an EKG, and a blood sample.  With the blood sample, a complete metabolic panel and a 
complete blood count (without differential) will be performed to ensure participants are medically fit to participate 
in the study.  
Participants will be required to fast (not eat any solid food; water consumption is acceptable and encouraged) 
two hours prior to the first study visit because food may influence pharmacokinetics of rapamycin. Participants 
will also be required to remain abstinent from drinking beginning the day preceding the initial in-person 
assessment session and the day preceding the (first) Retrieval cue exposure session and remain abstinent 
through the completion of the (second) Test session. Participants failing to meet the breathalyzer criterion (0.0) 
at the Assessment or Retrieval session will be allowed to reschedule their participation one time; however, if a 
participant fails the breathalyzer assessment on the second day, they will be dropped from the study. Lastly, 
there will be no abstinence requirement for the 10-day period between the Test and Follow-up sessions; 
however, participants will be required to abstain from drinking starting the day before the Follow-up cue 
exposure session. The Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised (CIWA-Ar) will be 
used to assess alcohol withdrawal at each study visit. Lastly, other drug use will be assessed via urine drug 
screen (UDS). A positive test will result in rescheduling/termination as described above for drinking (with the 
exception of cannabis/marijuana). 
iv. Laboratory Session Measures: (Our research team has extensive experience using all of the following 
measures). 
Self-Report Measures: The key measure that will be used to quickly and unobtrusively assess alcohol craving 
is: single-item verbal report of subjective craving to drink. Prior to any stimulus presentation, participants will be 
trained to provide a verbal report of a numeric value between 0 (none) and 100 (extreme) that best represents 
their current level of craving (“My craving/urge to drink right now is”). In addition, particpants will fill out two forms.  
The Mood Form64 (9-items) which will be used to assess immediate assessment of current negative and positive 
emotional states.  And a cue exposure rating form (CDMS) which will be used to asses various reactions to cue 
exposure. 
Physiological Measures: Heart rate (HR) will be collected via two electrodes along the bottom of the 
participant’s ribcage, rather than on the participant’s forearm, to minimize movement artifacts. Skin conductance 
(SC) will be recorded using Ag/AgCl electrodes attached to the second phalanx of the first and third fingers of 
the non-dominant hand. HR and SC signals will be amplified using ECG 100c and GSR 100c Biopac Modules 
and interfaced with the Biopac MP100 data acquisition system. 
v. Laboratory Session Stimuli: 
Alcohol Cues. Because we have been successful eliciting alcohol craving in our previous work with AUD 
individuals65,66 we will adopt a similar strategy in the proposed study. In particular, the alcohol cues will consist 
of the sight and smell of the participant’s preferred alcoholic beverage. The beverage will be placed close to the 
participant’s nose with the bottle of alcohol placed in their line of sight. Participants will be asked to smell and 


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visually inspect the beverage for one minute, after which they will be able to handle and smell the drink for an 
additional minute. This alcohol cue exposure sequence will occur in each of the three laboratory sessions (i.e., 
Retrieval, Test and Follow-up).  
vi. Randomization, Rapamycin Dosing, Preparation and Administration: 
Randomization. Stratified block randomization will be used to assign participants to groups while balancing 
treatment assignment on gender. This method, when used with smaller block sizes, is appropriate for small study 
sample sizes67 and has been used in a number of previous and ongoing studies by our research group.  
Sirolimus (Rapamycin; Rapamune®) Dosage Rationale and Potential Side Effects. The decision to employ a 
15-mg dose of rapamycin (sirolimus) in the proposed study was based on the following rationale. First, as noted 
above, Suris et al, 2013 employed 15 mg of rapamycin to disrupt trauma-related memories in combat veterans. 
The study results suggested, in a subsample of non-Vietnam era veterans, that 15 mg of rapamycin vs. placebo 
administered in conjunction with trauma memory reactivation was associated with decreased PTSD 
symptomatology at a 1-month follow-up assessment. Importantly, they also documented that this dose was not 
associated with any adverse medical consequences or side effects.  
There is strong animal and clinical pharmacokinetic (PK) and pharmacodynamic (PD) data to demonstrate 
the proposed 15-mg dosing regimen will demonstrate clinically relevant outcomes. Results from a number of 
clinical PK studies demonstrate that sirolimus is rapidly absorbed after oral ingestion, with peak whole blood 
concentrations occurring 1.0 to 1.3 hours after administration68-70. Additionally, sirolimus adequately crosses the 
blood brain barrier, with an estimated blood to brain ratio of 1:371. In a clinical PK study in health males, an 8 
mg/m2 one-time oral dose produced a whole blood Cmax of 115.2 ng/mL at 1.0 hours after ingestion. This 
corresponds to an approximate peak brain concentration of 38.4 ng/mL60. Additionally, the organ transplant 
animal and clinical data strongly support the proposed dosing strategy. Studies conducted in rats using sirolimus 
to prevent organ rejection utilized dosing ranges between 0.5 to 50 mg/kg per day72. However, maximum 
pharmacodynamic activity with sirolimus monotherapy in rat kidney and heart transplant models was 
demonstrated with a dose of 8 mg/kg intravenously. This dose correlated with a mean AUC0-24h of 27012 
g/L*h73. By using the trapezoidal rule, the AUC0- in rats for an 8 mg/kg dose would approximate 350 g/L*h. 
This dose of rapamycin (sirolimus) also demonstrated maximal lymphocyte protein kinase inhibition at 2 hours 
post-dose (i.e., maximal protein synthesis inhibition), with return of full function occurring at 12 to 24 hours post-
dose. Therefore, based on the above noted literature, a one-time 15-mg dose should produce substantial protein 
kinase inhibition in the brain within 1-1.3 hours of administration, while also being well-tolerated, with mild-
transient side effects. The current clinical use of sirolimus in organ transplantation also supports using the 15-
mg oral dose in this proposed study, as it is commonly given as a loading dose of 15 mg orally during the 
perioperative period73. 
The recently-updated labeling for sirolimus (dated 1/2018) includes warnings regarding health consequences 
associated with sirolimus use. These warnings include increased susceptibility to infection and possible 
development of lymphoma due to the medication’s immunosuppressive properties. The warnings that are 
potentially applicable to this protocol also include hypersensitivity reactions, angioedema, impaired or delayed 
wound healing, increased risk of opportunistic infections, and embryo-fetal toxicity. 
However, many of these health consequences were observed with regular sirolimus use rather than a one-
time dose, as will be the case in this study. Participants who are not willing to use an effective form of birth control 
during the course of the study and for twelve weeks after will be excluded from participating given the risk of 
embryo-fetal toxicity. Female participants will be pregnancy tested twice (including once on the same day as 
medication administration) and immediately excluded if the result is positive in order to avoid the risk of embryo-
fetal toxicity. Participants will receive a maximum of 15mg of sirolimus under medically supervised conditions.  
Rapamycin Preparation & Administration. Rapamycin (15-mg sirolimus) and placebo will be compounded, 
packaged and dispensed by the MUSC Investigational Drug Service (IDS). The IDS will work with the study 
Statistician (Baker) to oversee the randomization procedures for the study. Immediately after the cue exposure 
in the Retrieval session, 15 mg of rapamycin (sirolimus) or a matching placebo will be administered.  
vii. Laboratory Session Procedures: 
Session Preparation. Abstinence will be assessed (see above iii, Abstinence Assessment) at each laboratory 
session visit. If abstinence is confirmed, participants will be escorted to MUSC’s CTRC waiting room where they 
will remain until the laboratory is ready for cue exposure administration (approximately noon). Next, they will be 
escorted to the laboratory where they will sit quietly/read in order to acclimate to the environment until the cue 
exposure procedures begin. Following the acclimation period, HR and SC sensors will be placed, sound-
attenuating headphones will be fitted, and baseline assessments of subjective and physiological measures will 
be collected (see general procedures table below).    


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Retrieval session (1) procedure. The primary objective of this session is to elicit the retrieval of alcohol-
related memories. To achieve this objective, participants will be exposed to the alcohol cues as described above 
(sight, smell and handling of alcohol cues). A craving rating will be obtained midway through the alcohol cue 
exposure (i.e., the inquiry will be made by research staff via headphones). Immediately following the alcohol cue 
presentation, participants will provide the craving rating and complete the other study measures. Participants will 
receive medication immediately after the measures have been obtained. Collection of all study measures will 
occur 
every 
10-min 
after 
medication 
administration 
with the final occasion at 50-
min 
post-medication 
(see 
general procedures table to 
the left). Although HR and SC 
will be collected continuously 
during 
the 
alcohol 
cue 
exposure, only single time point measures will be collected thereafter. Possible medication side effects will be 
assessed using the Monitoring of Side Effects Scale (MOSES) and will be managed by a study physician (Gray) 
if necessary. Participants will be asked to complete a brief questionnaire that asks whether or not they thought 
they received study medication or placebo (blind effectiveness assessment). Lastly, the participant will be 
reminded of the drinking abstinence requirement and instructed not to drink or use other substances (abstinence 
serves to mitigate the confounding reconditioning effects of drinking on the reconsolidation processes initiated 
in this session). The participants will remain at the CTRC for a total of three hours after medication administration 
in order to permit continuous assessment of potential medication side-effects.  
Test session (2) procedure. Test session 2 will be identical to session (1) with the following exceptions. First, 
no medication will be administered. Second, at the end of the session, participants will receive a drinking diary 
in which to record the occurrence of any drinking behavior over the 10-day follow-up period (abstinence is not 
required during the 10 days preceding Follow-up session). Finally, the experimenter will provide compensation 
and schedule the Follow-up cue reactivity session. 
Follow-up session (3) procedure. The Follow-up session will be identical to Test session (2) with the 
following exceptions. First, drinking diary data will be collected (research staff will perform a TLFB assessment 
of drinking behavior if participants do not present with their dairy). Second, debriefing will take place to address 
questions/concerns. Recommendations for additional treatment will be provided if desired.  
viii. Participant Compensation:  
Participants will be compensated as follows: Screening and assessment = $50.00; Retrieval, Test and 
Follow-up sessions = $50.00. Maximum compensation for participation is $200.00.  
ix. Risks to Subjects:  
1. Study medication: The most common side effects of rapamycin (occurring in 30% or more of patients using 
rapamycin to prevent rejection of kidney transplants) include swelling in the arms or legs, elevated triglyceride 
level, high blood pressure, high cholesterol, increased creatinine level, abdominal pain, diarrhea, headache, 
fever, urinary tract infection, anemia, nausea, joint pain, pain, and low platelet count. Other side effects, such 
as stomatitis (swelling of and sores in the mouth), nausea, viral infection of the nose and throat, acne, chest 
pain, upper respiratory tract infection, headache, dizziness, and pain in the muscles, were reported in 20% 
or more of patients taking rapamycin for a lung disease known as lymphangioleiomyomatosis. Sirolimus use 
has been associated with rare serious side effects, including increased risk of infection(s), lymphoma 
(lymphatic cancer), allergic reactions, angioedema (swelling of the area under the skin), delayed wound 
healing, and embryo-fetal toxicity (as reported in studies with animals). The rare serious side effects of this 
medication were observed in studies where participants were taking rapamycin (sirolimus) daily for 2-3 years. 
In this study, the medication will be administered once under medically supervised conditions. Female 
participants will be tested for pregnancy twice, including once on the day of medication administration, to 
minimize the potential for harm to an unborn baby. 
 
2. Interviews: The interviews that the participant will undergo during the course of the study involve no specific 
risks or discomforts beyond those of a standard clinical interview situation, such as feeling upset at the review 
of psychiatric status, boredom, or fatigue. If a question makes a participant uncomfortable the participant 
may refuse to answer it without fear of penalty (i.e. loss of compensation or study dismissal). 
3. Experimental treatment: Participants will not receive any FDA-approved medications for the treatment of 
alcohol use disorder for the duration of their study participation (about 3-4 weeks).   
4. Placebo: If a participant is in a group that receives a placebo, the participant’s condition will go without active 
treatment for the duration of the study. (approximately 3-4 weeks)  


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5. Randomization: The experimental treatment participants receive may prove to be less effective or to have 
more side effects than other study treatment(s) or other available treatments.  
6. Pregnancy: We do not know if the study drug will affect mother’s milk or an unborn fetus. Therefore, breast-
feeding and pregnant women are not allowed to take part in the study. If a potential participant is pregnant 
or becomes pregnant, there may be risks to the embryo or fetus that are unknown at this time. Women who 
can become pregnant must take a pregnancy test before the start of the study. Women who are not currently 
pregnant but could become pregnant must continue to use an effective birth control method (such as a 
diaphragm, condoms with spermicide, surgical sterilization, oral contraceptives, an intra-uterine 
contraceptive device, or complete abstinence from sexual intercourse) beginning prior to the study and 
continuing until 12 weeks after receiving the study medication. Participants will be advised not father a child 
while on this study as the treatment may indirectly affect an unborn child. If a participant is sexually active 
and are at risk of causing a pregnancy, then the participant and his female partner(s) must use a method to 
avoid pregnancy that works well (such as a diaphragm, condoms with spermicide, surgical sterilization, oral 
contraceptive, or an intra-uterine contraceptive device) or the participant must not have sex.  Unless a 
participant cannot have children because of surgery or other medical reasons, the participant must be using 
an effective form of birth control before starting the study.  The participant must also agree to continue to use 
an effective form of birth control for 12 weeks after taking the study drug. 
7. Exposure to alcohol cues: Exposure to cues may produce some craving for alcohol or other discomfort. 
However, this discomfort is usually brief and the participant will be in the safety of an alcohol-free laboratory 
environment. Although previous studies do not show increased risk of alcohol craving or relapse after cue 
exposure, this possibility cannot be completely ruled out. 
8. Alcohol withdrawal: During the study, the participant will be asked to abstain from alcohol for three days, 
beginning the day before the first visit until the end of the second visit. You will also be asked to abstain the 
day before the final visit.  This has the potential to cause symptoms of withdrawal such as tremors, sweats, 
and anxiety.  
9. Blood drawing: The risks of drawing blood include temporary discomfort from the needle stick, bruising, and 
possible infection. Fainting could occur. 
10. Electrocardiogram (ECG): The ECG procedure may cause some mild discomfort during the placement and 
removal of the leads to and from the skin.  You may also experience some local irritation, redness, or burning 
in the areas where the leads are attached. 
11. Confidentiality: There is a risk of loss of confidentiality of personal information as a result of participation in 
this study.  Please refer to confidentiality section for detailed description of confidentiality protections for all 
participants.  
12. Unknown Risks: The experimental treatments may have unknown side effects. The researchers will let 
participants know if they learn anything that might make the participants change their minds about 
participating in the study. 
x. Data Analysis: 
Primary Hypothesis. The proportion of participants experiencing any adverse events will be reported and 
compared across treatment conditions using a Chi-Squared test statistic and overall adverse event counts and 
severity will be compared between groups using a simple Poisson modeling process. In the case of cue-elicited 
craving, mixed effects models will be used to preliminarily evaluate the hypothesized group differences and 
variance across the Test session measurement (24-hr. acute effect) and again at the 10-day Follow-up 
(maintenance effect) laboratory session. Other self-report measures (e.g., affect ratings) and HR/SC measures 
will be analyzed in a similar manner. Additional functional forms of the response measures, such as Area Under 
the Curve (AUC) and/or maximum within-session decrement in craving may be assessed to understand how 
treatment differences may occur. Although not specifically powered, models will be developed to additionally 
assess the effects of potential covariates (e.g., age) on the single-item craving outcomes and possible effect 
modification (through interaction terms).  
Secondary Hypothesis.  Treatment group differences on various indices of drinking behavior (total number 
of standard drinks consumed over the 10-day follow-up period, mean number of standard drinks consumed per 
drinking day, % days drinking, time to first drink) will be assessed using general linear regression models. 
Continuous outcomes (% drinking days) will be analyzed using normal linear models while time to first drink will 
be assessed using time to event models for efficacy analysis (Log-rank, Cox PH Models). While only large group 
differences are likely to be statistically detectable, analysis of drinking behavior is consistent with the overarching 
‘proof-of-concept’ theme of this research and will provide efficacy estimates to inform a power-based sample 
size determination for a larger study. 


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xi. Timeline: 
Since we have ongoing studies with a variety of substance using populations, an active recruitment network 
and extensive experience using cue reactivity paradigms, we anticipate start up to occur in approximately 4-
months. During this period, research staff will be trained, the protocol will be IRB approved at MUSC, an IND 
application will be approved by the FDA, and laboratory procedures and database(s) will be established. 
We will actively recruit participants for 7 months and plan to allow one month for final data cleaning/reduction, 
analysis and report/manuscript preparation (albeit manuscript preparation will begin sooner). Submission of a 
proposal for a more extensive controlled trial if the results are promising will occur as soon as possible. At a 
recruitment rate of approximately 2-3 AUD participants per month, we should have no difficulty in completing the 
study in a one-year timeframe.  
D. Inclusion/Exclusion Criteria:   
 
i. Inclusion 
Participants must (i) be treatment-seekers who are willing to remain abstinent from alcohol and drugs of 
abuse during specified periods of their study participation, (ii) meet criteria for alcohol use disorder according to 
DSM-V criteria and drink at least 30 standard drinks per week, (iii) be able to provide informed consent and 
function at an intellectual level sufficient to allow accurate completion of all assessment instruments, (iv) use one 
of the following methods of birth control: oral contraceptives, barrier methods (diaphragm or condoms with 
spermicide or both), surgical sterilization, use of an intra-uterine contraceptive device, or complete abstinence 
from sexual intercourse, (v) live within a 50-mile radius of our research program and have reliable transportation, 
(vi) consent to remain abstinent from alcohol and all non-prescription drugs prior to medication administration 
and testing sessions, (vii) consent to fast for a two-hour period prior to medication administration, and (viii) 
consent to random assignment to the rapamycin vs. placebo conditions.  
          ii. Exclusion 
Participants will be excluded if they (i) are undergoing other alcohol cessation treatment (such as Antabuse 
or Naltrexone), as this may confound results in the present study and because of potential/unknown interactions 
with study medications, (ii) are pregnant, nursing, or of childbearing potential and not using birth control, (iii) have 
evidence of or a history of significant endocrine, cardiovascular, pulmonary, renal, or neurological disease, as 
these conditions may affect heart rate or skin conductance measurement, (iv) have significant liver impairment 
(as indicated by alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) values that are three 
times the upper limit of normal) as rapamycin (sirolimus) is hepatically metabolized, (v) have an existing infection 
or immune system disorder, as rapamycin has known immunosuppressive properties, (vi) have a history of or 
current psychotic disorder, severe major depression (i.e. active and profound psychomotor retardation, persistent 
and intense suicidal ideation) or bipolar affective disorder as these may compromise both data integrity and the 
participant's ability to safely complete the study, (vii) currently take anti-arrythmic agents, psychostimulants, or 
any other agents known to interfere with heart rate and skin conductance monitoring, (viii) have known or 
suspected hypersensitivity to macrolide compounds (such as rapamycin/sirolimus), (ix) currently take 
medications that could adversely interact with the study medication, including but not limited to significant 
inhibitors of CYP2D6 or CYP3A4 (voriconazole, fluconazole, itraconazole, erythromycin, clarithromycin, 
diltiazem, verapamil, etc.), or significant inducers of CYP3A4, such as anticonvulsants (carbamazepine, 
phenobarbital, phenytoin, etc.) and antibiotics (rifabutin, rifapentine, etc.), (x) have a history of thrombocytopenia, 
idiopathic thrombocytopenia purpura (ITP) or have a platelet count of less than 100,000 cells per mm3, (xi) have 
any unhealed wounds, including but not limited to oral ulcers, foot ulcers, or recent surgical or traumatic wounds, 
(xii) have any planned surgeries within the next month, including surgical dental procedures, or (xiii) have a 
history of complicated alcohol withdrawal symptoms (including, but not limited to, symptoms such as seizures, 
hallucinations, and high blood pressure).  
E. Significance of the Project and Relationship to ARC Research Goals:  
Significance. AUDs are arguably the second greatest (behind smoking) addiction-related public health 
problem74,75. Craving is a central feature of AUD and it remains one of the primary catalysts for relapse to misuse. 
Therefore, any incremental gains made in the treatment of alcohol craving and drinking behavior would translate 
into significant reductions in the public health burden posed by AUD. To this end, favorable outcomes from this 
and subsequent studies could lead to a new generation of treatment adjuncts that would be brief, easy to 
administer and cost effective. These interventions could become a complementary treatment paradigm, 
operating synergistically with the current generation of pharmacotherapies and/or cognitive behavioral treatment 
approaches to reduce cue-elicited craving in AUD. Furthermore, since learning/memory processes are a primary 
etiological variable in all addictions, it seems evident that reconsolidation-based interventions could be devised 
for many other vulnerable addicted populations (i.e., cocaine, opiates, marijuana, etc.). 
Relationship to ARC Research Goals: The central mission of the ARC is treatment development and the 
proposed pilot directly aligns with this mission in that it seeks to provide preliminary empirical support for a novel 


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pharmacotherapy that targets the memory processes that undergird AUDs. Another theme of the ARC is 
translational science, where cross fertilization between basic and clinical science serves to advance the 
treatment of AUDs. The proposed project derives from this perspective in that it is empirically and conceptually 
based on a robust basic neuroscience literature in memory reconsolidation. The ARC’s emphasis on 
multidisciplinary collaborative science is also evident in the proposed pilot. Specifically, this project would be the 
first campus-wide effort to bring together investigators from addiction sciences and transplant medicine to 
advance medications development in the area of alcohol-related addiction. Lastly, this pilot project is 
conceptually congruent with the ongoing clinical components of the ARC (Anton & Schacht and Hanlon & 
Prisciandaro) in that it targets novel treatment development of alcohol cue-elicited craving.   
 
 
F. Pathway to Extramural Funding: 
The first step in a pathway to extramural funding is a strong research team. Drs. Saladin (PI, Clinical 
Psychologist, Dept. of Health Sciences and Research), Taber (Co-I, PharmD., Department Surgery, Transplant 
Medicine) and Gray (Medical Monitor, Psychiatrist, Dept. of Psychiatry and Behavioral Sciences), together with 
statistician Nathaniel Baker (Co-I, Department of Public Health Sciences), have all the necessary research and 
clinical expertise/skills to safely, efficiently and successfully execute the proposed pilot study. Additionally, the 
extramural funding potential for this project is high because the central hypothesis is based on a highly 
reproducible neuroscience phenomenon (memory reconsolidation) that has endured more than four decades of 
intense empirical scrutiny28. Thus, the combination of the strong research team and a solid, empirically-based 
hypothesis provide the context for a successful scientific endeavor. Positive findings from this pilot could lead 
either to a developmental/exploratory study, R21/R34, or to a larger scale clinical trial, RO1 (depending on the 
magnitude of the pilot findings). 
 
 


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