Effects of Commonly Used Medications on Mood and Choice
Phase: PHASE1
Conditions: Healthy
Sponsor: Johns Hopkins University

Date: February 25, 2021 
Principal Investigator: Dustin Lee 
Application Number: IRB00165287 
 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 1 of 22 
 
  
 
 
 
 
Study Title: Effect of Commonly Used Medications on Mood and Choice 
 
NCT # 03652740 
 
February 25, 2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Date: February 25, 2021 
Principal Investigator: Dustin Lee 
Application Number: IRB00165287 
 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 2 of 22 
 
 
JHM IRB - eForm A – Protocol 
 
• Use the section headings to write the JHM IRB eForm A, inserting the appropriate material 
in each. If a section is not applicable, leave heading in and insert N/A. 
• When submitting JHM IRB eForm A (new or revised), enter the date submitted to the field at 
the top of JHM IRB eForm A. 
 
************************************************************************************** 
 
1. 
Abstract 
a. Provide no more than a one page research abstract briefly stating the problem, the research 
hypothesis, and the importance of the research. 
 
This study will examine caffeine reinforcement as a prospective predictor of positive subjective and 
behavioral choice effects of commonly used drugs. Caffeine is a widely consumed psychoactive drug with 
mild psychomotor stimulant effects that has served as a useful model system for understanding drug 
reinforcement. Earlier data from our laboratory demonstrated that caffeine choosers showed higher ratings 
of pleasant effects and lower ratings of unpleasant effects when administered d-amphetamine relative to 
nonchoosers. It remains unknown, however, whether this effect is specific to d-amphetamine, which shares 
a dopaminergic mechanism of action with caffeine, or whether it reflects a broader dispositional 
vulnerability to drug reinforcement. Thus, the proposed study will systematically replicate our previous 
study with d-amphetamine to determine whether individual differences in caffeine choice predicts increases 
in surrogate measures of reinforcing effects (e.g., ratings of liking, take again, monetary value) of 
methylphenidate and nicotine. Eligible participants (desired n = 36 completers) will complete the study in 
three phases. In Phase 1 (initial abstinence), abstinence from caffeine will be established one week prior to 
drug-administration in order to reduce the impact of withdrawal from caffeine on subsequent experimental 
phases. Other dietary restrictions will also be implemented in Phase 1 to reduce caffeine-related 
expectancy. During Phase 1, participants will report to the laboratory to review their food and beverage 
intake up to three times per week and will provide saliva samples to be analyzed for caffeine content (3 
sessions). During Phases 2 and 3, participants will be administered placebo or drug-containing capsules 
under double-blind conditions. To facilitate blindness to the study drugs being administered, caffeine, 
nicotine, and methylphenidate are disclosed to participants during consent among a longer list of potential 
drugs they may receive including other prescription and over-the-counter stimulant, sedative, and 
antihistamine medications. During Phase 2 (choice phase), participants will choose between caffeine (200 
mg/70 kg) and placebo across 10 choice sequences. Each choice sequence consists of two exposure 
sessions (i.e., one session each of caffeine or placebo, order counterbalanced) and one choice session (i.e., 
choice between caffeine or placebo) for a total of 30 sessions in Phase 2. Following the choice phase, 
participants will complete the dose-effect phase (Phase 3) to measure the subjective reinforcing effects of 
methylphenidate (10, 20, and 40 mg/70 kg) and nicotine (1, 2, 3 and 4 mg/70 kg) under double-blind 
conditions. Phase 3 will consist of 13 total sessions including one session per drug/dose condition plus 
placebo (8 sessions), a replication of the four nicotine doses (4 sessions), and a final multiple-choice 
reinforcement session (1 session). During the multiple-choice reinforcement session, we will reinforce a 
randomly selected choice (i.e., drug vs. money) made by the participant after previous sessions as a 
surrogate measure of drug reinforcement. The identification of behavioral and pharmacological markers of 
vulnerability to the effects of drugs of abuse is important in order to inform future substance use disorder 
prevention and regulatory efforts. 
 
 

Date: February 25, 2021 
Principal Investigator: Dustin Lee 
Application Number: IRB00165287 
 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 3 of 22 
 
2. 
Objectives (include all primary and secondary objectives) 
 
Primary objective: Determine whether caffeine choice prospectively predicts positive subjective response 
to methylphenidate and nicotine. 
 
Secondary objective: Characterize and compare caffeine choosers and nonchoosers on subject 
demographics (e.g., age, sex), drug use history, and personality factors that may co-vary with caffeine 
choice and subjective drug response. 
 
3. 
Background (briefly describe pre-clinical and clinical data, current experience with procedures, 
drug or device, and any other relevant information to justify the research) 
 
Despite the known reinforcing effects of nicotine (Duke et al., 2015) and stimulants such as amphetamine 
or methylphenidate (Rush et al., 2001), only a small number of individuals who try these substances 
develop problematic use (de Wit, 1998). Therefore, it is important to identify individuals who are 
vulnerable to the reinforcing effects of different drugs. One possible predictor of substance use 
vulnerability may be caffeine reinforcement. Our laboratory has conducted extensive research examining 
caffeine as a model system for understanding substance use phenomena including reinforcement, tolerance, 
withdrawal, and continued use in spite of substance-related problems (e.g., Evans & Griffiths, 1992; 
Griffiths & Woodson, 1988; Griffiths, Bigelow, & Liebson, 1989; Juliano & Griffiths, 2004; Meredith et 
al., 2013). Prior work in our laboratory using a repeated choice procedure, which we have used to study 
reinforcing effects of caffeine and nicotine (e.g., Griffiths & Woodson, 1988; Duke et al., 2015), has 
demonstrated that caffeine choice predicts positive subjective response to d-amphetamine (Sigmon & 
Griffiths, 2011). The proposed research tests the generality of our previous finding to drugs with more 
diverse pharmacological mechanisms, namely methylphenidate and nicotine. The data collected will 
determine whether caffeine reinforcement is a marker for a general vulnerability to the subjective positive 
effects of drugs of abuse, which may ultimately inform substance use disorder prevention efforts. 
 
In the present study, we hypothesize that individual differences in caffeine reinforcement may predict 
vulnerabilities to the reinforcing effects of other drugs of abuse. In support of this hypothesis, research 
from our laboratory demonstrated that caffeine reinforcement predicts individual differences in the 
subjective and reinforcing effects of d-amphetamine (Sigmon & Griffiths, 2011). Using a repeated choice 
procedure developed to distinguish between caffeine choosers and caffeine avoiders (Griffiths & Woodson, 
1988), we showed that caffeine choice prospectively predicts positive subjective response to d-
amphetamine (Sigmon & Griffiths, 2011). In that study, choosers and nonchoosers of caffeine were 
identified using 10 independent choice trials in which subjects, who were blind to the dose conditions, 
repeatedly chose between caffeine (200 mg/70 kg) and placebo. Choosers of caffeine subsequently showed 
higher ratings of pleasant subjective effects and lower ratings of unpleasant subjective effects after 
receiving d-amphetamine. These data suggest that caffeine choice may be a clinically useful predictor of 
vulnerability to d-amphetamine abuse.  
 
It is unknown, however, whether this effect is specific to d-amphetamine, which shares a dopaminergic 
mechanism of action with caffeine, or whether it reflects a broader dispositional vulnerability to drug 
reinforcement. Thus, in the present study, we propose to systematically replicate our previous study to 
determine whether individual differences in caffeine choice predict increases in surrogate measures of 
reinforcing effects (e.g., ratings of liking, take again, monetary value) of more pharmacologically diverse 
drugs: methylphenidate and nicotine. Methylphenidate is of interest because it is a widely used 
dopaminergic stimulant having significant neuropharmacological differences from d-amphetamine. 

Date: February 25, 2021 
Principal Investigator: Dustin Lee 
Application Number: IRB00165287 
 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 4 of 22 
 
Nicotine is of interest because it is important to identify potential markers of vulnerability to nicotine use 
(e.g., tobacco smoking), which remains the single leading preventable cause of death in the United States 
(DHHS, 2014). This project will also extend our work examining individual differences in nicotine 
reinforcement in never-smokers (Duke et al., 2015).  
 
We hypothesize that caffeine choosers will show more positive subjective response to methylphenidate and 
nicotine relative to nonchoosers. Data showing that caffeine choice predicts abuse liability of other 
commonly used drugs would suggest caffeine use may be an early marker of vulnerability to substance use 
disorders, which would have important implications for education and prevention. For example, caffeine 
preferers (e.g., heavy caffeine consumers) could be identified as a high risk group for liking the effects of 
nicotine or stimulant drugs and potentially targeted for nicotine or drug use prevention interventions.  
 
4. 
Study Procedures 
a. Study design, including the sequence and timing of study procedures   
(distinguish research procedures from those that are part of routine care). 
 
After screening for eligibility, this double-blind, placebo controlled study will be conducted over a 
period of approximately 14-17 weeks across three phases, including an initial abstinence phase (Phase 1), a 
choice phase (Phase 2), and a dose-effect phase (Phase 3). Our goal is to have n = 36 participants complete 
the study. 
Procedural Changes Due to COVID-19. As an effort to protect study participants and study staff, 
participants will routinely answer questions to determine their risk of exposure and infection with the novel 
coronavirus known as COVID-19. As described in “Measures” section below, the exact nature of the risk 
assessment questions may change due to shifting Johns Hopkins institutional guidelines. Some of these 
screenings will occur remotely via phone or online survey (using HIPAA-compliant Qualtrics surveys), and 
some will occur during in-person visits. Johns Hopkins Participants who meet the threshold of risk criteria 
for COVID-19 according the screening questionnaire will be instructed not to come to the laboratory for 
the in-person visit and are instructed to contact their primary care provider or the Johns Hopkins COVID-
19 Response Team. If a person presents with symptoms or provides responses to screening questions above 
the risk threshold during an in-person visit, we have established a standard operating procedure that states if 
there is a suspected case of COVID-19, the participant is to be isolated in the session room. Study staff will 
immediately contact members of the Behavioral Pharmacology Research Unit medical team to notify them 
that there is a participant in the building with a possible case of the COVID-19 in order to determine safe 
next steps in order to minimize contact with the participant and provide them with the appropriate 
recommendations for care. 
In line with university guidelines concerning COVID-19, we require all participants to wear a mask 
when visiting our research unit. Surgical grade or N-95 masks are acceptable. If participants arrive without 
an appropriate mask, they may not be able to complete their scheduled research session if the study team 
does not have adequate supply of masks to provide them with one. Study staff will also wear masks and 
maintain 6 feet of distance whenever possible. Participants may need to remove their mask briefly for parts 
of the sessions, such as taking a breathalyzer test, providing saliva samples, or swallowing study capsules. 
The total time within 6 feet should be minimal (i.e., estimated at less than 5 minutes). For example, 
research assistants may pass briefly within six feet of the participant while leading them through locked 
doors to the private laboratory space. Research assistants will need to take a blood pressure measurement to 
determine eligibility, and fitting the cuff will require brief interactions within six feet. Research assistants 
will also need to do a visual mouth check of the participant to ensure the participant has swallowed the 
study capsules. This involves no contact but the research assistant may need to be within six feet for a few 
seconds in order to see under the participant’s tongue. Additional personal protective equipment will be 

Date: February 25, 2021 
Principal Investigator: Dustin Lee 
Application Number: IRB00165287 
 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 5 of 22 
 
used by staff if distancing cannot be maintained during study procedures (gloves, face shields, etc.). The 
research assistant should be able to conduct all structured interviews/ study measures from six feet away. 
For example, study staff will set up the computer/paper measure, and then invite the participant to complete 
the measure after stepping six feet away. Some study visits may be canceled or rescheduled if participants 
or study staff report symptoms or risk of COVID-19 or test positive for COVID-19.  
Much of these study procedures are already well-suited to minimize risk to research participants and 
study team members. For example, most study visits are expected to last less than 30 minutes and the 
research assistant does not need to be within six feet of the participant for any extended period of time. We 
also previously incorporated JHMI-credentialed Qualtrics surveys that are sent to the participants via 
email/text message at 1, 2, 3, and 4 hours after administration of the study capsules so that participant in-
person burden is limited. Although most brief sessions (typically less than 30 min) are still necessary due to 
the need to ingest study capsules and collect biospecimens (e.g., urine to check for pregnancy in females), 
we will allow some flexibility with study sessions that can be conducted remotely via phone or video visits 
using HIPAA-compliant software (e.g., HIPAA compliant JHMI Zoom instance), such as the last session to 
pick up final study payment and complete the end-of-study survey. All or part of some visits may occur via 
telephone or video visits where determined to be appropriate, and where determined by the investigator not 
to increase participant risks. 
Typically only one research staff (a research assistant) will interact with the participant at each visit. 
It is possible that a member of the BPRU medical staff will join if a medical concern arises or an 
Investigator if a protocol concern arises, but this will not be routine. If additional study staff (e.g., an 
investigator) would like to speak with the participant (e.g., to answer participant questions about study 
procedures), the research assistant may set up a brief video meeting using HIPAA-compliant software (e.g., 
HIPAA compliant JHMI Zoom instance) on the study computer so that the investigator can speak with the 
participant without in-person interaction. 
Finally, we have moved several of the in-person screening surveys to be administered remotely via 
JHMI-credentialed Qualtrics links as part of the preliminary screening in order to reduce the amount of 
time participants are in the laboratory for the in-person screening. We anticipate that the duration of in-
person screening may be able to be reduced 30-50%. It is still necessary to have in person screening due to 
the need for physical evaluation (e.g., blood pressure for eligibility; height/weight for drug dosing; urine 
drug screen) and because some of the mental health screenings may identify mental health conditions for 
which clinical action is immediately necessary. 
The Behavioral Pharmacology Research Unit has developed a thorough plan to implement physical 
distancing measures, cleaning protocols, and participant interaction protocols in order to minimize the risk 
of COVID-19 infection for staff and participants. Adequate personal protective equipment is available to 
the research unit, and staff are required to undergo PPE training according to School of Medicine 
guidelines. Research assistants and other study staff will continue to telework where possible to minimize 
interaction. 
Screening. After initial pre-screening conducted via phone, online self screener or online 
preliminary screening, individuals will come to the Behavioral Pharmacology Research Unit (BPRU) at the 
Johns Hopkins University School of Medicine on the Bayview Medical Campus to complete a battery of 
questionnaires assessing demographic variables and drug use history. They will receive a brief medical 
screening that will include assessment of blood pressure, urine toxicology, breathalyzer test, pregnancy 
testing (female volunteers only), medical history, and psychiatric questionnaires. Participants will also 
provide a saliva sample. In the present study, selected saliva samples will be analyzed for caffeine content. 
In the written informed consent form, we will also ask participants for permission to store their 
biospecimens for future research, as it is possible but not certain that future research may include gene 
sequencing (e.g., for markers related to addiction vulnerability) on saliva samples that are not used for 
caffeine testing. 

Date: February 25, 2021 
Principal Investigator: Dustin Lee 
Application Number: IRB00165287 
 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 6 of 22 
 
Phase 1: Initial Abstinence Phase (Week 1). In order to reduce possible caffeine withdrawal effects 
on the assessment of the reinforcing effects of caffeine, enrolled subjects will be required to remain 
caffeine abstinent throughout the study beginning one week before the initial choice session. As in some of 
our previous studies (e.g., Sigmon & Griffiths, 2011), to control for expectancy effects, participants will not 
be informed that caffeine is a primary focus of the study and will be asked to eliminate caffeine as well as 
various other caffeine-free foods and beverages from their diet. Including caffeine-free distractor items on 
the list of restricted foods and beverages will assist in maintaining participant blindness to the exact drugs 
under study. Specifically, participants will be asked to eliminate: coffee drinks of any kind (including 
decaffeinated), drinks/food/gum containing aspartame, energy drinks and supplements, hot chocolate, 
instant drink mixes, red wine, sodas and carbonated drinks of any type, tea (including decaffeinated), 
chocolate, coconuts, grapefruit and grapefruit juice, mussels, oysters, poppy seeds, and all prescription and 
over-the-counter medications. Any participant receiving appropriate medical prescriptions that are 
contraindicated to the study medication will be excluded from participation. Prescription contraceptives 
will not be exclusionary. Participants will not be asked to forego taking appropriate prescription medication 
in order to participate in this study. 
To ensure participants understand and comply with the dietary restrictions, participants will be 
asked to record the amounts and types of all foods, drinks, and medications they consume and the time of 
day the items are consumed during the first week of the study (Phase 1). During Phase 1 (i.e., initial 
abstinence phase), participants will come to the laboratory to provide a saliva sample, review food 
restrictions and food diaries up to three times per week (e.g., Monday, Wednesday, and Friday). Caffeine 
abstinence will be verified by randomly selecting regularly provided saliva samples for analysis. Data from 
non-compliant subjects may be excluded from analysis. Participants will be told that samples will be 
analyzed for compounds contained in the restricted foods. Analysis of saliva samples from past research 
indicates that the majority of subjects who are informed of the dietary restrictions and agree to enroll in the 
studies are compliant.  
Phase 2: Choice Phase (Weeks 2-8). During the choice phase (Phase 2), participants will report to 
the laboratory approximately 3-5 times per week, Monday through Friday, for brief visits. On each of these 
experimental days, subjects will provide a saliva sample, complete pre-drug subjective questionnaires, and 
ingest p.o. 2 identical, opaque size 0 color-coded capsules with water under double-blind conditions. To 
facilitate blindness, the drugs to be administered are disclosed to participants during consent among a 
longer list of potential drugs including other prescription and over-the-counter stimulant, sedative, and 
antihistamine medications. Thus, participants are aware that they may receive caffeine, nicotine, 
methylphenidate, or placebo and aware of the possible risks, but expectancy regarding the effects of study 
drugs is reduced. This strategy has been used successfully in past research (see section c. below for further 
information regarding justification for blinding procedures). 
Phase 2 will consist of ten test sequences of three experimental sessions per sequence. Each test 
sequence begins with two “no-choice” forced exposure days during which subjects will receive two 
different types of color-coded capsules on each day (e.g., 2 red capsules on Monday and 2 green capsules 
on Tuesday). Subjects will always receive placebo (e.g., microcrystalline cellulose) on one forced exposure 
day and caffeine anhydrous (200 mg/70 kg) on the other forced exposure day, with the order of exposure to 
caffeine and placebo counterbalanced across the trials. After leaving the laboratory, subjects will be 
required to complete subjective effects questionnaires at 1, 2, 3, and 4 hours after capsule ingestion. 
Measures will include subjective ratings of subjective drug effects (e.g., energetic, drowsy/sleepy, elated, 
jittery/shaky) and surrogate measures of reinforcement such as liking, take again, and monetary value, that 
we have used in previous research. These questionnaires will be completed online using Qualtrics survey 
technology or using conventional paper forms. When participants are completing their surveys online, a 
survey link will be sent to them via email or text message. Paper forms of surveys will be provided as a 
back-up in the event of technical issues with administering surveys via Qualtrics, in the event of difficulties 

Date: February 25, 2021 
Principal Investigator: Dustin Lee 
Application Number: IRB00165287 
 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 7 of 22 
 
with participant compliance for online assessments, or in the event the participant does not have a smart 
phone or computer access. On the subsequent “choice session” day, subjects will be shown their self-report 
data from the previous two exposure days to help them recall the specific drug effects (e.g., drug liking) 
associated with each color-coded capsule. Subjects will then choose one of the two types of color-coded 
capsules (e.g., 2 red capsules or 2 green capsules) and report the reason for their choice. They will then 
ingest the capsules they chose. After leaving the laboratory, subjects will again be required to complete 
subjective drug effect questionnaires at 1, 2, 3, and 4 hours after capsule ingestion. This 3-day test sequence 
(2 no-choice days followed by 1 choice day) will be repeated for a total of 10 consecutive test sequences 
(30 total sessions). For each subject, each 3-day choice sequence will be experimentally independent (e.g., 
each sequence will involve exposure and choice between novel color-coded capsules).  
Phase 3: Dose-Effect Phase (Weeks 9-14). After completing the choice phase, participants begin the 
acute dose-effect phase (Phase 3). During Phase 3, subjects will report to the laboratory approximately 2-3 
times per week, depending on schedule considerations. At least 48 hours will occur between completing the 
caffeine choice phase and beginning the dose-effect phase. Sessions during this phase will be separated by 
at least 48 hours (e.g., Monday, Wednesday, Friday sessions). These sessions will be similar to the forced 
exposure sessions during the Phase 2 except there will not be an opportunity to choose between capsules 
and capsules color will not change across sessions. At each visit, participants will have their blood pressure 
taken to ensure that it is ≤ 140 systolic and ≤ 90 diastolic prior to capsule administration, provide a saliva 
sample, complete pre-drug subjective questionnaires, and ingest p.o. 2 identical capsules with water under 
double-blind conditions. After leaving the laboratory, outcome measures will be assessed pre-capsule and 
at 1, 2, 3, and 4 hours post-capsule using the same measures as the Phase 2 (choice phase), with the 
addition of the multiple-choice procedure. The multiple-choice procedure will assess participant preference 
for “today’s drug” over various amounts of money ranging from -$30 (i.e., forego $30 rather than receive 
“today’s drug”) to $30 (i.e., receive $30 rather than receive “today’s drug”). As has been done in previous 
studies (e.g., Griffiths et al., 1993; Zacny & Gutierrez, 2009), one of the participant’s choices during the 
multiple-choice procedure will be randomly selected for reinforcement during the final session of Phase 3 
(see below).  
The acute effects of placebo and the two test drugs will be evaluated using a double-blind, cross-
over design in which each participant will be tested under each of 8 drug conditions: methylphenidate 
hydrochloride (10, 20, and 40 mg/70 kg; 60 mg is the maximum allowable dose of methylphenidate any 
individual would receive regardless of body weight) and nicotine base (prepared from nicotine hydrogen 
tartrate; 1, 2, 3 and 4 mg/70 kg; 6 mg is the maximum allowable dose of nicotine any individual would 
receive regardless of body weight) across one session per drug/dose condition plus placebo. Doses have 
been selected based on prior studies from our laboratory and others (e.g., Duke et al., 2015; Kollins et al., 
2009; Rush et al., 1998, 2001). Due to the fact that there was considerable variability in the positive 
subjective and discriminative stimulus effects of nicotine among never-smokers in our previously published 
study (Duke et al., 2015), the four nicotine doses will be replicated once within each subject. Dose 
conditions will be presented in ascending order for both methylphenidate and nicotine, but whether 
methylphenidate or nicotine are presented first will be counterbalanced. We will conduct one final 
administration session during which a prior choice made by the participant as a part of the multiple-choice 
procedure will be randomly selected and reinforced. If the selected choice was one of the study drugs, then 
the selected study drug will be administered to the participant on the final session using the same 
procedures as the rest of Phase 3. If money was selected, then the amount of money chosen by the 
participant will be added or subtracted from the session payment. In order to make the procedures of 
choosing drugs or money equivalent, participants who selected money will ingest placebo capsules. 
Following the multiple-choice reinforcement session, all participants are required to complete subjective 
effects questionnaires at 1, 2, 3, and 4 hours after capsule administration. The addition of the multiple-
choice reinforcement session results in a total of 13 sessions during Phase 3. Participants will return to the 

Date: February 25, 2021 
Principal Investigator: Dustin Lee 
Application Number: IRB00165287 
 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 8 of 22 
 
laboratory to receive their bonus payment for study completion so that we have the opportunity to review 
their subjective drug effects from the multiple-choice reinforcement session and discuss with them if 
necessary. 
 
Measures 
 
Screening/Descriptive Measures: The following measures will be administered at study screening, the 
online self-screener or online preliminary screening in order to establish patient eligibility and characterize 
the sample. Basic demographic information and personality measures will be used to explore possible 
differences between caffeine choosers and non-choosers and will be examined as potential covariates of 
individual differences in drug response following drug administration. The measures described will be 
administered via computer or using paper or pencil, and as such formatting or question wording may 
change slightly to adjust for computer vs. paper administrations. 
COVID-19 Questionnaire. We will administer a survey to assess any symptoms of COVID-19 that 
participants may be experiencing prior to each session. We will also be asking if participants have had 
any contact with a person they know has tested positively for COVID-19, or if they live or work in a 
high-risk facility (e.g., a homeless shelter). These screening questions may be conducted remotely via 
phone or online survey prior to sessions or in-person. The exact nature of the questions may change due 
to changing Johns Hopkins institutional guidelines. The current version of the screening questions has 
been incorporated into the revised telephone screening document uploaded to the eIRB website. 
Participants who meet the threshold of risk criteria for COVID-19 according the screening 
questionnaire will be instructed not to come to the laboratory for the in-person visit and are instructed to 
contact their primary care provider or the Johns Hopkins COVID-19 Response Team. If a person 
presents with symptoms or provides responses to screening questions above the risk threshold during an 
in-person visit, we have established a standard operating procedure that states if there is a suspected 
case of COVID-19, the participant is to be isolated in the session room. Study staff will immediately 
contact members of the Behavioral Pharmacology Research Unit medical team to notify them that there 
is a participant in the building with a possible case of the COVID-19 in order to determine safe next 
steps in order to minimize contact with the participant and provide them with the appropriate 
recommendations for care. 
 
Medical History and Demographic Questionnaire. We will administer a standardized medical history 
survey to assess demographic information (e.g., age, sex, marital status, education) and relevant 
medical history (e.g., medical and psychological conditions, hospitalizations, past drug research 
participation, prescriptions, allergies, contraception) to probe for contraindications to drug 
administration. We will also collect the following biometrics data: blood pressure, height, weight, 
balance, heart rate, and respiration. 
Psychiatric Assessment. The MINI International Neuropsychiatric Interview (MINI DSM-5, Lecrubier 
et al., 1997) will be used to exclude individuals with a current indication of serious psychiatric 
condition (e.g. schizophrenia, major depression). Current and past psychiatric diagnoses will also be 
assessed in the medical history and demographic questionnaire. The Beck Depression Inventory II 
(BDI-II; Beck, Steer, & Brown, 1996) will be used as a secondary assessment of depressive symptoms 
at screening and to describe the final sample. Participants who demonstrate significant psychiatric 
distress on either the BDI-II or the MINI DSM-5 will be provided with a list of emergency and 
treatment resources (e.g., 24-hr crisis response hotlines; local mental health referrals). A member of the 
study team will discuss the assessment responses with the participant and will encourage the participant 

Date: February 25, 2021 
Principal Investigator: Dustin Lee 
Application Number: IRB00165287 
 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 9 of 22 
 
to seek treatment, but will note that the study assessments are not considered a formal diagnosis. In the 
event of severe distress (e.g., suicidal ideation with intent to act, with or without a specific plan), one of 
the co-investigators or a member of the medical staff will discuss appropriate options for treatment 
referral, including escort to the emergency room if necessary. The MINI DSM-5 Alcohol Use Disorder 
and other Substance Use Disorder criteria, combined with the results of urine toxicology and the 
medical history questionnaire, will be used to exclude participants with evidence of a current substance 
use disorder (other than caffeine) that may interfere with study participation or increase the risk of 
study participation. Note: Given the low threshold for meeting DSM-5 criteria for mild Alcohol or 
Substance Use Disorder (i.e., 2-3 symptoms), individuals with a mild Alcohol or Substance Use 
Disorder designation may be included in the study if their alcohol or substance use is judged by the 
study investigators and medical team to be unlikely to interfere with study participation and unlikely to 
increase the risk of study participation. Individuals meeting criteria for Moderate (4-5 symptoms) or 
Severe Alcohol or Substance Use Disorder according to MINI for DSM-5 will always be excluded. 
Additional Drug Use/Prescription History. Internally developed, standardized measures of drug use 
history including a Prescription and Over-the-Counter Drug Questionnaire and Drug Use History 
Matrix will determine eligibility based on number of lifetime nonmedical uses (uses without a 
prescription) and past prescriptions of the administered drugs. Additionally, these questionnaires will 
give insight into the participant’s current drug use and means of administration. Drug use history is 
assessed across a comprehensive list of drug classes which includes: alcohol, nicotine, cannabis, 
synthetic marijuana, caffeine, ephedrine, sedatives/hypnotics, opioids, muscle relaxants, GHB, nitrous 
oxide, inhalants, MDMA, and dissociative anesthetic hallucinogens. 
Delay Discounting. Delay discounting describes the loss in subjective value of an outcome when there 
is a delay to that outcome. Individuals who use drugs tend to discount delayed rewards at a higher rate 
relative to those who do not use drugs, that is, individuals who use drugs are more likely to choose a 
smaller sooner reward over a larger delayed reward relative to nonusers. The present study will 
determine delay discounting of monetary rewards using a 5-trial adjusting delay task (Koffarnus & 
Bickel, 2014) at screening to compare choosers and non-choosers of caffeine on their decision-making. 
Personality Measures. Different dimensions of personality (e.g., greater sensation seeking, greater 
impulsivity) have been linked to patterns of substance use and substance use disorders (e.g., Stanford et 
al., 2009; Kotov et al. 2010). We will assess different aspects of personality in order to describe the 
sample and to determine whether choosers of caffeine differ from nonchoosers. Specifically, we will 
administer the Big Five Inventory and two measures assessing Sensation Seeking/Impulsiveness. Big 
Five Inventory. The Big Five Inventory is a 44-item self-report instrument based on the Big Five 
Factors of personality. The Big Five Factors of personality dimensions include: extraversion versus 
introversion, agreeableness versus antagonism, conscientiousness versus lack of direction, neuroticism 
versus emotional stability, openness versus closedness to experience (Goldberg, 1992; Goldberg, 1993; 
John & Srivastava, 1999). Sensation Seeking/Impulsiveness. Sensation seeking is a personality 
dimension that assesses the need for new, intense and varied experiences and the willingness to take 
risks for such experiences which has been shown to be a dispositional risk factor for drug use. This 
study will assess sensation seeking and impulsiveness using two personality assessment measures: a) 
the Brief Sensation Seeking Scale, an 8-item questionnaire assessing dimensions of experience seeking, 
boredom susceptibility, thrill and adventure seeking, and disinhibition (Hoyle, Stephenson, Palmgreen, 
Lorch, & Donohew, 2002) and b) the Barratt Impulsiveness Scale (BIS-11; Patton, Stanford, & Barret, 
1995), a 30-item instrument created to assess across subscales of attention, motor, self-control, 
cognitive complexity, perseverance and cognitive instability.  

Date: February 25, 2021 
Principal Investigator: Dustin Lee 
Application Number: IRB00165287 
 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 10 of 22 
 
Family Tree Questionnaire (FTQ). The Family Tree Questionnaire (FTQ) for Assessing Family History 
of Alcohol Problems (Mann, Sobell, & Sobell, 1985) is an instrument that allows participants to 
indicate each of their blood relative’s alcohol use and categorize it according to their knowledge of their 
family members' problematic use (e.g., never drank, social drinker, possible problem drinker, definite 
problem drinker, don't know/don't remember). We have modified this questionnaire to include two 
additional modules allowing participants to categorize family members' known history of tobacco use 
and other drug use. It is possible that participants who choose caffeine (or who show greater positive 
subjective response to other drugs) may have a greater number of relatives with problematic alcohol or 
drug use. 
Experimental Session Measures: The following measures will be administered to participants before 
capsule administration at experimental sessions (e.g., pre-drug subjective effects questionnaire) or at 1, 2, 
3, or 4 hours after capsule administration. These questionnaires will be completed online using Qualtrics 
survey technology or using conventional paper forms. When participants are completing their surveys 
online, a survey link will be sent to them via email or text message. Paper forms of surveys will be 
provided as a back-up in the event of technical issues with administering surveys via Qualtrics, in the event 
of difficulties with participant compliance for online assessments, or in the event the participant does not 
have a smart phone or computer access. Formatting or question wording may change slightly to adjust for 
computer vs. paper administrations. 
COVID-19 Questionnaire. The same COVID-19 Questionnaire procedure (described above) will be 
administered prior to every in-person session to ensure safety for participants and research staff.  
Subjective Effects Questionnaire. The Subjective Effects Questionnaire (SEQ) is an internally 
developed measure allowing participants to rate how they feel (e.g., energetic, drowsy/sleepy, elated, 
jittery/shaky) prior to ingesting the study drug and at 1, 2, 3, and 4 hours after capsule administration. 
Items on the subjective effects questionnaire were developed to detect effects of caffeine, nicotine, and 
stimulant drugs and we have successfully used the items in past research to show significant differences 
between choosers/nonchoosers and to detect significant drug dose effects (Duke, Johnson, Reissig, & 
Griffiths, 2015; Sigmon & Griffiths, 2011). 
Delay Discounting. The same brief delay discounting procedure (described above) may be administered 
during Phase 3 (acute dose-effect phase) at a single time point (e.g., 3 hr) per Phase 3 session following 
capsule administration to probe for acute drug effects on decision-making.  
Multiple-Choice Procedure. In the multiple-choice procedure, the subjective reinforcing value of the 
study drug dose is assessed by asking participants to indicate whether they would prefer to repeat 
“today’s drug” or take placebo capsules and money at the end of the study. The multiple-choice 
questionnaire asks participants make repeated choices between “today’s drug” over various amounts of 
money ranging from -$30 (i.e., forego $30 rather than receive “today’s drug”) to $30 (i.e., receive $30 
rather than receive “today’s drug”). The multiple-choice questionnaire will only be administered at a 
single time point (e.g., 4 hr) per session during all sessions of Phase 3. As has been done in previous 
studies (e.g., Griffiths et al., 1993; Zacny & Gutierrez, 2009), one of the participant’s choices during the 
multiple-choice procedure will be randomly selected for reinforcement during the final session of Phase 
3. If the selected choice was one of the study drugs, then capsules containing selected study drug will 
be administered to the participant on the final session using the same procedures as the rest of Phase 3. 
If money was selected, then the amount of money chosen by the participant will be added or subtracted 
from the session payment and the participant will receive a placebo capsule. A placebo capsule is 
administered if the choice was for money in order to make the procedures involved in choosing drug or 

Date: February 25, 2021 
Principal Investigator: Dustin Lee 
Application Number: IRB00165287 
 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 11 of 22 
 
money equivalent. This procedure has been successfully utilized in past research to determine and 
compare the subjective reinforcing value of administered drugs (Garrett & Griffiths, 1998; Griffiths, 
Rush, & Puhala, 1996; Griffiths, Troisi, Silverman, & Mumford, 1993). We hypothesize that choosers 
of caffeine may show greater subjective monetary value of the administered drugs. 
 
b. Study duration and number of study visits required of research participants. 
 
The duration of participation will be approximately 14-17 weeks, but may be longer in some 
instances due to participant and laboratory scheduling needs. Participants will be required to attend an in-
person screening session, 3 brief sessions during Phase 1 (initial abstinence), 30 brief sessions during Phase 
2 (i.e., two exposure sessions followed by one choice session for a total of ten choice sequences), and 13 
brief sessions during the during Phase 3 (dose-effect phase). Participants will return to the laboratory to 
receive their bonus payment for study completion so that we have the opportunity to review their subjective 
drug effects from the multiple-choice reinforcement session and discuss with them if necessary. Screening 
sessions will be approximately 2 hours in duration. All other sessions will usually last less than 30 minutes. 
 
c. Blinding, including justification for blinding or not blinding the trial, if applicable. 
 
As part of instructions during the informed consent process, volunteers will be given a list of drugs 
they may receive rather than informing them only of the specific drugs being administered. The list of 
potential substances provided to the volunteers during written informed consent will include the substances 
that will be administered (i.e., caffeine, methylphenidate, and nicotine), but will also contain other mood-
altering medications including sedatives, stimulants, and antihistamines that will never be administered. 
The purpose of this is to increase the degree to which participants are blind to the specific drug being 
studied and thereby reduce expectancy effects. This is consistent with previous practices in other research 
studies (e.g., Sigmon & Griffiths, 2011; Duke et al., 2015). Blindness to the specific study drugs 
administered will be maintained after the study to present the possible confounding of results that could 
occur if a past participant informed a current participant of the specific drugs administered. Further, 
blindness to the specific drugs administered also serves to reduce the likelihood that participants will seek 
out administered substances, even though the risk of participants seeking out substances after receiving 
them in a medically monitored setting is judged to be low. The informed consent document will list all the 
potential side effects of the administered medications so that participants may make an informed decision 
regarding their participation despite not knowing the specific drugs to be administered. The informed 
consent document will also state that participants will not be debriefed either during or after the study as to 
which drugs they received. Researchers will be blind to the drug conditions on any given session because a 
pharmacy member with no participant interaction will assign the randomized dose sequence and prepare 
the study drugs. Medical staff will be available to address any adverse events or break the medication blind 
if necessary. 
 
d. Justification of why participants will not receive routine care or will have current therapy 
stopped. 
N/A 
e. Justification for inclusion of a placebo or non-treatment group. 
 
A placebo condition has been included as a comparison for determining drug-related effects. 
 
f. Definition of treatment failure or participant removal criteria. 
 

Date: February 25, 2021 
Principal Investigator: Dustin Lee 
Application Number: IRB00165287 
 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 12 of 22 
 
Participants may voluntarily withdraw from the study at any time. They may also be removed if they have a 
significant adverse effect that we judge likely to be a reaction to a study drug, if they are noncompliant with 
study procedures or restrictions, if they become pregnant, or if new information becomes available that 
suggests continued study participation would put them at increased risk of adverse events. 
 
g. Description of what happens to participants receiving therapy when study ends or if a 
participant’s participation in the study ends prematurely. 
 
The proposed study is not a treatment study and participants are healthy volunteers. Neither study 
participation nor its termination will affect the ability of the participants to seek treatment services. 
Participants may withdraw from the study at any time without loss of benefits. 
 
5. 
Inclusion/Exclusion Criteria 
 
Inclusion Criteria 
1. Participant age is 18-65 years. 
2. Participant has a history of regular or intermittent caffeine use. 
3. Participant has less than 100 lifetime exposures to tobacco or nicotine-containing products (i.e., 
accepted definition of a never smoker according to the U.S. Centers for Disease Control). 
4. Participant has no nicotine use in the last year. 
5. The subject must be in good health as determined by medical history and vital signs. 
6. Participant Body Mass Index (BMI) must be between 18.5 and 34.9 (BMI<18.5 = Underweight; 
BMI>34.9 =  moderate-to-high-risk Obese). 
7. The subject is fluent in English (speaking, writing, and reading) and is capable of understanding and 
complying with the protocol. 
8. Females: Females of childbearing potential must use appropriate birth control (barrier methods, 
hormonal contraceptives, and/or intrauterine devices) during the entire duration of the study.  
Females who are not of childbearing potential must be postmenopausal for 2 years or have a history 
of hysterectomy and/or oophorectomy. 
 
Exclusion Criteria 
1. Subjects with known hypersensitivity or medical contraindication to caffeine, psychomotor 
stimulants, or nicotine. 
2. Subjects with a significant current neurological, hepatic, renal, endocrine, cardiovascular, 
gastrointestinal, pulmonary or metabolic disease for which administration of the study drugs would 
be contraindicated. 
3. Current indication of serious psychiatric condition (e.g. schizophrenia, major depression) according 
psychiatric assessments (BDI-II; MINI for DSM-5) or medical and psychiatric history 
questionnaires. 
4. Evidence of current substance use disorder (other than caffeine) that may interfere with study 
participation or increase the risk of study participation. Evidence of substance use disorder is 
assessed using DSM-5 substance use disorder criteria in the MINI for DSM-5, medical and 
psychiatric history questionnaires, and urine toxicology. Note: Given the low threshold for meeting 
DSM-5 criteria for mild Alcohol or Substance Use Disorder (i.e., 2-3 symptoms), individuals with a 
mild Alcohol or Substance Use Disorder designation may be included in the study if their alcohol or 
substance use is judged by the study investigators and medical team to be unlikely to interfere with 
study participation and unlikely to increase the risk of study participation. Individuals meeting 

Date: February 25, 2021 
Principal Investigator: Dustin Lee 
Application Number: IRB00165287 
 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 13 of 22 
 
criteria for Moderate (4-5 symptoms) or Severe Alcohol or Substance Use Disorder according to 
MINI for DSM-5 will always be excluded. 
5. Subjects with a diastolic blood pressure >90 mmHg or a systolic pressure of >140 mmHg. 
6. Use of prescription or over-the-counter medications that could interfere with the study. Oral 
contraceptives and estrogen replacement therapy, vitamins, and periodic use of over-the-counter 
analgesic medications are acceptable. 
7. A past prescription of methylphenidate which exceeded two weeks or occurred within the past year. 
8. Subjects unwilling or unable to comply with the protocol or scheduled appointments. 
9. Subjects with any other serious disease or condition that might affect life expectancy or make it 
difficult to successfully manage the subjects according to the protocol. 
10. Female participants:  Participants who are pregnant, breastfeeding, or planning to become pregnant. 
 
6. 
Drugs/ Substances/ Devices 
a. The rationale for choosing the drug and dose or for choosing the device to be used. 
 
As discussed previously, this study will administer oral caffeine, methylphenidate, and nicotine in order to 
determine whether individual differences in caffeine choice predicts increases in surrogate measures of 
reinforcing effects (e.g., ratings of liking, take again, monetary value) of methylphenidate and nicotine. 
Data showing that caffeine choice predicts abuse liability of other commonly used drugs would suggest 
caffeine use may be an early marker of vulnerability to use of methylphenidate and/or nicotine. 
Specifically, methylphenidate is of interest because it is a widely used dopaminergic stimulant having 
significant neuropharmacological differences from d-amphetamine, which was used in our previous study 
(Sigmon & Griffiths, 2011). Nicotine is of interest because it is important to identify potential markers of 
vulnerability to nicotine use (e.g., tobacco smoking), which remains the single leading preventable cause 
death in the United States (DHHS, 2014). This project will also extend our work examining individual 
differences in nicotine reinforcement in never-smokers (Duke et al., 2015). Drugs and doses to be 
administered in different study sessions as described in Study Procedures include: placebo (e.g., 
microcrystalline cellulose), caffeine anhydrous (200 mg/70 kg), nicotine base (1, 2, 3 and 4 mg/70 kg; 6 mg 
is the maximum allowable dose of nicotine any individual would receive regardless of body weight in order 
to reduce the likelihood of adverse effects for participants of a higher body weight), and methylphenidate 
hydrochloride (10, 20 and 40 mg/70 kg; 60 mg is the maximum allowable dose of methylphenidate any 
individual would receive regardless of body weight). The doses of nicotine base will be prepared from 
nicotine hydrogen tartrate. Doses have been selected based on prior studies from our laboratory and others 
which have used the proposed doses (or higher doses) and found them to be well-tolerated in non-drug 
abusing volunteers (e.g., Duke et al., 2015; Kollins et al., 2009; Rush et al., 1998, 2001; Sigmon & 
Griffiths, 2011). Maximum study dose of nicotine is consistent with what is currently available over-the-
counter in oral form (e.g., 4 mg lozenges or gum). Maximum study doses of oral methylphenidate are well-
within the practice parameters for the use of stimulant medications (i.e., up to 60 mg per day; Greenhill et 
al., 2002). 
 
b. Justification and safety information if FDA approved drugs will be administered for non-FDA 
approved indications or if doses or routes of administration or participant populations are 
changed. 
 
All the study drugs to be administered are legally marketed in the United States. Further, the study does not 
involve a route of administration, dose, or patient population that significantly increases the risk (or 
decreases the acceptability of the risk) associated with the use of the drug. Previous research has 
demonstrated that caffeine (Sigmon & Griffiths, 2011), nicotine (Duke et al., 2015), and methylphenidate 

Date: February 25, 2021 
Principal Investigator: Dustin Lee 
Application Number: IRB00165287 
 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 14 of 22 
 
(Kollins et al., 2009; Rush et al., 1998, 2001) at the proposed doses (or indeed at higher doses) and the 
proposed route of administration (oral) are well-tolerated in non-drug-abusing volunteers. Maximum study 
dose of nicotine is consistent with what is currently available over-the-counter in oral form (e.g., 4 mg 
lozenges or gum). Maximum study doses of oral methylphenidate are well-within the practice parameters 
for the use of stimulant medications (i.e., up to 60 mg per day; Greenhill et al., 2002). The study is not 
intended to be reported to FDA in support of a new indication or to support any other change in labeling of 
the drugs. The study does not intend to support a significant change in advertising for the drugs, and the 
investigation is not intended to promote or commercialize the drug products. As such, the proposed 
investigation is exempt from IND requirements because all of the criteria for an exemption in FDA 
regulations § 312.2(b) are met. 
 
c. Justification and safety information if non-FDA approved drugs without an IND will be 
administered. 
N/A 
 
7. 
Study Statistics 
a. Primary outcome variable. 
 
Primary outcome measures will be participant ratings assessed pre-drug and at 1, 2, 3, and 4 hours post-
administration during the Phase 3 (dose effect phase). Primary outcomes include subjective ratings (e.g. 
Subjective Effects Questionnaire, and surrogate measures of reinforcement such as liking, take again, 
monetary value). Primary outcomes will be compared between caffeine choosers and nonchoosers. 
Caffeine choosers and nonchoosers are individuals who choose caffeine or placebo, respectively, 7 or more 
times during Phase 2. 
 
b. Secondary outcome variables. 
 
Secondary outcome measures will be subject demographic characteristics, drug use history, personality 
factors (e.g., sensation seeking), and decision-making factors (i.e., delay discounting) that will be examined 
as they relate to caffeine choice. 
 
c. Statistical plan including sample size justification and interim data analysis. 
 
Our goal is to have 36 participants complete the study. Sample sizes from our previous research with 
caffeine choice and d-amphetamine (n = 19 included in analysis) supports the appropriateness of the 
proposed sample size. The somewhat larger group size will permit a more complete characterization of 
subject demographics (e.g., age, sex), drug use history, and personality factors that may co-vary with 
caffeine choice. Based on our previous study with caffeine choice and d-amphetamine, the dichotomous 
measure of caffeine reinforcement should provide approximately equal numbers of choosers and 
nonchoosers (about N=15 each) for this analysis (with about 6 volunteers failing to meet the criteria for 
either chooser or non-chooser). Repeated measures ANOVAs will be conducted with caffeine choice 
(chooser vs. nonchooser, drug dose (placebo & 2 doses of each drug) and time (1, 2, 3, and 4 hours, as 
appropriate) as factors. Planned comparisons will be conducted between caffeine choosers and nonchoosers 
at each drug dose. We will conduct correlational analyses between number of caffeine choices and peak 
effects for the drug conditions, subject demographics, drug use history, and personality factors. Significant 
effects will be p-value ≤ .05. Appropriateness of a sample size of N=15 per group was also supported by a 
power analysis for repeated measures ANOVA examining an interaction of the between-subjects factor of 
caffeine choice (2 groups) and within subjects factor of drug dose (4 observations; placebo and minimum 

Date: February 25, 2021 
Principal Investigator: Dustin Lee 
Application Number: IRB00165287 
 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 15 of 22 
 
of three doses for each drug) using an effect size of .25, correlation among repeated measurements of .5, 
desired power of .90, and α = .05. 
 
It is anticipated that in order to have 36 participants successfully complete the study, approximately 60 
participants may have to be enrolled in order to allow for the possibility of participant dropout (i.e., attrition 
of up to 40% of enrolled participants). In order to obtain 60 enrolled participants, we anticipate that as 
many as 150 individuals may need to be consented and screened for study eligibility during the in-person 
Screening session (i.e., a screening failure rate of approximately 60%). 
 
d. Early stopping rules.  
 
There are no early stopping rules in this study. 
 
8. 
Risks 
a. Medical risks, listing all procedures, their major and minor risks and expected frequency. 
 
The behavioral procedures employed in these studies are benign. There are minimal risks related to the 
behavioral and self-report assessments. Potential risks are that some individuals might feel uncomfortable, 
tired, or bored in answering some of the questions.  
 
This study involves periods of total abstinence from caffeine. Thus, there is a risk that participants will 
experience caffeine withdrawal consisting of headache, tiredness/fatigue, decreased energy/activeness, 
decreased alertness/attentiveness, drowsiness/sleepiness, decreased contentedness/well-being, depressed 
mood, difficulty concentrating, irritability, muzzy/foggy/not clearheaded, muscle pain/stiffness, flu-like 
symptoms, or nausea and/or vomiting. This is a transient phenomenon with little medical risk.  
 
Primary medical risks to participants are those related to the effects of the drugs under study. In the 
proposed research the risks associated with drug administration are expected to be minor. Yet, 
administration of any drug involves some risks simply because of individual differences in reactions to 
drugs. The main risk is that subjects will experience side-effects of the drugs which may be unpleasant. 
Side-effects could include agitation, anxiety, arousal, confusion, decreased appetite, dizziness, dry mouth, 
excitement, fatigue, flushing, gastrointestinal distress, head rush, headache, hypertension, hypotension, 
increased energy/activeness, insomnia, irritability, jitteriness, light-headedness, muscle tenseness, nausea, 
nervousness, pallor, palpitation, quickened respiration, relaxation, restlessness, sensory disturbances, skin 
rash, sweating, tachycardia, tension, tremors, vigor, and vomiting. Other more unlikely effects could 
include cardiac arrhythmias (irregular heart beat), pericardial (chest or heart) pain, seizures, convulsions, 
respiratory depression, and significant allergic reaction; these would constitute grounds for immediate 
termination from the study. Side-effects of the drugs are temporary, usually dissipating within several 
minutes to a few hours, and are generally dose-dependent as well. The risk of a serious adverse event is 
minimal due to the amount of drug the participants will receive. Thus, subjects may only experience side-
effects occasionally during the research. It is not anticipated that caffeine, methylphenidate, or nicotine will 
be impairing, and all three substances are known to have some acute performance-enhancement effects 
under certain conditions (Heishman et al., 2010; Linssen et al., 2014; McClellan et al., 2016).  
 
There is a theoretical risk that subjects might choose to seek out licit or illicit sources of drugs they 
received experimentally and liked. This risk is minimal since drugs are administered under blind 
conditions, at relatively low dosages, and in a setting that is not conducive to development of dependence. 
In support of this, several studies have shown that research participation does not increase subsequent drug 

Date: February 25, 2021 
Principal Investigator: Dustin Lee 
Application Number: IRB00165287 
 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 16 of 22 
 
use (e.g., Pratt & Davidson, 2005; Roux et al., 2012; Sommer et al., 2015; Vadhan et al., 2006). Our 
administration of substances to naïve individuals is consistent with statements issued by the College on 
Problems of Drug Dependence that concluded exposure of drug-naïve individuals in a medically monitored 
setting is unlikely to create addiction or exacerbate pre-existing risk factors for addiction (Adler, 1995).  
 
b. Steps taken to minimize the risks. 
 
All participants in the drug studies will be thoroughly informed of the various drug side-effects (including 
possible caffeine withdrawal symptoms) that they might experience. Since participation is voluntary, 
subjects can withdraw at any time if they find the behavioral procedures or drug effects undesirable. A 
member of the medical staff reviews information from Screening to determine medical eligibility. All 
women will receive a pregnancy test at screening. Pregnancy testing will be repeated every other week 
throughout the duration of study participation. Participant blood pressure will be confirmed to be ≤ 140 
systolic and ≤ 90 diastolic at the screening visit and also prior to capsule administration during Phase 3 of 
the study as a precaution against the potential hypertensive effects of methylphenidate. 
 
We anticipate that careful subject selection, careful dose selection, and careful subject monitoring will, as 
in the past, prevent any potential problems. The investigators on this project have had extensive experience 
over the last 40 years administering moderate and high doses of psychoactive drugs to healthy volunteer 
subjects and have rarely experienced any untoward reactions. Examples of our prior research with these 
compounds include: caffeine (e.g., Evans & Griffiths, 1992; Sigmon & Griffiths, 2011; Sweeney et al., 
2017; Griffiths et al., 1989); nicotine (e.g., Duke et al., 2015; Jones & Griffiths, 2003; Johnson et al., 2010; 
Sobel et al., 2004; Nemeth-Coslett et al., 1987; Chausmer et al., 2003); and methylphenidate (e.g., Griffiths 
et al., 2006). Again, the doses examined in the present study have been selected based on prior studies from 
our laboratory and others which have used the proposed doses (or higher doses) and found them to be well-
tolerated in non-drug abusing volunteers (e.g., Duke et al., 2015; Kollins et al., 2009; Rush et al., 1998, 
2001; Sigmon & Griffiths, 2011). The proposed study procedures, including allowing participants to leave 
the laboratory following capsule administration, were successful in our previous studies administering 
caffeine, d-amphetamine, and nicotine (i.e., Duke et al., 2015; Sigmon & Griffiths, 2011). The proposed 
doses of methylphenidate are generally comparable to the doses of d-amphetamine (Rush et al., 1998, 
2001) used in our prior study (Sigmon & Griffiths, 2011) and should not represent additional risk. Further, 
the use of a conservative ascending dose exposure for both drugs will be used to initially expose the 
volunteers to the effects of the study drugs to minimize unpleasant or adverse effects. The study physician, 
Dr. Annie Umbricht, or another member of the medical staff at the Behavioral Pharmacology Research 
Unit will be available 24 hours if there is an urgent medical problem related to participation in the research. 
 
c. Plan for reporting unanticipated problems or study deviations. 
 
All unanticipated problems and adverse events will be reported to the IRB and other relevant agencies as 
required and described in the Data and Safety Monitoring Plan. 
 
d. Legal risks such as the risks that would be associated with breach of confidentiality. 
 
There is a theoretical risk that a breach in confidentiality will occur. In order to protect against this risk, 
research staff are trained in procedures for protecting participant privacy and personal health information. 
Data are managed to maximally protect participant confidentiality (e.g., in locked rooms, on encrypted 
computers, using participant ID codes rather than personal information). Records and data are maintained 
on-site and will only be released outside of the study team with written authorization from the participant. 

Date: February 25, 2021 
Principal Investigator: Dustin Lee 
Application Number: IRB00165287 
 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 17 of 22 
 
The identity of subjects is not revealed in written records and documents with subjects’ names are shredded 
before disposal.  
 
e. Financial risks to the participants. 
 
There are no financial risks to the participants in this study. 
 
9. 
Benefits 
a. 
Description of the probable benefits for the participant and for society. 
 
Although not considered a direct benefit, participants in all of the proposed studies will be paid for their 
research participation. Through the study procedures, volunteers may gain insights into their personal use 
of drugs (e.g., caffeine) and how drugs affect them. The volunteers may find the behavioral tasks or 
personality measures interesting and gain insight into their own preferences. 
 
The knowledge to be gained from the present study is important to understanding individual vulnerabilities 
to substance use. This study investigates caffeine choice as a predictor of abuse potential pharmacologically 
diverse drugs nicotine and methylphenidate, which are of particular interest as abused drugs. Data from this 
project will contribute to a scientific understanding of drug abuse and will ultimately contribute to the 
development of improved prevention and treatment procedures. Specifically, data showing that caffeine 
choice predicts abuse liability of other abused drugs would suggest that caffeine use is an early marker of 
vulnerability to some substance use disorders. For example, study findings regarding caffeine choosers vs. 
nonchoosers may inform physicians that caffeine choosers are a potentially higher risk group for 
developing problematic substance use related to certain prescribed drugs. Overall, the possible risks to 
subjects of participation appear to be outweighed by the benefits to subjects and to society. 
 
10. 
Payment and Remuneration 
a. 
Detail compensation for participants including possible total compensation, proposed bonus, 
and any proposed reductions or penalties for not completing the protocol. 
 
Participants will be paid $35 for screening, $15 per session during Phase 1 (3 sessions), $20 per session (30 
sessions) during the Phase 2, $40 per session (13 sessions) during Phase 3, and will earn an $800 bonus for 
completing all the study sessions. Thus, compensation for participation will be up to $2000. Because a 
random choice of the participant is selected during the multiple-choice reinforcement session (final session 
of Phase 3), participants may receive up to $30 additional or have up to $30 deducted from their final study 
payment if they indicated they would prefer additional money or to forego money over receiving an 
additional dose of the specified study drug. If additional screening sessions are necessary, participants will 
be paid an additional $35, and if additional experimental sessions are necessary, such as in the event of 
procedural or computer error, participants would be paid at the same per-session rate (i.e., $20 per session 
during the Phase 2 and $40 per session during Phase 3). Additional sessions could increase earnings beyond 
$2000, but study staff will strive to minimize the need for any additional sessions. If a participant is 
discontinued due to noncompliance they will not receive the completion bonus. If a participant is 
discontinued due to adverse effects of the drug they will be considered as completed and will earn a bonus 
of $18 for each session completed during Phases 2 and 3. 
 
11. 
Costs 
a. 
Detail costs of study procedure(s) or drug (s) or substance(s) to participants and identify 
who will pay for them. 

Date: February 25, 2021 
Principal Investigator: Dustin Lee 
Application Number: IRB00165287 
 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 18 of 22 
 
 
Costs of participation include travel to and from study sessions. There are no other costs to participants. All 
study costs will be paid for by the research project, which is funded by NIH grant R01DA003890. 

Date: February 25, 2021 
Principal Investigator: Dustin Lee 
Application Number: IRB00165287 
 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 19 of 22 
 
References 
 
Adler MW. Human subject issues in drug abuse research. College on Problems of Drug Dependence. Drug 
Alcohol Depend. 1995 Feb; 37(2): 167-175. 
Beck, A. T., Steer, R. A., & Brown, G. K. (1996). Manual for the Beck Depression Inventory-II. San 
Antonio, TX: Psychological Corporation. 
Chausmer AL, Smith BJ, Kelly RY, Griffiths RR. Cocaine-like subjective effects of nicotine are not 
blocked by the D1 selective antagonist ecopipam (SCH 39166). Behav Pharmacol. 2003 Mar; 
14(2): 111-120. 
de Wit H. Individual differences in acute effects of drugs in humans: Their relevance to risk for abuse. 
NIDA Res Monogr. 1998 Mar; 169: 176-187. 
Duke, A. N., Johnson, M. W., Reissig, C. J., & Griffiths, R. R. (2015). Nicotine reinforcement in never-
smokers. Psychopharmacology, 232(23), 4243-4252. 
Evans SM, Griffiths RR. Caffeine tolerance and choice in humans. Psychopharmacology (Berl). 1992; 
108(1-2): 51-59. 
Garrett, B.E., & Griffiths, R.R. (1998). Physical dependence increases the relative reinforcing effects of 
caffeine versus placebo. Psychopharmacology, 139, 195-202. 
Goldberg, L.R. (1992). The development of markers for the Big-Five factor structure. Psychological 
Assessment, 4(1), 26-42. doi: 10.1037//1040-3590.4.1.26 
Goldberg, L.R. (1993). The structure of phenotypic personality traits. American Psychologist, 48(1), 26-34. 
doi:10.1037/0003-66X.48.1.26  
Greenhill, L. L., Pliszka, S., & Dulcan, M. K. (2002). Practice parameter for the use of stimulant 
medications in the treatment of children, adolescents, and adults. Journal of the American Academy 
of Child & Adolescent Psychiatry, 41(2), 26S-49S. 
Griffiths RR, Bigelow GE, Liebson IA. Reinforcing effects of caffeine in coffee and capsules. J Exp Anal 
Behav. 1989 Sep; 52(2): 127-140. PMCID: PMC1338955. 
Griffiths RR, Richards WA, McCann U, Jesse R. Psilocybin can occasion mystical-type experiences having 
substantial and sustained personal meaning and spiritual significance. Psychopharmacology (Berl). 
2006 Aug; 187(3): 268-83. 
Griffiths, R.R., Rush, C.R., & Puhala, K.A. (1996). Validation of the multiple-choice procedure for 
investigating drug reinforcement in humans. Experimental and Clinical Psychopharmacology, 4(1), 
97-106. doi: 10.1037/1064-1297.4.1.97 
Griffiths RR, Woodson PP. Reinforcing effects of caffeine in humans. J Pharmacol Exp Ther. 1988 Jul; 
246(1): 21-29. 
Griffiths, R. R., JR Troisi, I. I., Silverman, K., & Miumford, G. K. (1993). Multiple-choice procedure: an 
efficient approach for investigating drug reinforcement in humans. Behavioural 
pharmacology, 4(1), 3-14. 

Date: February 25, 2021 
Principal Investigator: Dustin Lee 
Application Number: IRB00165287 
 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 20 of 22 
 
Heishman, S. J., Kleykamp, B. A., & Singleton, E. G. (2010). Meta-analysis of the acute effects of 
nicotine and smoking on human performance. Psychopharmacology, 210(4), 453-469. 
Hoyle, R. H., Stephenson, M. T., Palmgreen, P., Lorch, E. P., & Donohew, R. L. (2002). Reliability and 
validity of a brief measure of sensation seeking. Personality and Individual Differences, 32(3), 401-
414. 
John, O.P., & Srivastava, S. (1999). The Big-Five trait taxonomy: History, measurement, and theoretical 
perspectives. In L.A. Pervin & O.P. John (Eds.), Handbook of personality: Theory and research 
(Vol. 2, pp. 102-138). New York: Guilford Press.  
Johnson MW, Strain EC, Griffiths RR. Effects of oral caffeine pretreatment on response to intravenous 
nicotine and cocaine. Exp Clin Psychopharmacol. 2010 Aug; 18(4): 305-315. PMCID: 
PMC3528786. 
Jones HE, Griffiths RR. Oral caffeine maintenance potentiates the reinforcing and stimulant subjective 
effects of intravenous nicotine in cigarette smokers. Psychopharmacology (Berl). 2003 Jan; 165(3): 
280-290. 
Juliano LM, Griffiths RR. A critical review of caffeine withdrawal: Empirical validation of symptoms and 
signs, incidence, severity, and associated features. Psychopharmacology (Berl). 2004 Oct; 176(1): 
1-29. 
Koffarnus, M. N., & Bickel, W. K. (2014). A 5-trial adjusting delay discounting task: accurate discount 
rates in less than one minute. Experimental and clinical psychopharmacology, 22(3), 222. 
Kollins, S. H., English, J., Robinson, R., Hallyburton, M., & Chrisman, A. K. (2009). Reinforcing and 
subjective effects of methylphenidate in adults with and without attention deficit hyperactivity 
disorder (ADHD). Psychopharmacology, 204(1), 73-83. 
Kotov, R., Gamez, W., Schmidt, F., & Watson, D. (2010). Linking “big” personality traits to anxiety, 
depressive, and substance use disorders: A meta-analysis. Psychological Bulletin, 136(5), 768. 
Lecrubier, Y., Sheehan, D. V., Weiller, E., Amorim, P., Bonora, I., Sheehan, K. H., ... & Dunbar, G. C. 
(1997). The Mini International Neuropsychiatric Interview (MINI). A short diagnostic structured 
interview: Reliability and validity according to the CIDI. European Psychiatry, 12(5), 224-231. 
Linssen, A. M. W., Sambeth, A., Vuurman, E. F. P. M., & Riedel, W. J. (2014). Cognitive effects of 
methylphenidate in healthy volunteers: a review of single dose studies. International Journal of 
Neuropsychopharmacology, 17(6), 961-977. 
Mann, R. E., Sobell, L. C., Sobell, M. B., & D., P. (1985). Reliability of a family tree questionnaire for 
assessing family history of alcohol problems. Drug and Alcohol Dependence, 15, 61-67.   
McLellan, T. M., Caldwell, J. A., & Lieberman, H. R. (2016). A review of caffeine’s effects on cognitive, 
physical and occupational performance. Neuroscience & Biobehavioral Reviews, 71, 294-312. 
Meredith SE, Juliano LM, Hughes JR, Griffiths RR. Caffeine use disorder: A comprehensive review and 
research agenda. J Caffeine Res. 2013 Sep; 3(3): 114-130. PMCID: PMC3777290. 

Date: February 25, 2021 
Principal Investigator: Dustin Lee 
Application Number: IRB00165287 
 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 21 of 22 
 
Nemeth-Coslett R, Henningfield JE, O'Keeffe MK, Griffiths RR. Nicotine gum: Dose-related effects on 
cigarette smoking and subjective ratings. Psychopharmacology (Berl). 1987; 92(4): 424-430. 
Patton, J.H., Stanford, M.S., & Barratt, E.S. (1995). Factor structure of the Barratt impulsiveness scale. 
Journal of Clinical Psychology, 51(6), 768-774. 
Pratt, W. M., & Davidson, D. (2005). Does participation in an alcohol administration study increase 
risk for excessive drinking? Alcohol, 37(3), 135-141. 
Roux, P., Tindall, C., Fugon, L., Murray, J., Vosburg, S. K., Saccone, P., ... & Foltin, R. W. (2012). 
Impact of in‐patient research participation on subsequent heroin use patterns: Implications for 
ethics and public health. Addiction, 107(3), 642-649. 
Rush CR, Essman WD, Simpson CA, Baker RW. Reinforcing and subject-rated effects of methylphenidate 
and d-amphetamine in non-drug-abusing humans. J Clin Psychopharmacol. 2001 Jun; 21(3): 273-
286. 
Rush, C. R., Kollins, S. H., & Pazzaglia, P. J. (1998). Discriminative-stimulus and participant-rated effects 
of methylphenidate, bupropion, and triazolam in d-amphetamine-trained humans. Experimental and 
Clinical Psychopharmacology, 6(1), 32-44. 
Sigmon SC, Griffiths RR. Caffeine choice prospectively predicts positive subjective effects of caffeine and 
d-amphetamine. Drug Alcohol Depend. 2011 Nov 1; 118(2-3): 341-348. PMCID: PMC3188327. 
Sobel BF, Sigmon SC, Griffiths RR. Transdermal nicotine maintenance attenuates the subjective and 
reinforcing effects of intravenous nicotine, but not cocaine or caffeine, in cigarette-smoking 
stimulant abusers. Neuropsychopharmacology. 2004 May; 29(5): 991-1003. 
Sommer, C., Seipt, C., Spreer, M., Blümke, T., Markovic, A., Jünger, E., ... & Zimmermann, U. S. (2015). 
Laboratory alcohol self-administration experiments do not increase subsequent real-life drinking in 
young adult social drinkers. Alcoholism: Clinical and Experimental Research, 39(6), 1057-1063. 
Stanford, M. S., Mathias, C. W., Dougherty, D. M., Lake, S. L., Anderson, N. E., & Patton, J. H. (2009). 
Fifty years of the Barratt Impulsiveness Scale: An update and review. Personality and Individual 
Differences, 47(5), 385-395. 
Sweeney MM, Meredith SE, Evatt DP, Griffiths RR. Effects of caffeine on alcohol reinforcement: 
Beverage choice, self-administration, and subjective ratings. Psychopharmacology (Berl ). 2017; 
234(5): 877-888.  
United States Department of Health and Human Services (DHHS). The Health Consequences of 
Smoking—50 Years of Progress: A Report of the Surgeon General. Atlanta: U.S. Department of 
Health and Human Services, Centers for Disease Control and Prevention, National Center for 
Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, 2014. 
Vadhan, N. P., Hart, C. L., Roe, B., Colley, J., Haney, M., & Foltin, R. W. (2006). Substance use and 
psychosocial outcomes following participation in residential laboratory studies of marijuana, 

Date: February 25, 2021 
Principal Investigator: Dustin Lee 
Application Number: IRB00165287 
 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 22 of 22 
 
methamphetamine and zolpidem. The American Journal of Drug and Alcohol Abuse, 32(4), 589-
597. 
Zacny, J. P., & Gutierrez, S. (2009). Within-subject comparison of the psychopharmacological profiles of 
oral hydrocodone and oxycodone combination products in non-drug-abusing volunteers. Drug & 
Alcohol Dependence, 101(1), 107-114