Dopaminergic Mechanisms Underlying Human Social Behavior: A Multimodal Approach
Phase: EARLY_PHASE1
Conditions: Decision Making, Executive Function, Dopamine
Sponsor: University of California, Berkeley

Title: Dopaminergic Mechanisms Underlying Human Social Behavior 
NCT Number: NCT04205994 
Protocol Approve Date: 11/2/2021

STUDY PROTOCOL  
Interested subjects will contact the study via the contact information provided in the study 
advertisement. Dr. Hsu, Dr. Kayser, or their research assistant(s) will then contact each 
potential subject by phone (or by each subject’s preferred method of communication) in order to 
set up a brief phone interview, during which the requirements for the study will be reviewed. Dr. 
Hsu, Dr. Kayser, or their research assistant(s) will then perform the initial phone screening to 
verify that subjects meet the criteria specified in the advertisement. The Recruitment Script 
Phone will be used for note taking during the call, but the sheet is then shredded after the call 
and the information is recollected when the subject arrives for her/his screening visit (if eligible), 
and after they provide signed informed consent. If a prospective subject is a staff under the 
supervision of either Dr. Hsu or Dr. Kayser, the supervising individual will not participate in the 
recruitment process in order to avoid potential coercion or undue influence. In addition, UCB 
students, in general, will be routinely screened (initial phone screening) by research assistants, 
rather than by faculty.  
For subjects who state that they are potentially eligible for enrollment, we will arrange an initial 
visit, at the subject’s convenience, to perform further screening and to gather initial behavioral 
data. The Subject Health screening sheets will be filled out immediately (and only) after 
obtaining written informed consent. The Tolcapone package insert will be shared with subjects 
to inform them of possible side effects. Consent will be obtained only at approved sites for this 
study, including either the subject suite in the UC Berkeley Imaging Center (BIC) or the clinic 
and testing rooms at the UCSF Research Clinic. Subjects will read through the consent form 
prior to signing the document; if for some reason a subject is unable to read the form, the 
consenting study investigator will read the forms to the subject. Subjects will be provided as 
much time as required for them to familiarize themselves with the contents of the consent form. 
Any questions the subject has concerning the contents of the consent form, or the consent 
process itself, will be answered prior to signing. Only after informed consent is obtained will the 
remainder of the initial visit, described below, be completed.  
We will administer an extensive questionnaire listing contraindications to MRI scanning. 
Because the MRI scanner attracts certain metals, subjects who may have metallic objects in 
their bodies will be excluded. (As an additional measure of protection, we will use a hand-held 
metal detector to screen subjects before entering the scanner.)  
Subjects will provide a saliva sample in order to determine catechol-O-methyltransferase 
(COMT) and dopamine receptor subtype 2 (DRD2) genotypes. DNA extraction and analysis will 
be conducted using standard methods to assess the Val158Met polymorphism of the COMT 
gene and the A1+ polymorphism in the DRD2 gene. Examiners and researchers who interact 
with study subjects or study data will remain blinded to genotype until the end of the study. 
Furthermore, genes affecting dopamine metabolism in addition to COMT and DRD2 will be 
examined (including the dopamine transporter variable number tandem repeat (DAT VNTR) and 
dopamine receptor subtype 4 single nucleotide polymorphism 521 (DRD4 SNP-521)). In order 
to further assess potential contraindications to tolcapone, a blood sample will be tested for 
routine chemistries including white cell count, red cell count, platelet count, hemoglobin, 
hematocrit, mean cell volume (MCV), mean cell hemoglobin (MCH), mean cell hemoglobin 
concentration (MCHC), red cell distribution width (RDW), mean platelet volume (MPV), 
neutrophils, lymphocytes, monocytes, eosinophils, and basophils. Additionally, because of 
potential hepatic effects of tolcapone, a hepatic screen will assay total protein, albumin, globulin, 
A/G ratio, bilirubin (total, direct, and indirect), alkaline phosphatase, aspartate aminotransferase 

(AST, aka serum glutamic oxaloacetic transaminase (SGOT)), and alanine aminotransferase 
(ALT, aka serum glutamic pyruvic transaminase (SGPT)). Elevation of plasma bilirubin, AST 
(SGOT), ALT (SGPT), or alkaline phosphatase greater than 3 times normal values will be 
grounds for subject exclusion. (Note that ongoing monitoring of liver enzymes will not be 
necessary, as only a single, counterbalanced dose of tolcapone will be administered to each 
subject.) The blood sample may also be used for genetic testing if the saliva sample is non-
diagnostic, compromised, or otherwise unavailable. Tests for blood chemistries following 
phlebotomy are currently performed at Quest Diagnostics in Berkeley, CA or the main laboratory 
at UCSF.  
Subjects will then be urine-screened for illicit drug use (Biotechnostix) and screened for 
intoxication via breathalyzer (Lifeloc Technologies). To confirm that subjects do not have 
potential drugs of abuse in their system, an on-site rapid urine-screening and a breathalyzer test 
will be done before administering tolcapone or placebo. Urine-screening will be done via an 
integrated test cup that includes a temperature sensor. The drug classes detected include 
cocaine, amphetamine, methamphetamine, tetrahydrocannabinol (THC), and opiates. 
Additionally, two opiates (methadone and oxycodone) may not be reliably detected by the 5-
Test Integrated cup, so urine dipstick screening (Innovacon, Inc.) will also be performed on each 
subject’s urine sample for these two  
compounds. These drugs have been chosen due to their possible interaction with tolcapone and 
their possible cognitive and cardiovascular effects. No identifiers will be put on the test cup and 
it will be read immediately and discarded by the researcher. Similarly, the results of the 
breathalyzer will be read and then the test will be discarded. Moreover, due to the potentially 
sensitive nature of this information, the results will not be written down. Subjects who test 
positive for any of these substances will be excluded from further participation in the study. 
Subjects will also be excluded if they regularly use medications that affect dopamine levels, or 
will have used these medications within two weeks of tolcapone administration (including 
tolcapone, except as part of our study, or any of the following: levodopa/carbidopa, entacapone, 
amantadine, pergolide, pramipexole, ropinirole, selegeline, isocarboxazid, phenelzine, 
tranylcypromine, clozapine, olanzapine, quetiapine, risperidone, ziprasidone, aripiprazole, 
fluphenazine, haloperidol, perphenazine, pimozide, thiothixene, trifluoperazine, loxapine, 
molindone, chlorpromazine, mesoridazine, thioridazine, dextroamphetamine, 
dexmethylphenidate, or methylphenidate).  
A licensed health care provider listed in the protocol will also conduct a brief physical exam. 
This exam will search for signs of medical illness, including jaundice or abdominal distension 
associated with liver disease, that would exclude subjects from participating in the study. (See 
exclusion criteria.) For the purposes of the exam, female subjects will not be limited to a female 
provider, and male subjects will not be limited to a male provider. However, our practice has 
been, and will continue to be, that a research subject may always request a male or female 
provider. If for some reason the requested provider is not available, a member of the research 
team of the requested gender can also be present for the exam, if desired.  
Female subjects will also be screened for pregnancy, as the effects of the study drug during 
pregnancy are not adequately known and the drug may appear in breast milk. Since subjects 
may not know they are pregnant, all female subjects recruited to participate in the study will be 
required to have a urine pregnancy test prior to each session of the study. They will self-
administer the test after coming into the research lab. These pregnancy tests have been in 

reliable use at the UC Berkeley Brain Imaging Center for approximately 10 years without any 
reported failures. Subjects will be provided with printed instructions in the use of the test.  
Active use of substances other than alcohol or tobacco, use of alcohol on the day of the meeting 
as assessed by breathalyzer testing, and/or a positive pregnancy test, will be grounds for 
exclusion.  
STATISTICAL ANALYSIS PLAN  
For each of the three arms of the study we plan to recruit a minimum of 35 subjects. The total 
number of subjects is consistent with both our initial behavioral results in a group of 35 patients 
and seminal neuroimaging papers that suggest numbers of at least 20 subjects per group are 
necessary for adequate reliability of fMRI results (Murphy and Garavan, 2004; Thirion et al., 
2007) – assuming certain standard estimates of signal-to-noise, spatial smoothing, and BOLD 
time series duration that are well-established in the fMRI literature across studies including 
perceptual, attentional, language-related, and executive tasks. Based on our previous data, for 
a behavioral effect size of 0.5 at a significance level of p = 0.05, our sample size will provide at 
least 88% power to detect a behavioral difference in a 2x2 ANOVA with factors of group and 
drug. For neuroimaging, our sample size will provide at least 80% power to detect a difference 
in the BOLD signal of 0.5% in a 2x2 (group x drug) ANOVA at a two-tailed significance of p = 
0.05, corrected (Desmond and Glover, 2002). For PET imaging, our sample will provide at least 
80% power to detect correlation of 0.3, which is on the lower end of effects observed in related 
studies at a two-tailed significance of p = 0.05 (Berry et al., 2017; Jonasson et al. 2017; Kodaka 
et al. 2013).  
REFERENCES  
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D'Esposito and W. J. Jagust (2017). "Dopamine Synthesis Capacity is Associated with D2/3 
Receptor Binding but Not Dopamine Release." Neuropsychopharmacology.  
Desmond JE & Glover GH (2002). Estimating sample size in functional MRI (fMRI) 
neuroimaging studies: statistical power analyses. J Neurosci Methods 118: 115-128.  
Jonasson, L. S., J. Axelsson, K. Riklund, T. S. Braver, M. Ogren, L. Backman and L. Nyberg 
(2014). "Dopamine release in nucleus accumbens during rewarded task switching measured by 
[(1)(1)C]raclopride." Neuroimage 99: 357-364.  
Kodaka, F., H. Ito, Y. Kimura, S. Fujie, H. Takano, H. Fujiwara, T. Sasaki, K. Nakayama, C. 
Halldin, L. Farde and T. Suhara (2013). "Test-retest reproducibility of dopamine D2/3 receptor 
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Murphy K & Garavan H (2004). An empirical investigation into the number of subjects required 
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Thirion B, Pinel P, Meriaux S, et al. (2007). Analysis of a large fMRI cohort: Statistical and 
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