<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02972554</url>
  </required_header>
  <id_info>
    <org_study_id>16-2498</org_study_id>
    <nct_id>NCT02972554</nct_id>
  </id_info>
  <brief_title>Does Propranolol Attenuate Inflammatory Responses to a Psychological Stressor?</brief_title>
  <official_title>Beta-Blockers and Inflammatory Responses to Acute Psychosocial Stress</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of North Carolina, Chapel Hill</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of North Carolina, Chapel Hill</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This randomized, double-blind, placebo-controlled study of propranolol will shed important&#xD;
      light on how sympathetic nervous system (SNS) activation influences psychological and&#xD;
      inflammatory responses to acute stress. Results from this study will inform both the basic&#xD;
      science literature that is attempting to map the physiological mechanisms by which&#xD;
      psychological stress may lead to poor mental and physical health, and may also ultimately&#xD;
      have therapeutic relevance for individuals who are experiencing high levels of stress that is&#xD;
      putting their health at risk. Utilizing a psychopharmacological approach allows for the&#xD;
      circumvention of many of the challenges of conducting this research in human populations, and&#xD;
      will allow for conclusions regarding causality, given that SNS activation will be&#xD;
      experimentally manipulated, rather than relying on correlational measures of SNS activity&#xD;
      that are difficult to assess and are not appropriate for asking if SNS activity causes&#xD;
      changes in psychology and biology.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Psychological stress is implicated in the onset and progression of many common and costly&#xD;
      chronic diseases, including cardiovascular disease, chronic pain conditions, and major&#xD;
      depressive disorder (Cohen et al., 2007; Kendler et al., 1999; Steptoe and Kivimäki, 2012).&#xD;
      An emerging body of evidence suggests that inflammation, indexed via levels of&#xD;
      pro-inflammatory cytokines and reactive proteins, may be a key biological mechanism by which&#xD;
      stress affects health (Baker et al., 2012; Miller et al., 2009; Slavich et al., 2010).&#xD;
      Indeed, psychological stressors can induce increases in inflammation (Slavich and Irwin,&#xD;
      2014; Kiecolt-Glaser et al., 2003; Rohleder, 2014; Steptoe et al., 2007), and greater levels&#xD;
      of inflammation may contribute to the development of disease (Capuron and Miller, 2004; Choy&#xD;
      and Panayi, 2001; DellaGiola and Hannestad, 2010; Raison and Miller, 2013; The Emerging Risk&#xD;
      Factors Collaboration, 2010). Despite this growing literature linking stress, inflammation,&#xD;
      and poor health, little is known about the precise physiological mechanisms linking&#xD;
      psychological stress and increases in inflammation.&#xD;
&#xD;
      One hypothesized mechanism that may translate psychological stress into increases in levels&#xD;
      of inflammation is activation of the sympathetic nervous system (SNS). The SNS is part of the&#xD;
      autonomic nervous system and is primarily indexed by release of the catecholamines&#xD;
      epinephrine (adrenaline) and norepinephrine (noradrenaline). Prior research in non-human&#xD;
      animal models has shown that stress-induced SNS activation leads to increases in levels of&#xD;
      pro-inflammatory cytokines inflammation (Bierhaus et al., 2003; DeRijk et al., 1994; Kop et&#xD;
      al., 2008; van Gool et al., 1990), while pharmacologically blocking sympathetic activation&#xD;
      attenuates the inflammatory response to stress (Bierhaus et al., 2003). However, no known&#xD;
      human studies to date have examined the relationship between psychological stress, SNS&#xD;
      activation, and inflammation. The present study is designed to address this major gap in our&#xD;
      knowledge of the physiological mechanisms that may link stress and disease.&#xD;
&#xD;
      A potential reason for the lack of human research linking stress, SNS activation, and&#xD;
      inflammation is that SNS activity is difficult to measure. Indeed, adrenaline and&#xD;
      noradrenaline are released into the bloodstream very rapidly during a stressor, making their&#xD;
      kinetics difficult to capture during typical laboratory-based stress paradigms. Indirect&#xD;
      measures of SNS activity may be acquired using psychophysiological approaches that involve&#xD;
      peripheral measures of electrical activity and efficiency of the heart; however, these&#xD;
      methods provide only indirect indicators of SNS activity, making them subject to criticism in&#xD;
      the psychoneuroimmunology community.&#xD;
&#xD;
      To circumvent these issues with assessment of SNS activity, the present study will employ a&#xD;
      psychopharmacological approach to experimentally block SNS activity using the drug&#xD;
      propranolol. Propranolol is a beta-blocker medication that is very commonly prescribed by&#xD;
      physicians in the United States for the treatment of hypertension, given that it blocked&#xD;
      adrenergic receptors that lead to relaxation of the cardiac muscle and smooth muscle tissue.&#xD;
      Interestingly, propranolol is also sometimes prescribed to individuals who have performance&#xD;
      anxiety (i.e., public speaking anxiety), as reducing SNS activity (i.e., eliminating the&#xD;
      increased heart rate, blood pressure, sweaty palms, etc., that typically accompany&#xD;
      anxiety-provoking situations) has been anecdotally observed to decrease perceptions of stress&#xD;
      during these situations. Psychological scientists have recently become more interested in the&#xD;
      role SNS activity may play in the formation and reconsolidation of fear memories, and a&#xD;
      number of studies have now used propranolol to investigate if blocking SNS activity may help&#xD;
      treat individuals with Post-Traumatic Stress Disorder (PTSD; Pitman et al., 2002; Vaiva et&#xD;
      al., 2003). However, only one known study to date has investigated if propranolol reduces&#xD;
      stress-induced immune system activation (Benschop et al., 1994), and this (now dated) study&#xD;
      did not specifically explore if propranolol reduces inflammatory responses to stress.&#xD;
      Furthermore, no known studies have examined if blocking SNS activity with propranolol changes&#xD;
      individuals' appraisals of the stressful situation, or their affective responses to stress.&#xD;
      Results from this study will complement and extend the existing work on how SNS activity&#xD;
      affects fear memories and stress by focusing on how propranolol affects inflammatory and&#xD;
      psychological responses to a stressor.&#xD;
&#xD;
      In addition to these primary goals of the present study, the investigators will also explore&#xD;
      the role of SNS activation in a number of additional exploratory tasks that are hypothesized&#xD;
      to be affected by sympathetic arousal. More specifically, the investigators will examine if&#xD;
      exposure to propranolol eliminates implicit biases toward out-group members (in this case,&#xD;
      African Americans), given that a very large literature suggests that many White Americans&#xD;
      hold implicit biases against African Americans (Wittenbrink et al., 1997; Nosek et al.,&#xD;
      2002). While it has been hypothesized that sympathetic arousal based on cultural stereotypes&#xD;
      associating African Americans with negativity may be leading to these implicit biases, no&#xD;
      known studies have investigated this issue. The investigators will also explore of SNS&#xD;
      activation is critical for empathy, or individual's ability to understand the emotional&#xD;
      states of others, for avoiding risky decisions, and for moral judgments. Thus, this study&#xD;
      will also answer a number of exploratory, unanswered questions in social psychology regarding&#xD;
      the role that sympathetic arousal plays in some of our most fundamental psychological&#xD;
      processes.&#xD;
&#xD;
      In sum, this randomized, double-blind, placebo-controlled study of propranolol will shed&#xD;
      important light on how SNS activation influences our psychological and inflammatory responses&#xD;
      to stress. Results from this study will inform both the basic science literature that is&#xD;
      attempting to map the physiological mechanisms by which psychological stress may lead to poor&#xD;
      mental and physical health, and may also ultimately have therapeutic relevance for&#xD;
      individuals who are experiencing high levels of stress that is putting their health at risk.&#xD;
      By utilizing psychopharmacological approaches, the investigators will circumvent many of the&#xD;
      challenges of conducting this research in human populations. The investigators will also be&#xD;
      in a place to draw strong conclusions regarding causality, given that they will have&#xD;
      experimentally manipulated SNS activation, rather than relying on correlational measures of&#xD;
      SNS activity that are difficult to assess and are not appropriate for asking if SNS activity&#xD;
      causes changes in psychology and biology.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">January 26, 2016</start_date>
  <completion_date type="Actual">October 10, 2017</completion_date>
  <primary_completion_date type="Actual">October 10, 2017</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in Interleukin-6 (IL-6)</measure>
    <time_frame>Pre-drug baseline; 60-min post-drug administration baseline before stressor; 30-min post-stressor; 60-min post-stressor; 90-min post-stressor</time_frame>
    <description>Measured in blood plasma using enzyme-linked immunosorbent assay. Log-transformed prior to analysis to correct for skew in data. Four different change scores were calculated: first, change at post-drug from pre-drug baseline; second, the change at 30-min post-stressor from post-drug baseline; third, change at 60-min post-stressor from post-drug baseline; and fourth, change at 90-min post-stressor from post-drug baseline.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in Salivary Cortisol</measure>
    <time_frame>Pre-drug baseline; 60-min post-drug administration baseline before stressor; 15-min post-stressor; 30-min post-stressor</time_frame>
    <description>Concentration of cortisol in saliva quantified quantified by chemiluminescence immunoassay with high sensitivity. Three different change scores were calculated from pre-drug to post-drug baselines, 15-min post-stressor from post-drug baseline, and 30-min post-stressor from post-drug baseline.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Salivary Alpha Amylase</measure>
    <time_frame>Pre-drug baseline; 60-min post-drug administration baseline before stressor; 15-min post-stressor</time_frame>
    <description>Concentration of alpha amylase in saliva quantified quantified by enzyme kinetic method. Two different change scores were calculated: first, the pre-drug to post-drug baseline change and, second, the 15-min post-stressor change from post-drug baseline.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Pre-Ejection Period</measure>
    <time_frame>Pre-drug baseline; 60-min post-drug administration baseline before stressor; 2-min before the stressor; 15-min during stressor, 7-min recovery post-stressor</time_frame>
    <description>Mean level pre-ejection period (PEP; centered at zero) derived from impedance cardiography and electrocardiogram. Four different change scores were calculated: first, the change in average PEP from the 5-min pre-drug baseline to the 5-min post-drug baselines; second, the change in average PEP that occurred during the 2-min anticipatory stress speech preparation phase of the Trier Social Stress Test (TSST) from the post-drug baseline; third, the change in average PEP that occurred across the 15-min of the TSST (speech + math tasks) from the post-drug baseline; fourth and finally, the change in average PEP that occurred across 7-min in a post-stressor recovery period as compared to the post-drug baseline.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Respiratory Sinus Arrhythmia</measure>
    <time_frame>Pre-drug baseline; 60-min post-drug administration baseline before stressor; 2-min before the stressor; 15-min during stressor, 7-min recovery post-stressor</time_frame>
    <description>Mean level respiratory sinus arrhythmia (RSA) derived from electrocardiogram; measure of heart rate variability assessed as the ratio of low-to-high frequencies in the respiratory-cardiac power spectrum. Four different change scores were calculated: first, the change in average RSA from the 5-min pre-drug baseline to the 5-min post-drug baselines; second, the change in average RSA that occurred during the 2-min anticipatory stress speech preparation phase of the Trier Social Stress Test (TSST) from the post-drug baseline; third, the change in average RSA that occurred across the 15-min of the TSST (speech + math tasks) from the post-drug baseline; fourth and finally, the change in average RSA that occurred across 7-min in a post-stressor recovery period as compared to the post-drug baseline.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Negative, High Arousal Emotion</measure>
    <time_frame>Pre-drug baseline; 60-min post-drug administration baseline before stressor; 2-min before the stressor; 1-min post-stressor</time_frame>
    <description>Self-report measure of affect (emotion) state using the Positive &amp; Negative Affect Schedule Negative Affect (PANAS). Answered on a Likert scale from 0 (&quot;not at all&quot;) - 6 (&quot;very much&quot;). Mean score range is from 0-6. Higher numbers indicate more negative, high arousal emotions; low numbers indicate less negative, high arousal emotions. Three change scores were calculated from the four different rating measurement time points: a change in negative, high arousal emotions at the post-drug baseline from the pre-drug baseline; a change in emotions right before the Trier Social Stress Task (TSST) from the post-drug baseline; and a change in emotions during the TSST from the post-drug baseline.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">92</enrollment>
  <condition>Stress, Psychological</condition>
  <condition>Inflammation</condition>
  <condition>Cortisol</condition>
  <condition>Sympathetic Nervous System</condition>
  <arm_group>
    <arm_group_label>Propanolol Hydrochloride</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>This is the experimental group given the beta-blocker</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>This is the control group given a placebo.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Propanolol hydrochloride</intervention_name>
    <description>One-time dose of 40mg of propranolol</description>
    <arm_group_label>Propanolol Hydrochloride</arm_group_label>
    <other_name>Inderal</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Outside casing matching that of active drug</description>
    <arm_group_label>Placebo</arm_group_label>
    <other_name>Sugar pill</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusionary Criteria:&#xD;
&#xD;
          1. Healthy volunteers&#xD;
&#xD;
          2. Age 18-25&#xD;
&#xD;
          3. Fluent in English&#xD;
&#xD;
        Exclusionary Criteria:&#xD;
&#xD;
          1. presence or history of chronic physical illness (especially disorders with an&#xD;
             inflammatory component, such as rheumatoid arthritis, asthma, allergies, or issues&#xD;
             that can affect the heart, including low-blood pressure or other heart conditions)&#xD;
&#xD;
          2. presence or history of psychiatric illness (depression, anxiety)&#xD;
&#xD;
          3. any current prescription medication use&#xD;
&#xD;
          4. currently pregnant or planning to become pregnant&#xD;
&#xD;
          5. engagement in a number of health--compromising behaviors that may affect levels of&#xD;
             pro-inflammatory cytokines, including cigarette smoking, excessive caffeine intake and&#xD;
             sleep disturbance (e.g., working night shifts)&#xD;
&#xD;
          6. body mass index (BMI) greater than 30, given that adiposity is known to relate to&#xD;
             baseline levels of inflammation&#xD;
&#xD;
          7. anxiety about or previous history of problems with blood draws (e.g., fainting)&#xD;
&#xD;
          8. any reported heart conditions&#xD;
&#xD;
          9. history of fainting spells&#xD;
&#xD;
         10. low pulse, as measured at beginning of session I (below 60)&#xD;
&#xD;
         11. low blood pressure, as measured at beginning of session I (below 80)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>25 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Keely A Muscatell, Ph.D</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of North Carolina at Chapel Hill, Psychology &amp; Neuroscience</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Howell Hall</name>
      <address>
        <city>Chapel Hill</city>
        <state>North Carolina</state>
        <zip>27599</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
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    <citation>van Gool J, van Vugt H, Helle M, Aarden LA. The relation among stress, adrenalin, interleukin 6 and acute phase proteins in the rat. Clin Immunol Immunopathol. 1990 Nov;57(2):200-10. doi: 10.1016/0090-1229(90)90034-n.</citation>
    <PMID>1698583</PMID>
  </reference>
  <reference>
    <citation>Wittenbrink B, Judd CM, Park B. Evidence for racial prejudice at the implicit level and its relationship with questionnaire measures. J Pers Soc Psychol. 1997 Feb;72(2):262-74. doi: 10.1037//0022-3514.72.2.262.</citation>
    <PMID>9107001</PMID>
  </reference>
  <verification_date>January 2018</verification_date>
  <study_first_submitted>October 26, 2016</study_first_submitted>
  <study_first_submitted_qc>November 20, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 23, 2016</study_first_posted>
  <results_first_submitted>October 19, 2018</results_first_submitted>
  <results_first_submitted_qc>November 29, 2018</results_first_submitted_qc>
  <results_first_posted type="Actual">December 19, 2018</results_first_posted>
  <last_update_submitted>November 29, 2018</last_update_submitted>
  <last_update_submitted_qc>November 29, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">December 19, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Inflammation</mesh_term>
    <mesh_term>Stress, Psychological</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Propranolol</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>October 12, 2016</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/54/NCT02972554/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>Healthy young adult participants were recruited from campus via flyers and listserv postings. All participants were screened over telephone to ensure they were healthy.</recruitment_details>
      <pre_assignment_details>No enrolled participants were excluded from the study before assignment to groups.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Propanolol Hydrochloride</title>
          <description>This is the experimental group given the beta-blocker, propanolol hydrochloride with a single 40mg tablet dosage.</description>
        </group>
        <group group_id="P2">
          <title>Placebo</title>
          <description>This is the control group given a placebo, which was a single placebo-matching active drug dose.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="44"/>
                <participants group_id="P2" count="48"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="44"/>
                <participants group_id="P2" count="48"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Propanolol Hydrochloride</title>
          <description>This is the experimental group given the beta-blocker, propanolol hydrochloride with a 40mg single tablet dosage.</description>
        </group>
        <group group_id="B2">
          <title>Placebo</title>
          <description>This is the control group given a placebo, which was a placebo-matching active drug single dosage.</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="44"/>
            <count group_id="B2" value="48"/>
            <count group_id="B3" value="92"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="44"/>
                    <measurement group_id="B2" value="48"/>
                    <measurement group_id="B3" value="92"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
          <units>Years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="20.07" spread="1.28"/>
                    <measurement group_id="B2" value="20.49" spread="1.56"/>
                    <measurement group_id="B3" value="20.28" spread="1.42"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="20"/>
                    <measurement group_id="B2" value="22"/>
                    <measurement group_id="B3" value="42"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="24"/>
                    <measurement group_id="B2" value="26"/>
                    <measurement group_id="B3" value="50"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="11"/>
                    <measurement group_id="B2" value="12"/>
                    <measurement group_id="B3" value="23"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="8"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="25"/>
                    <measurement group_id="B2" value="28"/>
                    <measurement group_id="B3" value="53"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="6"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="44"/>
                    <measurement group_id="B2" value="48"/>
                    <measurement group_id="B3" value="92"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Interleukin-6 (IL-6)</title>
          <description>Measured in blood plasma using enzyme-linked immunosorbent assay. All units are log transformed prior to analysis to correct for skew in data.</description>
          <units>log(picograms/mL)</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="-1.00" spread=".90"/>
                    <measurement group_id="B2" value="-.98" spread=".86"/>
                    <measurement group_id="B3" value="-.99" spread=".88"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Salivary Cortisol</title>
          <description>Concentration of cortisol in saliva quantified quantified by chemiluminescence immunoassay with high sensitivity.</description>
          <units>nanomole/L</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="11.51" spread="13.04"/>
                    <measurement group_id="B2" value="8.62" spread="12.05"/>
                    <measurement group_id="B3" value="10.07" spread="12.55"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Salivary Alpha-Amylase</title>
          <description>Concentration of alpha-amylase in saliva quantified by enzyme kinetic method.</description>
          <units>picograms/mL</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="44.68" spread="38.85"/>
                    <measurement group_id="B2" value="55.13" spread="47.17"/>
                    <measurement group_id="B3" value="49.91" spread="43.01"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Pre-Ejection Period</title>
          <description>Derived from impedance cardiography and electrocardiogram.</description>
          <units>milliseconds</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="119.97" spread="18.48"/>
                    <measurement group_id="B2" value="116.66" spread="13.49"/>
                    <measurement group_id="B3" value="118.32" spread="15.99"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Respiratory Sinus Arrhythmia</title>
          <description>Derived from electrocardiogram; measure of heart rate variability assessed as the ratio of low frequency/high frequency in the respiratory/cardiac power spectrum.</description>
          <units>ratio</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="6.86" spread="1.18"/>
                    <measurement group_id="B2" value="7.02" spread="1.02"/>
                    <measurement group_id="B3" value="6.94" spread="1.10"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Negative, High Arousal Emotion</title>
          <description>Self-report measure of affect (emotion) state using the Positive and Negative Affect Schedule (PANAS). Answered on a Likert scale from 0 (&quot;not at all&quot;) - 6 (&quot;very much&quot;). Mean score range is from 0-6. Higher numbers indicate more negative, high arousal emotions; low numbers indicate less negative, high arousal emotions.</description>
          <units>scores on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1.20" spread=".19"/>
                    <measurement group_id="B2" value="1.25" spread=".33"/>
                    <measurement group_id="B3" value="1.23" spread=".26"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Change in Interleukin-6 (IL-6)</title>
        <description>Measured in blood plasma using enzyme-linked immunosorbent assay. Log-transformed prior to analysis to correct for skew in data. Four different change scores were calculated: first, change at post-drug from pre-drug baseline; second, the change at 30-min post-stressor from post-drug baseline; third, change at 60-min post-stressor from post-drug baseline; and fourth, change at 90-min post-stressor from post-drug baseline.</description>
        <time_frame>Pre-drug baseline; 60-min post-drug administration baseline before stressor; 30-min post-stressor; 60-min post-stressor; 90-min post-stressor</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Propanolol Hydrochloride</title>
            <description>This is the experimental group given the beta-blocker, propanolol hydrochloride using a 40mg single tablet dosage.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>This is the control group given a placebo, which was a placebo-matching active drug</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Interleukin-6 (IL-6)</title>
          <description>Measured in blood plasma using enzyme-linked immunosorbent assay. Log-transformed prior to analysis to correct for skew in data. Four different change scores were calculated: first, change at post-drug from pre-drug baseline; second, the change at 30-min post-stressor from post-drug baseline; third, change at 60-min post-stressor from post-drug baseline; and fourth, change at 90-min post-stressor from post-drug baseline.</description>
          <units>log(picograms/mL)</units>
          <param>Mean</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="44"/>
                <count group_id="O2" value="48"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Post-drug from pre-drug baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value=".05" lower_limit="-.126" upper_limit=".226"/>
                    <measurement group_id="O2" value=".16" lower_limit="-.075" upper_limit=".395"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>30-min post-stress from post-drug baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value=".31" lower_limit=".016" upper_limit=".604"/>
                    <measurement group_id="O2" value=".24" lower_limit=".044" upper_limit=".436"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>60-min post-stress from post-drug baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value=".32" lower_limit=".006" upper_limit=".634"/>
                    <measurement group_id="O2" value=".19" lower_limit=".014" upper_limit=".366"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>90-min post-stress from post-drug baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value=".48" lower_limit=".206" upper_limit=".754"/>
                    <measurement group_id="O2" value=".46" lower_limit=".264" upper_limit=".656"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Salivary Cortisol</title>
        <description>Concentration of cortisol in saliva quantified quantified by chemiluminescence immunoassay with high sensitivity. Three different change scores were calculated from pre-drug to post-drug baselines, 15-min post-stressor from post-drug baseline, and 30-min post-stressor from post-drug baseline.</description>
        <time_frame>Pre-drug baseline; 60-min post-drug administration baseline before stressor; 15-min post-stressor; 30-min post-stressor</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Propanolol Hydrochloride</title>
            <description>This is the experimental group given the beta-blocker, propanolol hydrochloride using a 40mg single tablet dosage.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>This is the control group given a placebo, which was a placebo-matching active drug</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Salivary Cortisol</title>
          <description>Concentration of cortisol in saliva quantified quantified by chemiluminescence immunoassay with high sensitivity. Three different change scores were calculated from pre-drug to post-drug baselines, 15-min post-stressor from post-drug baseline, and 30-min post-stressor from post-drug baseline.</description>
          <units>nanomole/L</units>
          <param>Mean</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="44"/>
                <count group_id="O2" value="48"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Post-drug from pre-drug baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-6.42" lower_limit="-8.576" upper_limit="-4.264"/>
                    <measurement group_id="O2" value="-3.76" lower_limit="-5.524" upper_limit="-1.996"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>15-min post-stress from post-drug baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5.61" lower_limit="3.258" upper_limit="7.962"/>
                    <measurement group_id="O2" value="4.02" lower_limit="2.785" upper_limit="5.255"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>30-min post-stress from post-drug baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.1" lower_limit=".179" upper_limit="4.021"/>
                    <measurement group_id="O2" value="1.86" lower_limit=".978" upper_limit="2.742"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Salivary Alpha Amylase</title>
        <description>Concentration of alpha amylase in saliva quantified quantified by enzyme kinetic method. Two different change scores were calculated: first, the pre-drug to post-drug baseline change and, second, the 15-min post-stressor change from post-drug baseline.</description>
        <time_frame>Pre-drug baseline; 60-min post-drug administration baseline before stressor; 15-min post-stressor</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Propanolol Hydrochloride</title>
            <description>This is the experimental group given the beta-blocker, propanolol hydrochloride using a 40mg single tablet dosage.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>This is the control group given a placebo, which was a placebo-matching active drug</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Salivary Alpha Amylase</title>
          <description>Concentration of alpha amylase in saliva quantified quantified by enzyme kinetic method. Two different change scores were calculated: first, the pre-drug to post-drug baseline change and, second, the 15-min post-stressor change from post-drug baseline.</description>
          <units>picograms / mL</units>
          <param>Mean</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="44"/>
                <count group_id="O2" value="48"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Post-drug from pre-drug baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-7.50" lower_limit="-19.299" upper_limit="4.299"/>
                    <measurement group_id="O2" value="-6.36" lower_limit="-16.787" upper_limit="4.067"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>15-min post-stress from post-drug baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-15.68" lower_limit="-26.725" upper_limit="-4.635"/>
                    <measurement group_id="O2" value="6.73" lower_limit="-3.305" upper_limit="16.765"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Pre-Ejection Period</title>
        <description>Mean level pre-ejection period (PEP; centered at zero) derived from impedance cardiography and electrocardiogram. Four different change scores were calculated: first, the change in average PEP from the 5-min pre-drug baseline to the 5-min post-drug baselines; second, the change in average PEP that occurred during the 2-min anticipatory stress speech preparation phase of the Trier Social Stress Test (TSST) from the post-drug baseline; third, the change in average PEP that occurred across the 15-min of the TSST (speech + math tasks) from the post-drug baseline; fourth and finally, the change in average PEP that occurred across 7-min in a post-stressor recovery period as compared to the post-drug baseline.</description>
        <time_frame>Pre-drug baseline; 60-min post-drug administration baseline before stressor; 2-min before the stressor; 15-min during stressor, 7-min recovery post-stressor</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Propanolol Hydrochloride</title>
            <description>This is the experimental group given the beta-blocker, propanolol hydrochloride using a 40mg single tablet dosage.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>This is the control group given a placebo, which was a placebo-matching active drug</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Pre-Ejection Period</title>
          <description>Mean level pre-ejection period (PEP; centered at zero) derived from impedance cardiography and electrocardiogram. Four different change scores were calculated: first, the change in average PEP from the 5-min pre-drug baseline to the 5-min post-drug baselines; second, the change in average PEP that occurred during the 2-min anticipatory stress speech preparation phase of the Trier Social Stress Test (TSST) from the post-drug baseline; third, the change in average PEP that occurred across the 15-min of the TSST (speech + math tasks) from the post-drug baseline; fourth and finally, the change in average PEP that occurred across 7-min in a post-stressor recovery period as compared to the post-drug baseline.</description>
          <units>milliseconds</units>
          <param>Mean</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="44"/>
                <count group_id="O2" value="48"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Post-drug from pre-drug baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7.14" lower_limit="1.711" upper_limit="12.569"/>
                    <measurement group_id="O2" value=".86" lower_limit="-3.148" upper_limit="4.868"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>TSST-prep from post-drug baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-5.33" lower_limit="-9.828" upper_limit="-.832"/>
                    <measurement group_id="O2" value="-10.92" lower_limit="-14.859" upper_limit="-6.980"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>TSST from post-drug baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-.80" lower_limit="-6.259" upper_limit="4.659"/>
                    <measurement group_id="O2" value="-10.69" lower_limit="-14.816" upper_limit="-6.564"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Post-stress recovery from post-drug baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value=".21" lower_limit="-4.063" upper_limit="4.483"/>
                    <measurement group_id="O2" value="-1.19" lower_limit="-5.120" upper_limit="2.740"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Respiratory Sinus Arrhythmia</title>
        <description>Mean level respiratory sinus arrhythmia (RSA) derived from electrocardiogram; measure of heart rate variability assessed as the ratio of low-to-high frequencies in the respiratory-cardiac power spectrum. Four different change scores were calculated: first, the change in average RSA from the 5-min pre-drug baseline to the 5-min post-drug baselines; second, the change in average RSA that occurred during the 2-min anticipatory stress speech preparation phase of the Trier Social Stress Test (TSST) from the post-drug baseline; third, the change in average RSA that occurred across the 15-min of the TSST (speech + math tasks) from the post-drug baseline; fourth and finally, the change in average RSA that occurred across 7-min in a post-stressor recovery period as compared to the post-drug baseline.</description>
        <time_frame>Pre-drug baseline; 60-min post-drug administration baseline before stressor; 2-min before the stressor; 15-min during stressor, 7-min recovery post-stressor</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Propanolol Hydrochloride</title>
            <description>This is the experimental group given the beta-blocker, propanolol hydrochloride using a 40mg single tablet dosage.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>This is the control group given a placebo, which was a placebo-matching active drug</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Respiratory Sinus Arrhythmia</title>
          <description>Mean level respiratory sinus arrhythmia (RSA) derived from electrocardiogram; measure of heart rate variability assessed as the ratio of low-to-high frequencies in the respiratory-cardiac power spectrum. Four different change scores were calculated: first, the change in average RSA from the 5-min pre-drug baseline to the 5-min post-drug baselines; second, the change in average RSA that occurred during the 2-min anticipatory stress speech preparation phase of the Trier Social Stress Test (TSST) from the post-drug baseline; third, the change in average RSA that occurred across the 15-min of the TSST (speech + math tasks) from the post-drug baseline; fourth and finally, the change in average RSA that occurred across 7-min in a post-stressor recovery period as compared to the post-drug baseline.</description>
          <units>Ratio</units>
          <param>Mean</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="44"/>
                <count group_id="O2" value="48"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Post-drug from pre-drug baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value=".11" lower_limit="-.173" upper_limit=".395"/>
                    <measurement group_id="O2" value=".27" lower_limit="-.025" upper_limit=".563"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>TSST-prep from post-drug baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value=".36" lower_limit=".076" upper_limit=".644"/>
                    <measurement group_id="O2" value="-.43" lower_limit="-.734" upper_limit="-.126"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>TSST from post-drug baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-.06" lower_limit="-.332" upper_limit=".212"/>
                    <measurement group_id="O2" value="-.87" lower_limit="-1.20" upper_limit="-.540"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Post-stress recovery from post-drug baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value=".36" lower_limit=".088" upper_limit=".632"/>
                    <measurement group_id="O2" value="-.26" lower_limit="-.593" upper_limit=".073"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Negative, High Arousal Emotion</title>
        <description>Self-report measure of affect (emotion) state using the Positive &amp; Negative Affect Schedule Negative Affect (PANAS). Answered on a Likert scale from 0 (&quot;not at all&quot;) - 6 (&quot;very much&quot;). Mean score range is from 0-6. Higher numbers indicate more negative, high arousal emotions; low numbers indicate less negative, high arousal emotions. Three change scores were calculated from the four different rating measurement time points: a change in negative, high arousal emotions at the post-drug baseline from the pre-drug baseline; a change in emotions right before the Trier Social Stress Task (TSST) from the post-drug baseline; and a change in emotions during the TSST from the post-drug baseline.</description>
        <time_frame>Pre-drug baseline; 60-min post-drug administration baseline before stressor; 2-min before the stressor; 1-min post-stressor</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Propanolol Hydrochloride</title>
            <description>This is the experimental group given the beta-blocker, propanolol hydrochloride using a 40mg single tablet dosage.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>This is the control group given a placebo, which was a placebo-matching active drug</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Negative, High Arousal Emotion</title>
          <description>Self-report measure of affect (emotion) state using the Positive &amp; Negative Affect Schedule Negative Affect (PANAS). Answered on a Likert scale from 0 (&quot;not at all&quot;) - 6 (&quot;very much&quot;). Mean score range is from 0-6. Higher numbers indicate more negative, high arousal emotions; low numbers indicate less negative, high arousal emotions. Three change scores were calculated from the four different rating measurement time points: a change in negative, high arousal emotions at the post-drug baseline from the pre-drug baseline; a change in emotions right before the Trier Social Stress Task (TSST) from the post-drug baseline; and a change in emotions during the TSST from the post-drug baseline.</description>
          <units>score on a scale</units>
          <param>Mean</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="44"/>
                <count group_id="O2" value="48"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Post-drug from pre-drug baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-.10" lower_limit="-.141" upper_limit="-.059"/>
                    <measurement group_id="O2" value="-.13" lower_limit="-.185" upper_limit="-.075"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>TSST-prep from post-drug baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value=".18" lower_limit=".122" upper_limit=".238"/>
                    <measurement group_id="O2" value=".37" lower_limit=".300" upper_limit=".440"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>TSST stressor from post-drug baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value=".61" lower_limit=".532" upper_limit=".689"/>
                    <measurement group_id="O2" value=".76" lower_limit=".678" upper_limit=".842"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>From the time of randomization until 9 months following.</time_frame>
      <desc>All participants were carefully prescreened to ensure no contra-indications for the low dose (40 mg) of propranolol.</desc>
      <group_list>
        <group group_id="E1">
          <title>Propanolol Hydrochloride</title>
          <description>This is the experimental group given the beta-blocker propanolol hydrochloride. All subjects in this group received a single dose of 40mg of propanolol in a single tablet.</description>
        </group>
        <group group_id="E2">
          <title>Placebo</title>
          <description>This is the control group given a placebo. All subjects in this group received a single dose of the placebo in a single tablet.</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="44"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="48"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="44"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="48"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="44"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="48"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <limitations_and_caveats>1. Not all salivary alpha amylase samples were assayed in duplicate because there was not enough saliva for the 15-min post-stress time point. 2. For the first ten subjects, a shorter version of the PANAS with 20 rather than full 40 items was used.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Dr. Keely A. Muscatell</name_or_title>
      <organization>University of North Carolina at Chapel Hill</organization>
      <phone>919-843-9113</phone>
      <email>kmuscatell@unc.edu</email>
    </point_of_contact>
  </clinical_results>
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02972554
org study id: 16-2498
nct id: NCT02972554
lead sponsor: 
has dmc: No
This randomized, double-blind, placebo-controlled study of propranolol will shed important
      light on how sympathetic nervous system (SNS) activation influences psychological and
      inflammatory responses to acute stress. Results from this study will inform both the basic
      science literature that is attempting to map the physiological mechanisms by which
      psychological stress may lead to poor mental and physical health, and may also ultimately
      have therapeutic relevance for individuals who are experiencing high levels of stress that is
      putting their health at risk. Utilizing a psychopharmacological approach allows for the
      circumvention of many of the challenges of conducting this research in human populations, and
      will allow for conclusions regarding causality, given that SNS activation will be
      experimentally manipulated, rather than relying on correlational measures of SNS activity
      that are difficult to assess and are not appropriate for asking if SNS activity causes
      changes in psychology and biology.
Psychological stress is implicated in the onset and progression of many common and costly
      chronic diseases, including cardiovascular disease, chronic pain conditions, and major
      depressive disorder (Cohen et al., 2007; Kendler et al., 1999; Steptoe and Kivimäki, 2012).
      An emerging body of evidence suggests that inflammation, indexed via levels of
      pro-inflammatory cytokines and reactive proteins, may be a key biological mechanism by which
      stress affects health (Baker et al., 2012; Miller et al., 2009; Slavich et al., 2010).
      Indeed, psychological stressors can induce increases in inflammation (Slavich and Irwin,
      2014; Kiecolt-Glaser et al., 2003; Rohleder, 2014; Steptoe et al., 2007), and greater levels
      of inflammation may contribute to the development of disease (Capuron and Miller, 2004; Choy
      and Panayi, 2001; DellaGiola and Hannestad, 2010; Raison and Miller, 2013; The Emerging Risk
      Factors Collaboration, 2010). Despite this growing literature linking stress, inflammation,
      and poor health, little is known about the precise physiological mechanisms linking
      psychological stress and increases in inflammation.

      One hypothesized mechanism that may translate psychological stress into increases in levels
      of inflammation is activation of the sympathetic nervous system (SNS). The SNS is part of the
      autonomic nervous system and is primarily indexed by release of the catecholamines
      epinephrine (adrenaline) and norepinephrine (noradrenaline). Prior research in non-human
      animal models has shown that stress-induced SNS activation leads to increases in levels of
      pro-inflammatory cytokines inflammation (Bierhaus et al., 2003; DeRijk et al., 1994; Kop et
      al., 2008; van Gool et al., 1990), while pharmacologically blocking sympathetic activation
      attenuates the inflammatory response to stress (Bierhaus et al., 2003). However, no known
      human studies to date have examined the relationship between psychological stress, SNS
      activation, and inflammation. The present study is designed to address this major gap in our
      knowledge of the physiological mechanisms that may link stress and disease.

      A potential reason for the lack of human research linking stress, SNS activation, and
      inflammation is that SNS activity is difficult to measure. Indeed, adrenaline and
      noradrenaline are released into the bloodstream very rapidly during a stressor, making their
      kinetics difficult to capture during typical laboratory-based stress paradigms. Indirect
      measures of SNS activity may be acquired using psychophysiological approaches that involve
      peripheral measures of electrical activity and efficiency of the heart; however, these
      methods provide only indirect indicators of SNS activity, making them subject to criticism in
      the psychoneuroimmunology community.

      To circumvent these issues with assessment of SNS activity, the present study will employ a
      psychopharmacological approach to experimentally block SNS activity using the drug
      propranolol. Propranolol is a beta-blocker medication that is very commonly prescribed by
      physicians in the United States for the treatment of hypertension, given that it blocked
      adrenergic receptors that lead to relaxation of the cardiac muscle and smooth muscle tissue.
      Interestingly, propranolol is also sometimes prescribed to individuals who have performance
      anxiety (i.e., public speaking anxiety), as reducing SNS activity (i.e., eliminating the
      increased heart rate, blood pressure, sweaty palms, etc., that typically accompany
      anxiety-provoking situations) has been anecdotally observed to decrease perceptions of stress
      during these situations. Psychological scientists have recently become more interested in the
      role SNS activity may play in the formation and reconsolidation of fear memories, and a
      number of studies have now used propranolol to investigate if blocking SNS activity may help
      treat individuals with Post-Traumatic Stress Disorder (PTSD; Pitman et al., 2002; Vaiva et
      al., 2003). However, only one known study to date has investigated if propranolol reduces
      stress-induced immune system activation (Benschop et al., 1994), and this (now dated) study
      did not specifically explore if propranolol reduces inflammatory responses to stress.
      Furthermore, no known studies have examined if blocking SNS activity with propranolol changes
      individuals' appraisals of the stressful situation, or their affective responses to stress.
      Results from this study will complement and extend the existing work on how SNS activity
      affects fear memories and stress by focusing on how propranolol affects inflammatory and
      psychological responses to a stressor.

      In addition to these primary goals of the present study, the investigators will also explore
      the role of SNS activation in a number of additional exploratory tasks that are hypothesized
      to be affected by sympathetic arousal. More specifically, the investigators will examine if
      exposure to propranolol eliminates implicit biases toward out-group members (in this case,
      African Americans), given that a very large literature suggests that many White Americans
      hold implicit biases against African Americans (Wittenbrink et al., 1997; Nosek et al.,
      2002). While it has been hypothesized that sympathetic arousal based on cultural stereotypes
      associating African Americans with negativity may be leading to these implicit biases, no
      known studies have investigated this issue. The investigators will also explore of SNS
      activation is critical for empathy, or individual's ability to understand the emotional
      states of others, for avoiding risky decisions, and for moral judgments. Thus, this study
      will also answer a number of exploratory, unanswered questions in social psychology regarding
      the role that sympathetic arousal plays in some of our most fundamental psychological
      processes.

      In sum, this randomized, double-blind, placebo-controlled study of propranolol will shed
      important light on how SNS activation influences our psychological and inflammatory responses
      to stress. Results from this study will inform both the basic science literature that is
      attempting to map the physiological mechanisms by which psychological stress may lead to poor
      mental and physical health, and may also ultimately have therapeutic relevance for
      individuals who are experiencing high levels of stress that is putting their health at risk.
      By utilizing psychopharmacological approaches, the investigators will circumvent many of the
      challenges of conducting this research in human populations. The investigators will also be
      in a place to draw strong conclusions regarding causality, given that they will have
      experimentally manipulated SNS activation, rather than relying on correlational measures of
      SNS activity that are difficult to assess and are not appropriate for asking if SNS activity
      causes changes in psychology and biology.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Basic Science
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Change in Interleukin-6 (IL-6)
time frame: Pre-drug baseline; 60-min post-drug administration baseline before stressor; 30-min post-stressor; 60-min post-stressor; 90-min post-stressor
description: Measured in blood plasma using enzyme-linked immunosorbent assay. Log-transformed prior to analysis to correct for skew in data. Four different change scores were calculated: first, change at post-drug from pre-drug baseline; second, the change at 30-min post-stressor from post-drug baseline; third, change at 60-min post-stressor from post-drug baseline; and fourth, change at 90-min post-stressor from post-drug baseline.
measure: Change in Salivary Cortisol
time frame: Pre-drug baseline; 60-min post-drug administration baseline before stressor; 15-min post-stressor; 30-min post-stressor
description: Concentration of cortisol in saliva quantified quantified by chemiluminescence immunoassay with high sensitivity. Three different change scores were calculated from pre-drug to post-drug baselines, 15-min post-stressor from post-drug baseline, and 30-min post-stressor from post-drug baseline.
measure: Change in Salivary Alpha Amylase
time frame: Pre-drug baseline; 60-min post-drug administration baseline before stressor; 15-min post-stressor
description: Concentration of alpha amylase in saliva quantified quantified by enzyme kinetic method. Two different change scores were calculated: first, the pre-drug to post-drug baseline change and, second, the 15-min post-stressor change from post-drug baseline.
measure: Change in Pre-Ejection Period
time frame: Pre-drug baseline; 60-min post-drug administration baseline before stressor; 2-min before the stressor; 15-min during stressor, 7-min recovery post-stressor
description: Mean level pre-ejection period (PEP; centered at zero) derived from impedance cardiography and electrocardiogram. Four different change scores were calculated: first, the change in average PEP from the 5-min pre-drug baseline to the 5-min post-drug baselines; second, the change in average PEP that occurred during the 2-min anticipatory stress speech preparation phase of the Trier Social Stress Test (TSST) from the post-drug baseline; third, the change in average PEP that occurred across the 15-min of the TSST (speech + math tasks) from the post-drug baseline; fourth and finally, the change in average PEP that occurred across 7-min in a post-stressor recovery period as compared to the post-drug baseline.
measure: Change in Respiratory Sinus Arrhythmia
time frame: Pre-drug baseline; 60-min post-drug administration baseline before stressor; 2-min before the stressor; 15-min during stressor, 7-min recovery post-stressor
description: Mean level respiratory sinus arrhythmia (RSA) derived from electrocardiogram; measure of heart rate variability assessed as the ratio of low-to-high frequencies in the respiratory-cardiac power spectrum. Four different change scores were calculated: first, the change in average RSA from the 5-min pre-drug baseline to the 5-min post-drug baselines; second, the change in average RSA that occurred during the 2-min anticipatory stress speech preparation phase of the Trier Social Stress Test (TSST) from the post-drug baseline; third, the change in average RSA that occurred across the 15-min of the TSST (speech + math tasks) from the post-drug baseline; fourth and finally, the change in average RSA that occurred across 7-min in a post-stressor recovery period as compared to the post-drug baseline.
measure: Change in Negative, High Arousal Emotion
time frame: Pre-drug baseline; 60-min post-drug administration baseline before stressor; 2-min before the stressor; 1-min post-stressor
description: Self-report measure of affect (emotion) state using the Positive & Negative Affect Schedule Negative Affect (PANAS). Answered on a Likert scale from 0 ("not at all") - 6 ("very much"). Mean score range is from 0-6. Higher numbers indicate more negative, high arousal emotions; low numbers indicate less negative, high arousal emotions. Three change scores were calculated from the four different rating measurement time points: a change in negative, high arousal emotions at the post-drug baseline from the pre-drug baseline; a change in emotions right before the Trier Social Stress Task (TSST) from the post-drug baseline; and a change in emotions during the TSST from the post-drug baseline.
arm group label: Propanolol Hydrochloride
arm group type: Experimental
description: This is the experimental group given the beta-blocker
arm group label: Placebo
arm group type: Placebo Comparator
description: This is the control group given a placebo.
intervention type: Drug
intervention name: Propanolol hydrochloride
description: One-time dose of 40mg of propranolol
arm group label: Propanolol Hydrochloride
other name: Inderal
intervention type: Other
intervention name: Placebo
description: Outside casing matching that of active drug
arm group label: Placebo
other name: Sugar pill
criteria: 
gender: All
minimum age: 18 Years
maximum age: 25 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Keely A Muscatell, Ph.D
role: Principal Investigator
affiliation: University of North Carolina at Chapel Hill, Psychology & Neuroscience
facility: 
country: United States
citation: Adler N, Stewart J. The MacArthur Scale of Subjective Social Status. 2007. http://www.macses.ucsf.edu.
citation: Baker DG, Nievergelt CM, O'Connor DT. Biomarkers of PTSD: neuropeptides and immune signaling. Neuropharmacology. 2012 Feb;62(2):663-73. doi: 10.1016/j.neuropharm.2011.02.027. Epub 2011 Mar 22.
PMID: 21392516
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responsible party type: Sponsor
mesh term: Inflammation
mesh term: Stress, Psychological
mesh term: Propranolol
sharing ipd: No
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: 1. Not all salivary alpha amylase samples were assayed in duplicate because there was not enough saliva for the 15-min post-stress time point. 2. For the first ten subjects, a shorter version of the PANAS with 20 rather than full 40 items was used.
point of contact: 