Does Propranolol Attenuate Inflammatory Responses to a Psychological Stressor?
Condition: Stress, Psychological; Inflammation; Cortisol; Sympathetic Nervous System
MeSH terms: Inflammation; Stress, Psychological
Study type: Interventional
Phase: Phase 4

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Propanolol hydrochloride; Placebo
Intervention type(s): Drug; Other
Intervention description(s): One-time dose of 40mg of propranolol; Outside casing matching that of active drug
Other intervention name(s): Inderal; Sugar pill
Intervention MeSH terms: Propranolol
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Basic Science