SUBSTANCE USE AND ADDICTION AFFECT MORE THAN THE BRAIN: THE PROMISE OF NEUROCARDIAC INTERVENTIONS

Abstract

Purpose of Review

Addiction and excessive substance use contribute to poor mental and physical health. Much research focuses tightly on neural underpinnings and centrally-acting interventions. To broaden this perspective, this review focuses on bidirectional pathways between the brain and cardiovascular system that are well-documented and provide innovative, malleable targets to bolster recovery and alter substance use behaviors.

Recent Findings

Cardiovascular signals are integrated via afferent pathways in networks of distributed brain regions that contribute to cognition, as well as emotion and behavior regulation, and are key antecedents and drivers of substance use behaviors. Heart rate variability (HRV), a biomarker of efficient neurocardiac regulatory control, is diminished by heavy substance use and substance use disorders. Promising evidence-based adjunctive interventions that enhance neurocardiac regulation include HRV biofeedback, resonance paced breathing, and some addiction medications.

Summary

Cardiovascular communication with the brain through bidirectional pathways contributes to cognitive and emotional processing but is rarely discussed in addiction treatment. New evidence supports cardiovascular-focused adjunctive interventions for problematic substance use and addiction.

Introduction

Substance use is a widely-recognized contributor to the global burden of disease, with alcohol and other drug use linked to many of today’s most common psychological and physical health problems, including anxiety and depression, cardiovascular disease, liver disease, and cancers [1]. Most research and clinical practices related to substance use focus on substance use disorders (SUD). While this focus is of clear importance, a more expansive view is emerging that considers how substance use can broadly reduce health and increase risk for disease, disorder, and illness, even in the absence of ‗addiction’ per se. This new framework suggests that frontline healthcare providers can play a pivotal role in assessing substance use behaviors. This article further suggests that such providers can intervene in problematic substance use using body-based strategies that are both simple to learn and simple to teach. This article proposes that body-based interventions allow the health risks of substance use to be perceived as analogous in many ways to those from sedentary lifestyle, poor diet, and insufficient sleep. In doing so, they may also serve to reduce the stigma associated with substance misuse.

This article focuses on neuroscience-informed, body-based intervention strategies that are gaining popularity and research support. Specifically, we emphasize the role of the cardiovascular system in subjective experiences and learned behaviors, which include substance use and addiction. We then present heart rate variability (HRV) biofeedback and resonance paced breathing as body-focused interventions that harness inherent regulators of body-brain communication to instigate neuroplasticity [2, 3]. These interventions have been shown both to improve physiological health and to support emotion regulation and cognitive control [4, 5]. Finally, we align the use of body-focused interventions to current pharmacotherapies and conclude with an overview of how a body-focused approach to substance use and addiction expands our view of health, disease, and recovery, while simultaneously adding precision and personalization.

The case for considering the body in substance use and addiction

Anyone who has experienced the racing heart of fear, the broken heart of loss, or the fluttering heart of love knows that body states are an intrinsic component of subjective experience. Rapid advances in the field of interoception add an empirical base to these human experiences [6, 7]. Moreover, interoception provides a mechanism to explain how body states play a critical role in learned behavior. Namely, body states provide sensory and visceral context to neural processes. This sensory and visceral context is increasingly being recognized as a powerful factor in drug-seeking behavior [8] and addictive disorders [9, 5].

In the case of the cardiovascular system, while changes in heart rate and blood pressure serve as essential and broadly utilized health biomarkers, more recent research has also demonstrated that these changes become embedded features of cognitive-emotional experience [5, 4]. This has significant implications for how we view cardiovascular system processing; it is not simply a passive, static indicator of life, but an active, dynamic contributor to it. This perspective aligns with research across a range of physiological systems, most notably the immune and digestive systems that interact with the autonomic nervous system and brain to support cognitive and emotional regulation [10, 11].

Anatomically, the cardiovascular system and its bidirectional connections to the brain have been well-elaborated [12]. Only more recently, however, has research moved the conceptualization of cardiovascular physiology beyond reflexive blood pressure control [13–15]. Cardiovascular information enters the brain at the nucleus tractus solitarius in the brainstem, which is then propagated to structures that control heart rate and peripheral resistance (i.e., vasculature tone and blood pressure), as well as to structures linked to cognition and emotion, namely the medial prefrontal cortex, insula, basolateral amygdala, thalamus, hypothalamus, and ventral tegmental area. This adds further support for how bodily signals become an embedded component of learned behaviors. The high degree of overlap between these structures and those delineated in prominent addiction theories is noteworthy [5].

The cardiovascular system has several advantages over other body systems as an intervention target to improve both physical and mental health. Most notably, it is easy to monitor and easy to manipulate. Additionally, there are established normative cardiovascular parameters (e.g., resting average blood pressure of 120/80) that are widely used as medical biomarkers. Beyond these static biomarkers, dynamic indices, such as heart rate variability (HRV), are gaining prominence in clinical science [16], in part because of the increasing availability of low-cost, ambulatory HRV monitoring tools like wearable electrocardiographs and photoplethysmographs, and smartphone apps. Acceptability of HRV monitors is further bolstered by general knowledge that HRV is associated with, and predicts, variations in fitness and health. Psychologically and physiologically healthy individuals typically present with relatively higher levels of HRV, while those with underlying health conditions, including SUD, commonly show relatively lower HRV levels [17, 18] (see Heiss et al., 2021 for an exception). HRV can be measured at rest or in response to a wide variety of challenges and, in 5 minutes or less, multiple measures of HRV can be obtained. Multiple HRV measures directly reflect inherent physiological control mechanisms, most notably vagal (e.g., parasympathetic activation) and baroreflex control mechanisms [19, 13, 20].

Research in our laboratories focuses on the baroreflex control mechanism. This mechanism is well known because it ensures reflexive control of blood pressure through closed-loop feedback systems that modulate heart rate, stroke volume, and vascular tone [19, 13, 21, 22]. The heart rate baroreflex is particularly well understood; heart rate accelerations and/or vasoconstriction lead to an increase in blood pressure that is detected by baroreceptors present in arterial walls; this information is conveyed to the brain that then signals heart rate deceleration via efferent parasympathetic signaling. As noted above, the afferent heart rate and blood pressure information is also conveyed to higher-order subcortical and cortical structures that embed this information within a cognitive-emotional context and communicate with midbrain and brainstem structures to influence subsequent cardiovascular adjustments. In this way, cardiovascular and other bodily feedback becomes integrated within conscious elements of executive control and emotion regulation, as well as in attention bias, salience, and craving processes that operate largely outside of awareness [23, 10].

Changing cardiovascular physiology leads to clinical benefit

HRV biofeedback and resonance paced breathing are two closely related bio-behavioral interventions that engage autonomic regulatory processes through slow, paced breathing. Both interventions evoke strong neuroplastic responses [24, 25] and produce positive clinical changes across multiple physical and mental health disorders including hypertension, asthma, anxiety, depression, post-traumatic stress disorder, and SUD [25, 26]. Both HRV biofeedback and resonance paced breathing are techniques that manipulate respiratory sinus arrhythmia, a physiological phenomenon that links respiratory and cardiovascular functioning [27]. When the respiratory sinus arrhythmia is entrained to the inherent internal rhythm of the baroreflex, an exponential whole-system cardiovascular response is observed. In HRV biofeedback, an individual’s resonance frequency (i.e., the frequency at which minimal respiratory input elicits maximal cardiovascular response) is precisely identified, and then breathing at this frequency is guided by biofeedback equipment (i.e., where one’s dynamic pulse wave is displayed on a screen to guide breathing frequency). For most individuals, the resonance frequency is ~0.1Hz, which is equivalent to 6 breaths per minute, though there is some inter-individual variability based on body size and blood volume [28, 27]. Resonance paced breathing is based on the same physiological principles but instead of utilizing individualizing biofeedback, breathing is simply paced at 0.1Hz using a digital app or clock.

Most research to date has focused on multi-week courses of HRV biofeedback and demonstrated that breathing at one’s precise resonance frequency confers the greatest physiological and psychological benefits [29, 30]. Yet, evidence is growing that even brief episodes of resonance paced breathing similarly support cardiovascular health, autonomic homeostasis, cognitive and emotional self-regulation, and may reduce autonomic allostatic load during stress states [25, 31]. Meta analytic evidence supports the use of HRV biofeedback and resonance paced breathing across a wide range of disorders [25]. Medium-to-large effect size decreases in anxiety and stress have been observed in response to HRV biofeedback and resonance paced breathing [25, 31], consistent with positive modulatory effects on brain regions dually involved in autonomic nervous system control [32] and addiction [33, 5]. A substantial body of work indicates HRV biofeedback benefits individuals with difficulty regulating affect such as depressive disorders [e.g., 34, 35–37] and PTSD [e.g., 38, 39–42], both of which are highly co-morbid with SUD. Such interventions need not be seen as stand-alone measures; rather, interventions that enhance baroreflex sensitivity may facilitate cognitive, behavioral, and motivational therapies for SUD.

Early successes with HRV biofeedback and resonance paced breathing for disorders that involve emotion dysregulation gave rise to a growing body of work exploring the potential benefits of HRV biofeedback for SUD. It was posited that HRV biofeedback could enhance communication between neural and cardiovascular systems that modulate physiological arousal in response to internal and external cues that are antecedent to substance use, thus increasing behavioral flexibility and reducing relapse risk [43, 4]. A recent systematic review [44] suggests that HRV biofeedback may reduce craving, citing work involving short [3 sessions; 45], moderate [6 sessions; 46, 47], and longer term [8 sessions; 48, 49] interventions. Studies by Penzlin and colleagues also showed HRV biofeedback led to reductions in anxiety in patients with alcohol use disorder [47], and a trend towards lower alcohol use relapse at one-year follow-up compared to controls [46].

Brief (e.g., 5 minutes) assessment of neurocardiac processes may have utility predicting who will show positive clinical benefit from biobehavioral interventions such as HRV biofeedback. For example, higher resting HRV was associated with lower craving in alcohol dependent outpatients [50]. Further, in a clinical trial of HRV biofeedback for SUD, lower resting baseline HRV was associated with increases in craving over three weeks in an inpatient SUD group who received treatment as usual (TAU) [45]. However, this effect was not present in the group that received HRV biofeedback in addition to TAU. Thus, the intervention appeared to dissociate the relationship between initial physiological vulnerability and craving changes during treatment. These findings suggest that HRV biofeedback may be an especially useful adjunctive treatment for those showing evidence of weaker autonomic regulation (i.e., lower HRV), although further study is needed to support this hypothesis.

The benefits of HRV biofeedback are not limited to those with mental and physical health conditions. Evidence has shown that in the wider population, practicing resonance breathing, in some cases only for 5 or 10 minutes, can improve cognitive performance [51], decrease performance anxiety [52], reduce stress, and improve sleep quality [53, 54]. This suggests that resonance breathing not only confers benefit in persons with disorders, but more broadly it enhances baroreflex signaling and the integration of cardiovascular signals with neural processes responsible for cognitive and emotional regulation for all people. The scope of potential application of this intervention thus extends across the continuum of preclinical, high-risk, substance use disordered, and recovering populations.

Such applications are supported by recent technological advances that have given rise to small, light-weight, wearable biosensors and smartphone applications that use photoplethysmography to enable wearers to engage in HRV biofeedback on-the-go [55–57]. Additionally, some second-generation ambulatory, biosensor-based technologies that monitor autonomic arousal in real time can be used to prompt wearers to engage in brief bursts of HRV biofeedback to normalize autonomic output during periods of stress/high autonomic arousal [58]. These just-in-time interventions may serve as useful tools to buffer salient contextual triggers and urges to use alcohol and other drugs, as well as anxiety and stress. We recently observed, for example, that a single 5-minute session of resonance paced breathing decreased neural activation to alcohol cues in visual representation and attentional processing brain regions, while at the same time increasing activation in regions associated with behavioral control, internally directed cognition, and brain-body integration across low risk drinkers and those who met criteria for alcohol use disorder [24]. In addition to their potential for direct clinical benefit, the advent of ambulatory HRV biofeedback and paced breathing devices has profound implications for the accessibility and scalability of HRV biofeedback and resonance paced breathing because they are affordable, usually integrate with the end-user’s smartphone, and do not require a provider to administer the intervention. These characteristics make implementation through mobile technologies especially useful for underserved and hard-to-reach populations.

Support for body-focused intervention from pharmacotherapy

A number of on- and off-label medications are commonly used in the treatment of SUD. Though generally speaking these medications are thought to confer benefit by mitigating withdrawal symptoms and/or reducing craving, the specific mechanism of action for most SUD medications is not known [59, 60]. Some of these medications have well documented, direct cardiovascular effects, while others have likely or implied effects on cardiac modulation. It is possible that several of these medications may help support SUD recovery indirectly through normalization of neurocardiac processes.

For instance, the drugs acamprosate (best known by the brand name Campral), and topiramate (best known as Topamax) are widely prescribed to individuals with SUD because of their capacity to reduce craving and substance use [61]. These are hypothesized to support SUD recovery in a number of ways, all of which help modulate neuronal hyperexcitability associated with substance use and drug withdrawal states [particularly alcohol and benzodiazepines; 62, 63]. Evidence suggests that these medications also reduce physiological arousal, as evidenced by reduced heart rate [64, 65], mean arterial blood pressure [66], galvanic skin conductance [65, 67, 68], and blood cortisol [69], along with increases in HRV [67]. It is possible that acamprosate and topiramate are effecting benefit for some individuals at the level of the brain by inhibiting neural hyperexcitation, while for others the greatest benefit may be derived from the peripheral effects of the medications via reduced physiological arousal.

The postulate that these medications may confer benefit through cardiovascular modulation is supported by a large body of research indicating that a number of adrenergic-targeting medications including prazosin and doxazosin (alpha-1 adrenergic inverse agonists, or “alpha-blockers”) and propranolol (beta 1-and-2 adrenergic antagonist, or “beta-blockers”) that are widely used to treat hypertension, reduce craving and the use of alcohol and other drugs [70–78]. Potentially, these medications support SUD recovery by dampening high basal levels of sympathetic arousal commonly observed in individuals with SUD [75, 74, 77]. Whereas the effects on blood pressure are primarily driven by countering noradrenergic-mediated vasoconstriction via adrenergic receptors in the smooth muscle of the vasculature, effects on craving and substance use likely derive from direct actions on noradrenergic receptors found throughout the central nervous system. However, the role of these medications on altering baroreflex sensitivity and heart rate variability (Petersen et al., 2018) cannot be ruled out as potential mechanisms of action in addiction medicine.

In preliminary studies, Wilcox et al. [79] and Haass-Koffler et al. [80] observed greater reductions in alcohol use among individuals receiving prazosin or doxazosin compared to placebo in those with high resting blood pressure, but not healthy resting blood pressure. Examination of beta blocker efficacy in decreasing cocaine craving indicated drops in both craving and autonomic arousal to cocaine cues [77], though the relationship between the two has yet to be examined. While these ideas require further investigation, they present the potential for prescribers to use a brief assessment of basal heart rate and HRV to determine who might benefit most from these medications. Given heart rate/HRV can be easily measured using small, inexpensive and non-invasive devices—for instance, while a patient waits to be seen by their provider or using the pulse-oximeter when nursing staff take patients’ vitals—this may be a scalable precision medicine approach that could help match SUD medications to patients.

Conclusion: Body-Brain-Behavior

A continuum of alcohol and drug use behaviors can have multiple and intersecting negative effects on mental and physical health. Substance use behavior change and recovery from addiction thus can be facilitated by holistic interventions that span the brain-body divide. Neurocardiac adjunctive interventions offer an evidence-based approach to bolster an underlying physiological pathway between the brain and body via the baroreflex mechanism. HRV biofeedback modulates the baroreflex mechanism to improve cardiovascular health, help reduce craving responses to salient environmental cues, and promote cognitive control and emotion regulation. The baroreflex mechanism also may be modulated via a number of medications used to treat substance use disorders. There is utility in identifying homogeneous subgroups of persons who may be most likely to benefit from either behavioral or pharmacologic interventions that improve neurocardiac signaling. Recent advances in biosensors and smartphone applications offer the potential for just-in-time behavioral interventions such as HRV biofeedback and resonance paced breathing that are accessible to large numbers of persons and may have value in interrupting automatic trigger states that interfere with conscious goals to reduce or stop substance use. Given the health promoting benefits and absence of negative side effects from such biobehavioral approaches, greater utilization by practitioners and further investigation by researchers could have substantial impact on holistic recovery from addiction and broadly improve public health.

Human and animal rights

All reported studies/experiments with human or animal subjects performed by the authors have been previously published and complied with all applicable ethical standards (including the Helsinki declaration and its amendments, institutional/national research committee standards, and international/national/institutional guidelines).

Figure 1.

Schematic highlighting the subjective, physiological, and neurological effects of heart rate variability biofeedback and resonance paced breathing on the continuum of substance use behaviors.