The neurobiology of love and addiction: Central nervous system signaling and energy metabolism

Abstract

Despite our ongoing fascination with love’s pleasures and pain, psychologists and neurobiologists have only recently begun to explore the neurobiological connections shared by feelings of romantic love and the experience of drug addiction. Functional imaging studies have revealed that feelings resulting from romantic love and those resulting from active drug use both activate the central reward system, which is a series of forebrain and midbrain structures that transmit signals primarily via dopamine release. Similarly, the relaxation response, which is a series of behaviors designed to alleviate stress-related physiologic sequelae, may also be helpful as an adjunct therapy for drug withdrawal. The benefits of the relaxation response and related mind-body practices may stem directly from its impact on mitochondria, organelles that are central to balanced energy production. Nitric oxide (NO) is a central neurotransmitter and also a key regulatory molecule that modulates mitochondrial respiration and oxygen utilization. Thus, we propose that observed behaviorally mediated changes that emerge from engaging the relaxation response may be the result of NO-mediated improvements in mitochondrial bioenergetics. Future research might focus on elucidating the important links between cellular bioenergetics, the relaxation response, and the central reward system and might explore NO modulation as a potentially effective target for drug development.

Love is like a narcotic. At first it brings the euphoria of complete surrender. The next day, you want more.

– Paulo Coelho (1994)

Introduction

We are all familiar with the profound emotional impact of romantic love. Apart from our own experiences, true love remains among the most frequent themes explored in drama, fiction, music, and poetry since time immemorial. Interestingly, and despite our ongoing fascination with love’s pleasures and pain, psychologists and neurobiologists have only recently begun to explore the physiological connections between romantic love and the experience of drug addiction. In this narrative review, we will discuss our current understanding of this field and suggest some directions for future research.

Romantic love and addiction

From a psychologist’s perspective, romantic love is a response involving intimacy and passion in which the loved party is often idealized (American Psychological Association, 2018a, 2018b). When requited, romantic love features feelings of mutual appreciation, desire, and excitement, together with a wish for physical proximity. Anthropologist H. E. Fisher and colleagues (2016) discussed romantic love as a “natural addiction” and an evolutionary adaptation that developed together with mechanisms that facilitate long-term bonding and effective child-rearing. By contrast, neurobiologists might define romantic love as a motivational state that involves the neurochemical activation of pleasure centers in the central nervous system (CNS) (Esch & Stefano, 2005a, 2005b; Seshadri, 2016).

At first glance, romantic love and drug addiction (also known as substance use disorder) appear to be completely unrelated phenomena. The psychological literature defines addiction as a state of mental and/or physical dependence on drugs or other substances (e.g., alcohol, tobacco) and/or behaviors (e.g., gambling) (American Psychological Association, 2018a, 2018b). By contrast, the clinical/neurobiological definition focuses on addiction as a chronic relapsing disorder involving complex interactions among brain circuits and the emergence of a negative emotional state (American Society of Addiction Medicine, 2019; Koob & Volkow, 2016).

While these definitions of romantic love and addiction are both formal and distinct, recent studies focused on dissecting brain pathways and neurochemical activation patterns tell another story. Interestingly, in their 1975 book entitled “Love and Addiction,” authors Stanton Peele and Archie Brodsky (1975) were among the first to highlight the links between these two phenomena and consider the possibility of developing novel rehabilitation and treatment strategies based on these observations. While this possibility was discussed phenomenologically in earlier literature, the results of recent mechanistic/imaging studies revealed that both romantic love and addictive substances can activate what is known as the central “reward pathway” (Lewis et al., 2021). The components and activities of the reward pathway and its responses to romantic love and substance use are discussed in the following sections.

The reward pathway

The reward pathway (also known as the mesolimbic-mesofrontal dopaminergic system) is a complex series of forebrain and midbrain structures that signal to one another to reinforce pleasurable activities. Pleasurable stimuli activate this circuit by triggering the ventral tegmental area (VTA) to generate dopaminergic signals. These signals are received and processed by the nucleus accumbens (NAc) with additional roles played by the prefrontal cortex, the hippocampus, the striatum, and the amygdala (National Institute on Drug Abuse, 2007; Lewis et al., 2021; Esch & Stefano, 2010).

The central reward system is activated in individuals who are experiencing emotions associated with romantic love or engaged in drug use. In the mammalian brain, opiate drugs activate the central reward system by binding to endogenous receptors. While these receptors exist throughout the CNS (Dhaliwal & Gupta, 2023), specific Mu-type opiate receptors are found at high density in the VTA, NAc, and prefrontal cortex. Morphine binds to these receptors and promotes dopaminergic signaling (Valentino & Volkow, 2018; Dhaliwal & Gupta, 2023). Moreover, recent positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) studies have shown that drug use activates central reward circuits, as well as brain regions involved in motivation, memory, and cognitive control (Volkow et al., 2003; Murnane et al., 2023).

Interestingly, functional imaging studies performed on patients experiencing romantic love revealed similar findings (reviewed in Zeki, 2007; Fisher et al., 2005). For example, Aron et al. (2005) performed fMRI studies on both males and females reported to be intensely “in love” and found that exposure to object-specific stimuli led to the activation of dopamine-rich areas associated with mammalian reward and motivation, including the right VTA. Similarly, Song et al. (2015) performed resting state fMRI on a series of volunteers and found increased functional connectivity within the reward, motivation, and emotional regulation networks (including the amygdala, and NAc) among those identified as currently “in love” (Fig. 1). These findings are confirmed by recent studies (Rinne et al., 2024). Similarly intriguing, Burkett et al. (2011) reported that specific blockade of opiate Mu-receptors in the mammalian brain (females of the monogamous prairie vole, Microtus ochrogaster) resulted in diminished partner preference.

Fig. 1.

CNS reward system involvement in love, drug administration – motivation, memory regulation. Explanations see text; CNS = central nervous system

Neurotransmitters within the reward pathway

Dopamine

Dopamine is the primary neurotransmitter involved in reward and motivation, romantic love, pleasure derived from social approval, and responses to substance use. Both D1 and D2-type dopamine receptors have been identified in the NAc, a key region that responds to dopaminergic signaling from the VTA (Lewis et al., 2021). Although dopamine was originally discovered in the 1950 s and characterized using more traditional biochemical methods (Iversen & Iversen, 2007; Carlsson, 2000), PET has been used to explore the contributions of dopamine in the reinforcing effects of drugs, the long-term brain changes in drug-addicted subjects, and factors associated with vulnerability to addiction (Volkow et al., 2007; Tomkins & Sellers, 2001).

Dopamine plays a key intermediary role in a broader biochemical system, including the biosynthesis of endogenous morphine and its interactions with nitric oxide (NO) and nitric oxide synthase (NOS); both of these factors influence mitochondrial function and adenosine triphosphate (ATP) production. Endogenous morphine modulates mitochondrial respiration and redox homeostasis in part via its interactions with NO signaling (Stefano et al., 2012; Stefano et al., 2015). Dopamine, a catecholamine precursor to endogenous morphine in certain cell types, may thus indirectly influence mitochondrial bioenergetics (Zhu et al., 2005). The implication is that dopamine withdrawal (such as that occurring in response to stress or addiction) could disrupt this network, diminishing the efficiency of ATP synthesis and increasing oxidative stress.

Oxytocin and vasopressin

Oxytocin and vasopressin play critical roles in social bonding and attachment responses. Oxytocin is released during loving interactions, social connections (e.g., feeling appreciated), and even during certain reward-related activities (e.g., trust-building tasks) (Rigney et al., 2022; Carter, 2017; Insel, 2010). Oxytocin receptors are also concentrated primarily in the VTA and NAc, where they modulate dopamine release (Peris et al., 2016). Vasopressin V1a receptors also modulate dopamine signaling in the brain, notably in the ventral pallidum (Carter, 2017; Insel, 2010). While these molecules enhance the emotional salience of rewarding and bonding experiences, they have also been implicated in drug-induced reward responses (Wronikowska-Denysiuk et al., 2023).

Gamma-aminobutyric acid

Gamma-aminobutyric acid (GABA) is a neurotransmitter synthesized primarily in specific GABAergic neurons that are widely distributed throughout the CNS. Recent technical advances, including the availability of proton magnetic resonance spectroscopy, have led to an improved understanding of the role of this neurotransmitter in health and disease (Shyu et al., 2022). Among its actions in the CNS, GABA modulates the central reward system primarily via its interactions with dopaminergic neurons (Volkow et al., 2019).

Other agents

Other endogenous signaling molecules that interact with the central reward system with implications for drug addiction include enkephalins and beta-endorphin (reviewed in Rysztak & Jutkiewicz, 2022; Roth-Deri et al., 2008; Le Merrer et al., 2009; Zalewska-Kaszubska & Czarnecka, 2005). The central role of NO as both a neurotransmitter and modulator of bioenergetic balance is discussed below.

The relaxation response

First described by Herbert Benson & colleagues (1975), the relaxation response is a physical state of deep rest that can alter one’s emotional and physical responses to stress. While long understood as a means to alleviate stress-related physiologic responses (Beary et al., 1974), more recent studies suggest that invoking the relaxation response may be helpful as an adjunct therapy for drug withdrawal (Klajner et al., 1984; Lotfinia et al., 2024) and may even have a positive impact on those suffering from similar symptoms that have developed after a love relationship has ended. In the following sections, we will explore the physiology of the relaxation response with this in mind.

The rationale for the use of relaxation techniques (e.g., slow, diaphragmatic breathing and meditative states) rests on the assumption that they can restore balance in autonomic tone, reduce systemic stress responses, and enhance mitochondrial efficiency independent of direct dopamine replacement. These effects are mediated through reductions in sympathetic activity, normalization of cortisol and inflammatory markers, and upregulation of mitochondrial biogenesis and oxidative phosphorylation (Brown & Gerbarg, 2005; Gautam et al., 2021a; 2021b). Relaxation may also activate vagal pathways that modulate NO production and mitochondrial function, potentially compensating for the metabolic disruptions associated with dopamine withdrawal (Tracey, 2002; Stefano et al., 2012). Thus, while relaxation therapy may not lead to direct restoration of dopamine levels, it can still improve mitochondrial ATP production and reduce stress-related metabolic dysregulation through parallel pathways, thereby supporting its use even in cases of dopaminergic deficiency.

The impact of the relaxation response on neurotransmitters and metabolic bioenergetics

The health benefits associated with the relaxation response stem from reestablishing a balance between the sympathetic and parasympathetic branches of the autonomic nervous system (Esch & Stefano, 2010). In addition, emerging evidence links relaxation response to enhanced mitochondrial bioenergetics, improved insulin secretion, reduced inflammation, and diminished activation of stress-related pathways (Karrasch et al., 2023; Bhasin et al,. 2013; Picard et al., 2018). However, while these associations suggest adaptive physiological changes, they fail to define a unified mechanism underlying the relaxation response's clinical efficacy. We propose that relaxation response and similar mind-body practices promote systemic metabolic advantages by synchronizing the functions of peripheral organ systems and the CNS to optimize ATP production and energy balance (Stefano et al., 2019). In this regard, it is important to mention that dopamine, the prototype catecholamine, plays a crucial role as a chemical intermediate in endogenous morphine biosynthesis in animals (Stefano et al., 2015). Endogenous morphinergic signaling, alongside NO-coupled systems, has evolved as a modulator of energy metabolism and mitochondrial respiration (Stefano et al., 2015). This concept aligns with the concept of mitochondrial “enslavement” during eukaryotic evolution, a step that was potentially mediated by endogenous morphine (Stefano & Kream, 2017; Bressan & Kramer, 2021).

We hypothesize that the relaxation response and similar mind-body practices may promote systemic advantages by synchronizing the activities of various organs and organ systems (e.g., the respiratory, cardiovascular, and musculoskeletal systems, among others) with the central nervous system (CNS) as a means to optimize ATP production and overall energy balance. Although this idea remains a hypothesis at this time, emerging research supports its biological plausibility. For example, Bhasin & colleagues (2018) reported that practices eliciting the relaxation response resulted in a significant increase in the expression of genes associated with energy metabolism and mitochondrial function, notably mitochondrial ATP synthase. These results suggest that mind-body interventions can directly enhance cellular energy production and potentially its utilization (Dusek et al., 2006; Stefano et al., 2001). Conceptually, the relaxation response may serve as a physiological counterbalance to the stress-induced"fight-or-flight"state by shifting toward parasympathetic dominance—a state characterized by reductions in blood pressure, heart rate, and overall oxygen consumption. Collectively, these responses are indicators of a coordinated physiological alignment that fosters energy efficiency and restorative function across multiple systems (Furlan et al., 2023; Priest & Tontonoz, 2019; Ye & Medzhitov, 2019).

Nitric oxide plays numerous physiologic roles, largely depending on precisely when and how it is produced (reviewed in Stefano et al., 2000). Under homeostatic conditions, small amounts of NO are synthesized continuously by both endothelial and neuronal NOS (eNOS and nNOS, respectively). Constitutive NO synthesis regulates blood flow, supports communication between nerve cells, and protects cells from oxidative damage (Epstein et al., 1993). By contrast, inducible NOS (iNOS) is activated during infections or inflammation. This enzyme, which produces much larger amounts of NO, assists with pathogen elimination. However, if overproduced or if its synthesis is sustained for long periods, excess NO can lead to oxidative stress and tissue damage, thereby contributing to chronic conditions, such as neurodegeneration or autoimmune disease (Nathan, 1992; Calabrese et al., 2007). In short, although constitutive NO production supports health, inducible NO can become a “double-edged sword” if regulation fails.

Synchronization of neural networks within the central nervous system requires energy metabolism, and thus effective and efficient mitochondrial function. Theta and gamma rhythms facilitate efficient communication and support critical cognitive processes. These oscillatory activities are energetically demanding; substantial quantities of ATP are required to maintain synaptic transmission, ion gradients, and neurotransmitter recycling. Mitochondria meet these demands through oxidative phosphorylation, thereby linking energy production to neural signaling. Metabolic regulatory factors, including the NAD⁺/NADH ratio and adenosine monophosphate-activated protein kinase, also modulate neuronal excitability and network synchrony, integrating cellular energy status with electrophysiological dynamics. Disruptions in mitochondrial function impair neural synchronization and contribute to cognitive decline in neurodegenerative diseases, while improved mitochondrial efficiency enhances network coherence. This reciprocal relationship suggests that energy metabolism is not only a substrate for brain activity but also a critical modulator of the brain’s functional connectivity (Attwell & Laughlin, 2001; Buzsáki & Draguhn, 2004; Fries, 2005; Kann et al., 2014; Yellen, 2018).

Notably, our previous studies highlighted the contributions of novel morphine-selective Mu-3 type opiate receptors on the inner mitochondrial membranes of human cells whose activities are coupled to NO release (Stefano, 1999; Stefano & Kream, 2009; Stefano et al., 2015); several reports describe the functional links between these receptors and the constitutive form of NOS, leading to responses previously attributed to NO alone (Esch et al., 2020; Toda et al., 2008; Toda et al., 2009; Mastronicola et al., 2004; Hervera et al., 2011). Other studies highlighted the selective impairment of neuronal Mu-type opiate receptors in response to mitochondrial oxidative damage (Raut et al., 2006; 2007).

The benefits of the relaxation response may indeed stem directly from its impact on mitochondria, which are organelles that are central to energy production. As discussed in the previous section, NO is a messenger/neurotransmitter and also a key regulatory molecule that plays an important role in modulating mitochondrial respiration and oxygen utilization and thus may play a critical role in promoting the relaxation response (Dusek et al., 2006; Stefano et al., 2006; Mantione et al., 2007). A large body of clinical and pre-clinical literature has established a key regulatory role for NO in maintaining normative rates of mitochondrial respiration and oxygen utilization (Stefano et al., 2019). Behaviorally mediated practices like the relaxation response and related mind-body interventions likely function effectively, because they support the synchronization of peripheral and central nervous systems based on their impact on mitochondrial function, leading to optimized ATP production. For instance, controlled breathing exercises associated with a relaxation response may enhance cortical-limbic integration, brainstem respiratory rhythms, and pulmonary gas exchange, further improving mitochondrial efficiency (Garner et al., 2019; Gothe et al., 2019). The physiological and clinical benefits of relaxation, particularly those facilitated by breathing-based mind-body practices, most likely emerge from a convergence of biochemical, neurological, and psychosocial pathways, with mitochondrial ATP optimization serving as a central mechanism. Slow, diaphragmatic breathing increases parasympathetic (vagal) tone and enhances oxygen availability, which in turn supports more efficient oxidative phosphorylation within the mitochondria. This leads to improved ATP synthesis, reduced production of reactive oxygen species, and stabilization of cellular redox states, all factors that are essential for maintaining energy homeostasis in neurons, immune cells, and endocrine tissues (Gautam et al., 2021a; 2021b).

Within our proposed working model, behaviorally mediated improvements of whole-body cellular bioenergetics result from the convergence of biochemical and biophysical processes within the mitochondrial matrix that lead to the optimized synthesis of ATP from ADP and inorganic phosphate via characterized chemiosmotic-driven events (Fig. 2). Furthermore, dynamic recycling of NO and inorganic nitrite by intramitochondrial nitrite reductases has been empirically demonstrated to represent a biochemical switching mechanism that is precisely regulated by minute variations in oxygen tension (Kream & Stefano, 2009; Stefano et al., 2019; Stefano & Kream, 2011; 2016).

Fig. 2.

Interrelatedness of MBM and the relaxation/love responses via mitochondrial energy regulation. Explanations see text; MBM = mind/body medicine; ATP = adenosine triphosphate; NO = nitric oxide

Love, stress, and reward

The deep significance of romantic bonding is reflected in the physiological response triggered by falling in love, which closely resembles a stress response, mobilizing physical energy and strength. Falling in love initiates a neurochemical cascade, including the release of stress hormones, such as rising cortisol levels (Esch & Stefano, 2005a; 2005b; Acevedo et al., 2012). Dopaminergic reward pathways become highly active and exhibit elevated testosterone levels in males. Studies have also found a decline in serotonin levels, which is similar to patterns observed in obsessive-compulsive disorder and depression (Marazziti et al., 2021). Over time, these neurochemical fluctuations stabilize: cortisol and serotonin levels return to baseline, testosterone decreases, while dopaminergic activity remains heightened. At this stage, the bonding neuropeptides oxytocin and vasopressin increase, reinforcing attachment and long-term connection (Esch & Stefano, 2005a; 2005b; Marazziti et al., 2021). The normalization of cortisol and adrenaline levels naturally decline as one feels secure in a relationship (Foerster & Kanske, 2022; Olds & Schwartz, 2023). Thus, love itself can be a source of stress (Stefano & Esch, 2005; Esch et al., 2024). Emotional pain, such as the loss of a loved one, activates the same brain regions involved in processing physical pain, demonstrating sharing (Kross et al., 2011). Importantly, individuals who describe themselves as “madly in love” with long-term partners continue to exhibit high activity in dopaminergic reward pathways, similar to the early stages of romantic love (Acevedo et al., 2012). At the same time, their brains show increased calming activity in regions rich in opioid and oxytocin receptors, suggesting a shift toward deeper emotional security and attachment (Acevedo et al., 2012; 2020). Furthermore, strong social connections contribute significantly to both mental and physical health (Esch et al., 2024).

Interestingly, the loss of love can have physiological consequences as well, such as broken heart syndrome (Wittstein et al., 2005). Many patients in Wittstein’s original study developed symptoms following the loss of a loved one, exhibiting signs resembling a heart attack or heart failure, including altered EKG patterns and elevated cardiac injury markers. However, unlike a typical heart attack caused by coronary artery disease, their arteries remained unobstructed. Instead, the underlying mechanism appears to involve an acute stress response, marked by excessive sympathetic nervous system activation and a surge of stress hormones that only temporarily weakens the heart muscle. Thus, broken heart syndrome demonstrates the intricate link between love and stress, highlighting the profound interplay between the brain’s reward and stress systems—again demonstrating the sharing of specific CNS pathways.

In a 2021 study, Tawakol and colleagues analyzed a large database of PET and CT scans from patients with and without broken heart syndrome (Radfar et al., 2021). The researchers examined brain images taken before individuals developed the condition in the amygdala, which represents an important brain region in the stress response (Salamon et al., 2005). Their findings revealed that broken heart syndrome exhibitors had heightened amygdala activity, indicating that the brain plays a role in the disorder (Radfar et al., 2021). Furthermore, those with the highest amygdala activity not only had a greater likelihood of developing the condition but also experienced its onset sooner than those with lower activity levels. Taken together, these findings underscore the deep interconnection between love, stress, neural pathways, and physiological health. Love and strong relationships do more than shape emotion; they actively regulate stress and promote well-being (Stefano et al., 2019; Esch et al., 2024). Therefore, mind and body are inextricably linked, reinforcing the impact of love on overall health. Its importance can hardly be overestimated and will certainly become even clearer in future research.

Relaxation strategies may also lead to improved mitochondrial function by regulating glucose metabolism and insulin secretion. As pancreatic β-cells are highly dependent on mitochondrial ATP generation to trigger insulin release in response to glucose, enhanced ATP production contributes directly to this signaling cascade (Maechler & Wollheim, 2001). At the same time, optimized mitochondrial function can limit inflammasome activation and suppress the production of proinflammatory cytokines by maintaining mitochondrial integrity and reducing oxidative stress. Finally, relaxation strategies also stimulate the vagus nerve, which independently limits inflammation via the cholinergic anti-inflammatory reflex, which is a mechanism that suppresses NF-κB activity and inflammatory cytokine expression that does not rely directly on ATP production (Tracey, 2002).

The psychological and emotional effects of relaxation also contribute to its physiological impact. Cognitive reappraisal, a core feature of many mind-body interventions, alters the impact of stressors and limits the activation of the hypothalamic-pituitary-adrenal axis. Downregulation of these responses results in lower cortisol levels and decreased sympathetic nervous system activity, which further protects mitochondrial function and improves systemic metabolic efficiency (Black & Slavich, 2016). Additionally, the practice of relaxation and mindfulness has been shown to increase dopamine availability in key brain regions associated with motivation, reward, and cognitive control. As a whole, these effects may indirectly enhance mitochondrial activity and reinforce adaptive neuroplasticity (Esch, 2014; Tang et al., 2015; Fu et al., 2017).

There are also several published studies that address the impact of relaxation techniques on glucose metabolism. Septimar and colleagues (2021) reported that diabetic patients who participated in progressive muscle exercises (i.e., Benson’s relaxation techniques) exhibited improved blood sugar levels compared with controls. Similarly, Gowri et al. (2022) reported significant improvements in glycemic control and diminished insulin resistance among diabetic patients participating in an integrated yoga therapy program.

Social and emotional cues, such as perceived safety and social support, also shape the physiological benefits of relaxation. Oxytocin and serotonin, neurochemicals associated with trust, bonding, and affective regulation, influence mitochondrial resilience and stress reactivity (Lee et al., 2018). These findings suggest that ATP optimization may be only one part of a broader integrative framework in which bioenergetics, neuroendocrine responses, immune signaling, and emotional-cognitive processing interact dynamically with one another.

Taken together, the benefits of relaxation cannot be attributed to a single mechanism. Rather, they emerge from the coordinated interaction of mitochondrial energy regulation, cognitive-emotional modulation, and autonomic recalibration. Adenosine Triphosphate optimization plays a foundational role in this network, as this mechanism supports the high metabolic demands associated with stress resilience and recovery, but its effects are amplified by the top-down influence of neural circuits governing perception, emotion, and social behavior. Thus, these interdependent mechanisms can help guide the design of integrative therapies that address both the cellular and psychological dimensions of chronic stress and metabolic imbalance.

Nitric oxide modulation has also been implicated as a central mediator in the positive outcomes of loving-kindness meditation (Kemper et al., 2014). In a previous study, we suggested that NO autoregulatory pathways coupled with endorphin and endogenous morphinergic mechanisms may play a central role in generating emotional “in love” responses (Esch & Stefano, 2005a; 2005b) (Fig. 2). Moreover, previous studies by Leza and colleagues (1996) revealed elevated levels of NOS in brain tissue during drug withdrawal and that administration of NOS inhibitors could attenuate the physical symptoms associated with opioid withdrawal (Adams et al., 1993; Majeed et al., 1994; Kimes et al., 1993). More recently, Kalamarides and colleagues (2024) found that the administration of a NOS inhibitor also limited the negative symptoms that frequently emerge after opioid withdrawal. These findings not only underscore a potentially important link between cellular bioenergetics and drug dependence, but they also suggest NO modulation as a potentially important target for drug development.

The seemingly contradictory roles of NOS can be clarified by recognizing the dose- and context-dependent effects of NO on mitochondrial function and neural health. Physiological levels of NO produced by constitutive forms of NOS (e.g., nNOS) can regulate mitochondrial respiration. In this setting, NO reversibly inhibits cytochrome c oxidase and helps to fine-tune ATP production, redox signaling, and neural plasticity (Brown & Cooper, 1994; Dromparis & Michelakis, 2012). However, during drug withdrawal or severe emotional stress, excessive NO production, often driven by upregulation of inducible NOS (iNOS), can lead to nitrosative stress, mitochondrial dysfunction, and neuronal damage secondary to elevated levels of peroxynitrite and other reactive nitrogen species (Itzhak et al., 2000; Cunha-Oliveira et al., 2008). Thus, therapeutic NOS modulation is not aimed at eliminating NO signaling entirely; instead, the goal is to restore NO levels to the physiological range to preserve mitochondrial function while preventing toxic overproduction. In this context, we hypothesize that relaxation-based therapies may help reestablish autonomic balance and normalize NOS activity, thereby supporting ATP optimization without the detrimental effects associated with NOS overactivation.

Future directions

Among the directions for future research, we recognize that our current understanding of the links between cellular bioenergetics and the central reward pathway remains limited. Another topic of interest in this context is the role of gene transcription (Esch & Stefano, 2004). This phenomenon is of particular interest to those studying the impact of chronic drug use and addiction. Among recent findings, drug use leads to the upregulation of numerous transcription factors, including ΔFosB, cAMP response element binding protein, and nuclear factor-kappa B (NF-κB) (Crews et al., 2011; Nestler, 2012); some of these responses have been directly linked to NO activation (Xu et al., 2013; Winick-Ng et al., 2012; Hemish et al., 2003). Other genes implicated in this process include glucocorticoid receptor, NAc1 transcription factor, early growth response factors, and signal transducers and activators of transcription (Nestler, 2001; Nestler et al., 2012). Epigenetic changes that develop in response to long-term drug use have also been identified (Robison & Nestler, 2011). Equally intriguing are the findings of Murray and colleagues (2018), who reported differential expression of a wide variety of immune system genes, notably up-regulation of innate immune responses (e.g., type I interferons) in circulating leukocytes in a 2-year longitudinal study of young women engaging in new relationships.

Conclusions

While many have recognized qualitative behavioral similarities between falling in love and drug addiction (i.e., falling in love with a fellow human being vs. falling “in love” with opiates), advances in functional imaging methods have permitted researchers to confirm many of the neurobiological links between these phenomena. Recent research has highlighted the brain’s reward system and its central role in events associated with both drug addiction and these interpersonal responses. Among these findings, we highlight the central role(s) played by NO in both signal transmission and bioenergetic modulation. Future studies might focus on further exploration of this critical dual role and likewise examine its links to gene transcription and epigenetic modulation in both neural and peripheral tissues.

Funding

Open Access funding enabled and organized by Projekt DEAL. This work did not receive any special funding and was produced using our own resources (no funding declared).

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