1 Introduction

SUDs are defined as brain diseases characterized by compulsion for drug seeking and intake despite severe negative consequences related to the loss of control and emergence of a negative emotional state (Liu and Li, 2018). According to the 5th Edition of the Diagnostic and Statistical Manual of Mental Disorders (American Psychiatric Association, 2013), SUDs can be classified as mild, moderate or severe. The recently published data from The World Health Organization and the United Nations Office on Drugs and Crime showed that 64 million people worldwide were suffering from SUDs in 2022, which accounts for an increase of 3% over 5 years (Drugs and Crime, 2024), while the global prevalence of mental disorders was 13.0% (Castaldelli-Maia and Bhugra, 2022). Interestingly, the SUD prevalence among individuals with major depressive disorder was 25% (Hunt et al., 2020) and 33% among people with bipolar disorder (Hunt et al., 2016). Also, there is strong evidence of comorbidity of SUD with generalized anxiety disorder (Alegria et al., 2010) and posttraumatic stress disorder (PTSD; McCauley et al., 2012).

Stress is a natural and adaptive response required to sustain life that can be interpreted as any stimulus that changes physiological and/or psychological states (Schneiderman et al., 2005; Le Moal, 2007). Neurons located in the dorsomedial parvocellular subdivision of the paraventricular nucleus of the hypothalamus release corticotropin-releasing factor (CRF) in the hypophyseal portal system in response to stressors, which binds to CRH receptor type 1 (CRHR1) in hypophysis and leads to adrenocorticotropic hormone secretion in the systemic circulation, culminating in glucocorticoids (GCs) release [cortisol in humans and corticosterone (CORT) in rodents]. The GC hormones have genomic (slow) and non-genomic (fast) actions through the mineralocorticoid (MR) or glucocorticoid (GR) receptors. The cytosolic GC-MR/GR complex translocates to the cell nucleus and modulates gene expression by binding to the DNA's glucocorticoid-responsive element (GRE) regions (Beato and Sanchez-Pacheco, 1996) for long-lasting genomic effects. The CORT acts through classical MR and GR inserted in or attached to the plasma membrane for rapid non-genomic action, facilitating or inhibiting ion channels, receptors, and neurotransmitter signaling (Groeneweg et al., 2011). As a crucial stress mediator, GCs play an important role in arousal, cognition, mood, immunity, inflammatory reactions (Oster et al., 2017), and SUD (Mantsch and Gasser, 2015). According to allostasis, depending on the stress nature, intensity, and chronicity, the energy demand may be higher than the organism's resource (allostatic overload), leading to maladaptive responses (McEwen and Wingfield, 2003). Indeed, stress can be a significant risk factor for the development of both psychiatric disorders and SUDs (McGrath and Briand, 2019).

Some limbic regions, such as the ventral tegmental area (VTA), nucleus accumbens (NAc), prefrontal cortex (PFC), amygdala, and bed nucleus of the stria terminalis (BNST), are crucial for governing stress response and different drug use stages. For example, the VTA dopaminergic neurons release dopamine (DA) to other regions responsible for reward processing, such as the NAc and the PFC (Kielbinski et al., 2019). In contrast, the VTA inhibitory interneurons mediate reward-seeking reduction via NAc communication in stressed animals (Lowes et al., 2021). The amygdala is involved in emotional processing, highly responsive to stressors, and strongly related to the withdrawal period, playing a significant role in symptoms such as anxiety, irritability, and unease symptoms present in patients experiencing withdrawal (Stamatakis et al., 2014; Gilpin et al., 2015). More recent data showed that stress disruption of reward responses depends on the amygdala-NAc pathway (Madur et al., 2023). Indeed, the SUD implications in reward and stress (“anti-reward”) systems have long been stated (Volkow et al., 2016).

Given the association between stress and SUD (Nikbakhtzadeh et al., 2023), it is fundamental to clarify what is currently known about the cellular, molecular, and genetic mechanisms governing the relationship between stress and drug use responses to identify new therapeutic targets. We will first address the shared anatomical and neuroendocrine basis of SUD and stress. Then, despite several research models of stress that differ in neurobiological and behavioral effects from each other, we will give a special focus to early life stress (ELS) and cellular stress (i.e., oxidative stress and neuroinflammation) on SUD. Finally, we will explore genetic hallmarks of stress and HPA-axis regulation related to SUD.

1.1 Anatomical and neuroendocrine features of stress and SUD

A three-stage model—including binge/intoxication, withdrawal/negative effects, and preoccupation/anticipation—has been used to explain the transition from drug use to SUD (Koob and Volkow, 2010; Figure 1A). The drug-induced activation of the D1 dopamine receptor in the mesolimbic pathway (from VTA to NAc) and inhibition of D2 receptors in the striatocortical pathway (from the cerebral cortex to striatum) are classically associated with reinforcing, positive drug effects present during binge stage—even though μ-opioid receptors and endocannabinoid systems are also involved (Volkow and Morales, 2015). However, sustained drug intake leads to a dynamic readjustment of physiological parameters, including long-term brain changes that result in increased SUD risk and relapse. This process is referred to as the allostatic theory of addiction (Koob and Le Moal, 1997, 2001), which ultimately leads to withdrawal/negative effects. Indeed, the increase in reward threshold due to dopaminergic system downregulation is an early hallmark of drug-induced neuroadaptations, leading to the deficit in natural reward experience called anhedonia (Volkow et al., 2009). In addition to the dopaminergic system, CRF, dynorphin, and hypocretin are also modulated by chronic drug intake and related to the withdrawal/negative feelings stage. The CRF system is responsible for HPA-axis dysregulation followed by alterations in the extended amygdala, an extra-hypothalamic area composed of the central amygdala (CeA), BNST, and a transition zone in the posterior part of the medial NAc (Koob, 2008). The dynorphin-κ opioid system also modulates the extended amygdala. At the same time, hypocretin (derived exclusively from the lateral hypothalamus) interacts with noradrenergic, cholinergic, serotonergic, histaminergic, and dopaminergic systems, in addition to its role in HPA axis regulation (Koob, 2008). Regarding the preoccupation/anticipation stage, prefrontal cortex (PFC) dysfunction has been associated with the loss of control and compulsive drug-taking characteristic of this stage because of its role in decision-making and self-regulation (Figure 1A). Transcranial direct current stimulation (tDCS) over the dorsolateral prefrontal cortex (DLPFC) reduced craving immediately after the session and 1 month later in individuals with methamphetamine-use disorder (Alizadehgoradel et al., 2020). Moreover, individuals with SUD showed decreased left dorsal anterior cingulate cortex (dACC) and right middle frontal gyrus (MFG) activation compared to healthy controls (Le et al., 2021).

Figure 1. Brain regions and molecular effects involved in substance use and addiction. The three main domains of addiction neurocircuitry correspond to distinct functional areas, including binge/intoxication, associated with reward and incentive salience (activation of D1 dopamine receptor in the VTA-NAc pathway and D2 receptor inhibition in the striatum-cortex pathway—NMDAR are also involved in D2R response); withdrawal/negative affect, linked to negative emotional states and stress (brain reward systems downregulation and stress circuitry sensitization—dopaminergic, CRF, opioid, GABA, and dynorphin systems are involved); and preoccupation/anticipation, related to craving, impulsivity, and executive function; decision making and behavioral control are impaired in consequence of, but not restricted to, mPFC dysfunction (A). Drugs of abuse increase oxidative stress levels in the brain, initiating a continuous cycle that sustains neuroinflammation. The oxidative stress caused by substance use can compromise mitochondrial function, resulting in increased generation of free radicals. Increased oxidative stress contributes to the nuclear translocation and activation of NF-κB in microglial cells and induces the NLRP3 inflammasome activation. In addition, the drug use activates TLR4, which also triggers the activation of microglial NF-κB. Once in the nucleus, NF-κB promotes the increased expression of NOX and iNOS enzymes and pro-inflammatory cytokines, such as TNF-α and IL-1β. The increase in oxidative stress, pro-inflammatory cytokines and NLRP3 ultimately intensifies microglial and astrocytic activation, leading to a cycle of inflammation and oxidative stress in the brain (B).

Notably, the neuroanatomical and neurotransmitter systems governing SUD substantially overlap with stress response. In this regard, ethanol intake was prevented by prior GR (but not MR) antagonism (Koenig and Olive, 2004). Both stress and GCs increase DA synthesis (Baik, 2020) and reduce its clearance (Parnaudeau et al., 2014), which influences the sensitization to psychomotor stimulants, increases substance-induced conditioned place preference and self-administration of cocaine, amphetamine, heroin, and relapse to cocaine seeking (Yap and Miczek, 2008). Given that contextual memory retrieval depends on the hippocampal GR (Roozendaal et al., 2003), it could be part of the mechanism governing the intense craving and anxiety reported by SUD patients in response to stress and drug-cue exposure (Smith et al., 2023). Also, stress and stimulants cause maladaptive decision-making through epigenetic changes in the dorsal striatum (Murphy and Heller, 2022). Therefore, stress influences many substance use aspects, from consumption maintenance through neurotransmitter systems modulation to a contextual association that elicits drug use resumption (Nazeri et al., 2017; Goldfarb and Sinha, 2018; Mukhara et al., 2018).

1.2 The early-life stress implications for SUD

The ELS is among the major risk factors for psychiatric disorders development—for example, substance use, mood, anxiety, and posttraumatic stress disorders are clinical outcomes of severe ELS (Berhe et al., 2022). Neglect, trauma, family dysfunction, or abuse in general has about 3.6 million annual reports, and ~702,000 children are confirmed victims of abuse or neglect (Forster et al., 2018). ELS has been associated with a higher risk of mood disorders (Forster et al., 2018; Andersen, 2019) and SUD (Goodwin et al., 2004; Kirsch and Lippard, 2022). Substance abuse can emerge to alleviate suffering, anxiety, and childhood trauma, resulting in substance dependence to manage their emotional experiences, establishing a vicious cycle (Bushnell et al., 2019).

The proper development of the CNS requires essential cellular processes and must be fine-tuned to ensure its adequate formation (Andersen, 2003). It is known that substance use alters the structure and function of serotonergic and dopaminergic neurons during adolescence, making the developing brain highly susceptible to the neurotoxic effects of drug exposure (Squeglia et al., 2012; Pfefferbaum et al., 2018). For example, neural activation and volume of cortical areas in adolescents predict alcohol consumption and alcohol-related problems (Norman et al., 2011; Cheetham et al., 2014). On the other hand, ELS can affect neurons and glial cells during neurodevelopment (Schafer and Stevens, 2015; Allen and Lyons, 2018; Johnson and Kaffman, 2018; Li and Barres, 2018), including structures and components of the reward system (Lukkes et al., 2009; Hanson et al., 2021; Moustafa et al., 2021). Indeed, there is an important link between ELS and SUD development through adolescent substance use (Kirsch and Lippard, 2022). Rodent models show that different stressors during adolescence or the corresponding pre-adolescence period increase drug consumption during adulthood (Kosten et al., 2000, 2004; Baarendse et al., 2014; Garcia-Pardo et al., 2015). Maternal separation (MS), an ELS closer to the time of birth, has also been shown to increase self-administered alcohol drinking and morphine preference during adulthood (Jaworski et al., 2005; Vazquez et al., 2005; Michaels and Holtzman, 2008; Gondre-Lewis et al., 2016; Lewis et al., 2016). Previous studies reported arginine vasopressin gene expression changes and HPA axis activation after MS (Murgatroyd and Spengler, 2011; de Almeida Magalhaes et al., 2018). The HPA axis's ability to influence substance use seems to be so important that it has been placed as a potential target to assess the probability of relapse in cocaine-dependent individuals (Sinha et al., 2006). The ELS occurring in a range from weaning to early adulthood can affect substance use (McCool and Chappell, 2009; Lopez et al., 2011), suggesting that any period during early life is sensitive to stress effects with crucial implications for SUD development.

1.3 SUD and stress at cellular level

Stress occurs not only at psychological and physiological levels but also at a cellular level, e.g., oxidative stress and neuroinflammation. Recent findings highlight oxidative stress and inflammation as pivotal factors in drug-induced disruption of brain homeostasis (Berrios-Carcamo et al., 2020). For example, research in mice has demonstrated that the administration of indomethacin, a potent anti-inflammatory agent, reduced methamphetamine-induced neuroinflammation (Goncalves et al., 2008) and prolonged use of various addictive substances elevates inflammatory responses in the periphery and central nervous system (CNS; Cahill and Taylor, 2017; Leclercq et al., 2017; Hofford et al., 2019; Kohno et al., 2019). This situation could initiate an inflammatory response through increased microglial and astrocytic reactivity (Kraft and Harry, 2011; Clark et al., 2013; Colombo and Farina, 2016). Moreover, increased microglial and astrocytic reactivity has been observed in response to amphetamines (Zhang et al., 2015), cocaine (Periyasamy et al., 2018), ethanol, nicotine (Alfonso-Loeches et al., 2010; Quintanilla et al., 2018, 2019), opioids (Wang et al., 2012), and cannabinoids (Cutando et al., 2013; Zamberletti et al., 2015). These cells can sense cellular environmental alterations and trigger inflammatory responses through pattern recognition receptors, including Toll-like receptors (TLRs; Kraft and Harry, 2011; Fischer and Maier, 2015). Microglia respond to pro-inflammatory signals by altering their reactivity and gene expression, leading to elevated production of oxidative enzymes like NADPH oxidase (NOX) and inducible nitric oxide synthase (iNOS). This response increases the generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS; Block et al., 2007). Cocaine and opioids induce TNF-α, IL-1β, and IL-6 release through microglial and astrocytic TLR4 activation, and IL-1β, IL-6, IL-18, IL-33, MCP-1, and TNF-α production via NF-κB and NLRP3 inflammasome pathways (Hutchinson et al., 2010; Crews et al., 2013; Northcutt et al., 2015; Pan et al., 2016; Bayazit et al., 2017; Eidson et al., 2017; Berrios-Carcamo et al., 2020; Figure 1B).

Studies in animal models have shown that chronic alcohol use increases pro-inflammatory cytokines, inhibits neurogenesis, and induces long-term behavioral changes (Nixon and Crews, 2002; Pascual et al., 2007). Furthermore, excessive DA released in response to methamphetamine undergoes oxidation, leading to the formation of toxic quinones. This process triggers oxidative stress, causes mitochondrial dysfunction, and damages presynaptic membranes by generating free radicals like superoxide and hydrogen peroxide (Shah et al., 2012). The cause of oxidative stress in the brain may be due to excessive production of free radicals, decreased activity of antioxidant enzymes, or decreased concentration of reducing factors (Lin and Beal, 2006; Kaminski et al., 2024), where ROS and RNS, for example, exert toxic effects on the CNS cellular components, resulting in neuronal death (Berg et al., 2004). Several studies showed that SUDs and oxidative stress are linked since the presence of one correlates with the other's development (Cunha-Oliveira et al., 2010; Zahmatkesh et al., 2017; Kaminski et al., 2024). Cannabis smoke exposure increases oxidative stress, like tobacco's effect (Aguiar et al., 2019), leading to increased ceruloplasmin and lipid hydroperoxides and decreased free thiol (Bayazit et al., 2020). Indeed, tetrahydrocannabinol (THC), a psychoactive substance found in cannabis, increases lipoperoxidation and reduces superoxide dismutase (SOD) enzyme activity in brain tissue (Kopjar et al., 2019). Exposure to amphetamines damages the mitochondrial membrane and oxidates lipids and proteins through increased ROS production (Brown and Yamamoto, 2003; Fitzmaurice et al., 2006; Perfeito et al., 2013; Basmadjian et al., 2021). Cocaine depletes reduced glutathione (GSH) in the heart and liver (Graziani et al., 2016), decreases catalase activity in the striatum and mPFC (Macedo et al., 2005), and glutathione peroxidase and GSH reduction in HPC (Mahoney, 2019). Finally, studies indicate that heroin increases ROS production and oxidative damage to proteins and lipids in the brain and liver (Graziani et al., 2016), decreases SOD, CAT, and GPx activity, and GSH/glutathione disulfide ratio reduction (Cemek et al., 2011; Zahmatkesh et al., 2017; Salarian et al., 2018; Tomek et al., 2019).

1.4 Genetic hallmarks of SUD

Some fundamental questions, such as “Why are some individuals more vulnerable to SUDs than others?” and “Does stress influence individual vulnerability?” remain unanswered. A possible mechanism for individual vulnerability to stress-induced substance use is through epigenetic modulation (Figure 2). There is substantial evidence for ELS-induced epigenetic changes influencing substance use in adulthood (Provencal and Binder, 2015). Also, ELS seems to induce dense DNA methylation of the GR gene (NR3C1), which correlates with major depressive disorder (Holmes et al., 2019). Interestingly, substance use also induces epigenetic changes, such as post-translational modifications, acetylation, methylation, phosphorylation, ubiquitination, SUMOylation, crotonylation, citrullination, and ADP-ribosylation, as well as methylation of the DNA itself (Nestler, 2014; Walker and Nestler, 2018). Several miRNAs are regulated after drug exposure (Doura and Unterwald, 2016), with the expression of some in striatum neurons altering drug-related behaviors (Hollander et al., 2010; Chandrasekar and Dreyer, 2011; Quinn et al., 2015).

Figure 2. The influence of DNA epigenetics on vulnerability to SUD. Individual differences (e.g., environment, habits, life history, genetic background), as well as stress and/or drug exposure may lead to epigenetic alterations in different life stages. The single nucleotide polymorphisms and post-translational modifications of HPA-axis genes or mediators can sustain maladaptive behavior and substance use disorder.

Additionally, it is well known that minor genetic variations between the population correlate with variations in disorder development risk. Single nucleotide polymorphisms (SNPs) in genes associated with the HPA axis can modify the risk for drug abuse and abstinence symptoms. For example, the NR3C2 gene located in the 4q31.1v chromosome encodes the MR. The rs1040288 SNP results in a displacement of G to C nucleotide in an intronic region of the gene and has been identified as a risk factor for cocaine and heroin abuse in a non-population-specific manner (Levran et al., 2014). Regarding ELS, there is an association between childhood physical neglect and the SNP rs5522-Val allele modulating crack/cocaine abuse (Rovaris et al., 2015). The rs5522 SNP consists of an A/G transition in an exonic region of the gene, which results in a substitution of isoleucine to a valine.

On the other hand, GR is encoded by the NR3C1 gene located at the 5q31-32 chromosome. Atypical GR sensitivity underpins the pathophysiology of drug abuse, continuation, and relapse. The rs41423247 SNP consists of a displacement of G to C nucleotide in an intronic region of the gene. This SNP homozygous mutation has been associated with depression (Peng et al., 2018). Its minor allele C is a risk factor for higher depressive symptoms during early abstinence from crack/cocaine abuse, while the CC genotype appears to correlate with late abstinence (Rovaris et al., 2016). The rs41423247 minor allele C and rs10052957 minor allele G (an SNP that results in displacement of A to G) have been associated with an increased risk for cocaine abuse and a higher burden of depression when combined in a haplotype (Schote et al., 2019).

2 Discussion and conclusions

This mini-review explores how substance use alters brain circuits involved in reward processing and stress response (the “anti-reward” system), linking these changes to the three-stage model of SUD and their anatomical and endocrine features. It integrates cellular stress, which is closely tied to SUD. Depending on its nature, intensity, and duration, stress impacts HPA axis modulation, brain plasticity, and cellular processes (Albernaz-Mariano et al., 2025). Thus, ELS was highlighted due to its strong translational body of evidence and association with blunted stress responses and increased SUD risk (initiation, maintenance, relapse), mediated by ELS-induced reward and stress pathways changes. Finally, individual vulnerability to SUD was examined through (epi)genetics, emphasizing how drug use and life experiences can alter gene expression and increase SUD risk in susceptible individuals.

In conclusion, substance use can disrupt major brain circuits and neuroendocrine systems, resulting in altered behavioral responses to reward and stress. Furthermore, exposure to stress, particularly early-life stress (ELS), may increase susceptibility to substance use disorder (SUD) during adolescence and adulthood. Cellular stress induced by either stress or SUD plays a significant role in this process, offering potential therapeutic targets. Additionally, genetic factors may provide a means to identify at-risk individuals, enabling early intervention and prevention of SUD development.

Introduction

Substance Use Disorders (SUDs) are recognized as brain diseases, characterized by an uncontrollable drive to seek and consume drugs, despite severe negative consequences. This condition involves a loss of control over drug intake and the emergence of a negative emotional state. SUDs can be classified as mild, moderate, or severe. In 2022, approximately 64 million people globally were affected by SUDs, representing a 3% increase over five years. It is notable that SUDs frequently occur alongside other mental health conditions; for instance, 25% of individuals with major depressive disorder and 33% of those with bipolar disorder also experience SUD. There is also strong evidence of SUD comorbidity with generalized anxiety disorder and post-traumatic stress disorder.

Stress is a fundamental and adaptive biological response essential for survival, defined as any stimulus that alters physiological or psychological states. A key part of the body's stress response involves specific brain neurons releasing corticotropin-releasing factor, which triggers a cascade leading to the release of glucocorticoids (GCs). These hormones, such as cortisol in humans, have both slow, long-lasting effects on gene expression and rapid actions influencing neural signaling. GCs are vital mediators of stress, affecting arousal, cognition, mood, immunity, and inflammatory reactions. They also play a significant role in SUD. When stress is severe or chronic, the body's energy demands can exceed its resources, leading to maladaptive responses. Stress is a considerable risk factor for developing both psychiatric disorders and SUDs.

Several brain regions, particularly those involved in the limbic system, are critical for managing stress responses and different stages of drug use. For example, the ventral tegmental area (VTA) and nucleus accumbens (NAc) are central to reward processing, while the prefrontal cortex (PFC) is involved in decision-making. The amygdala, which is highly sensitive to stress, processes emotions and contributes to withdrawal symptoms like anxiety. Disruptions in the amygdala's connection to the NAc can affect reward responses under stress. The implications of SUD for both reward and "anti-reward" (stress) systems have long been established.

Understanding the cellular, molecular, and genetic mechanisms that link stress to drug use responses is crucial for identifying new treatment targets. This discussion will first examine the shared anatomical and neuroendocrine foundations of SUD and stress. It will then focus on early life stress and cellular stress, such as oxidative stress and neuroinflammation, and their impact on SUD. Finally, genetic factors related to stress and the body's stress response system will be explored in relation to SUD.

Anatomical and Neuroendocrine Features of Stress and SUD

The progression from drug use to SUD can be understood through a three-stage model: binge/intoxication, withdrawal/negative effects, and preoccupation/anticipation. The initial binge/intoxication stage is associated with the rewarding effects of drugs, primarily involving dopamine activity in the brain's mesolimbic pathway. However, continuous drug use leads to significant brain changes and an increased risk of SUD and relapse. This is explained by the allostatic theory of addiction, where the brain adjusts its physiological parameters in response to chronic drug exposure. This adjustment ultimately leads to the withdrawal/negative effects stage, marked by a decreased experience of natural rewards. Beyond dopamine, other systems involving corticotropin-releasing factor, dynorphin, and hypocretin are also affected, leading to changes in brain regions like the extended amygdala, which is involved in negative emotional states. The preoccupation/anticipation stage is characterized by a loss of control and compulsive drug-taking, often linked to impaired function in the prefrontal cortex, a brain area crucial for decision-making and self-regulation.

The brain regions and neurotransmitter systems that govern SUD significantly overlap with those involved in the stress response. For instance, stress and stress hormones increase dopamine synthesis and reduce its clearance, which can enhance sensitivity to stimulants and increase the likelihood of drug self-administration and relapse. The hippocampus, a brain region involved in memory and containing stress hormone receptors, may contribute to the intense craving and anxiety experienced by individuals with SUD when exposed to stress or drug-related cues. Furthermore, both stress and stimulants can lead to maladaptive decision-making through changes in gene expression in certain brain areas. Therefore, stress profoundly influences many aspects of substance use, from maintaining consumption through altering neurotransmitter systems to triggering relapse via contextual associations.

The Early-Life Stress Implications for SUD

Early life stress (ELS), encompassing neglect, trauma, family dysfunction, or abuse during childhood, is a major risk factor for developing psychiatric disorders, including substance use, mood, anxiety, and post-traumatic stress disorders. Millions of children are reported as victims of abuse or neglect annually. ELS is associated with a higher risk of mood disorders and SUD, with substance use sometimes emerging as a coping mechanism to alleviate suffering, anxiety, and the emotional impact of childhood trauma, leading to a cycle of dependence.

The proper development of the central nervous system (CNS) requires precise regulation of cellular processes. Substance use during adolescence can alter the structure and function of brain cells, making the developing brain particularly vulnerable to the harmful effects of drugs. For example, brain activity and volume in adolescents can predict future alcohol consumption. ELS can also affect the development of neurons and glial cells, including those in the reward system, thereby increasing vulnerability to SUD. Studies in animal models show that various stressors during adolescence or pre-adolescence can increase drug consumption later in adulthood. Maternal separation, a form of ELS early in life, has been shown to increase alcohol and morphine consumption in adulthood, along with activating the body's stress response system. The ability of this stress response system to influence substance use is so significant that it is considered a potential target for predicting relapse in individuals with cocaine dependence. ELS occurring at any point from weaning to early adulthood can impact substance use, suggesting that critical periods exist where stress can have significant implications for SUD development.

SUD and Stress at Cellular Level

Stress manifests not only at psychological and physiological levels but also at a cellular level, involving processes like oxidative stress and neuroinflammation. Recent research highlights that these cellular changes are crucial in how drugs disrupt brain balance. For example, anti-inflammatory agents have been shown to reduce drug-induced brain inflammation in animal models. Prolonged use of various addictive substances elevates inflammatory responses throughout the body and in the brain, which can initiate an inflammatory response by increasing the activity of specific brain cells called microglia and astrocytes.

These activated microglia and astrocytes can sense changes in the cellular environment and trigger inflammatory responses. This leads to increased production of enzymes that generate reactive oxygen species and reactive nitrogen species, which are harmful molecules. Drugs such as cocaine and opioids can activate inflammatory pathways, leading to the release of pro-inflammatory substances. This intensified activation of brain cells and release of inflammatory chemicals creates a cycle of inflammation and oxidative stress in the brain.

Chronic alcohol use in animal models increases pro-inflammatory chemicals, hinders the growth of new brain cells, and causes long-term behavioral changes. Similarly, excessive dopamine released in response to methamphetamine becomes toxic, leading to oxidative stress, damage to cellular powerhouses (mitochondria), and harm to nerve cell membranes. Oxidative stress in the brain can result from an overproduction of harmful free radicals, reduced activity of protective enzymes, or lower levels of protective compounds. These reactive species can damage brain cells, potentially leading to cell death.

Studies consistently show a link between SUDs and oxidative stress, where the presence of one often correlates with the development of the other. For instance, exposure to cannabis smoke increases oxidative stress, similar to tobacco, leading to specific chemical changes in the blood. The psychoactive component of cannabis can increase lipid damage and reduce the activity of antioxidant enzymes in brain tissue. Amphetamines damage mitochondrial membranes and oxidize cellular components. Cocaine depletes vital protective compounds in organs and reduces antioxidant enzyme activity in the brain. Heroin increases harmful reactive oxygen species and oxidative damage in the brain and liver, while also reducing the activity of protective enzymes and critical antioxidant levels.

Genetic Hallmarks of SUD

Fundamental questions persist regarding why some individuals are more vulnerable to SUDs and how stress influences this vulnerability. One possible mechanism involves epigenetic modulation, which refers to changes in gene activity that do not alter the underlying DNA sequence. There is strong evidence that early life stress can induce such epigenetic changes, influencing substance use in adulthood. For example, ELS appears to increase specific DNA modifications on a gene related to the body's stress response, which correlates with major depressive disorder. Interestingly, substance use itself can also cause epigenetic changes, including various modifications to proteins associated with DNA and changes to the DNA itself. Additionally, the expression of small RNA molecules can be altered after drug exposure, influencing drug-related behaviors.

Beyond epigenetics, minor genetic variations, known as single nucleotide polymorphisms (SNPs), contribute to differences in disorder risk within the population. SNPs in genes associated with the body's stress response system can modify the risk for drug abuse and withdrawal symptoms. For example, a specific SNP in the gene encoding the mineralocorticoid receptor has been identified as a risk factor for cocaine and heroin abuse. Similarly, a particular SNP in the glucocorticoid receptor gene, which governs stress hormone sensitivity, has been linked to depression. This SNP has also been associated with more severe depressive symptoms during early abstinence from crack/cocaine abuse, with a specific genetic makeup correlating with late abstinence. When combined, certain SNPs in this gene have been linked to an increased risk for cocaine abuse and a higher burden of depression.

Discussion and Conclusions

This review highlights how substance use alters brain circuits involved in reward processing and stress response, linking these changes to the three-stage model of SUD and their anatomical and neuroendocrine characteristics. It integrates the role of cellular stress, which is closely connected to SUD development. Stress, depending on its nature, intensity, and duration, impacts the body's stress response system, brain adaptability, and cellular processes. Early life stress was emphasized due to strong evidence linking it to altered stress responses and increased SUD risk (initiation, maintenance, and relapse), mediated by changes in reward and stress pathways induced by ELS. Finally, individual vulnerability to SUD was examined through genetic and epigenetic factors, underscoring how drug use and life experiences can modify gene expression and increase SUD risk in susceptible individuals.

In conclusion, substance use can disrupt major brain circuits and neuroendocrine systems, leading to altered behavioral responses to reward and stress. Furthermore, exposure to stress, especially during early life, may increase susceptibility to substance use disorder during adolescence and adulthood. Cellular stress, whether induced by stress itself or by SUD, plays a significant role in this process, offering potential targets for therapeutic interventions. Additionally, understanding genetic factors may allow for the identification of individuals at higher risk, enabling earlier intervention and prevention of SUD development.

Introduction

Substance Use Disorders (SUDs) are recognized as brain diseases, characterized by an uncontrollable urge to seek and consume drugs despite severe negative consequences. These disorders involve a loss of control and the development of negative emotional states. The Diagnostic and Statistical Manual of Mental Disorders (DSM-5) classifies SUDs as mild, moderate, or severe. In 2022, approximately 64 million people globally were affected by SUDs, representing a 3% increase over five years. This prevalence is notable when considering that the global prevalence of mental disorders was 13.0%. Interestingly, SUD prevalence is significantly higher among individuals with major depressive disorder (25%) and bipolar disorder (33%). There is also strong evidence of SUD comorbidity with generalized anxiety disorder and post-traumatic stress disorder (PTSD).

Stress is a natural and adaptive response essential for survival, defined as any stimulus that alters physiological or psychological states. When exposed to stressors, specific neurons in the hypothalamus release corticotropin-releasing factor (CRF). This triggers a cascade that leads to the secretion of adrenocorticotropic hormone and, ultimately, glucocorticoids (GCs), such as cortisol in humans. GCs exert both slow, long-lasting genomic actions through mineralocorticoid (MR) or glucocorticoid (GR) receptors, and rapid, non-genomic actions affecting ion channels and neurotransmitter signaling. As crucial mediators of stress, GCs play important roles in arousal, cognition, mood, immunity, and inflammatory reactions, and are significantly involved in SUDs. The concept of allostasis suggests that prolonged or intense stress can lead to an allostatic overload, where the body's energy demands exceed its resources, resulting in maladaptive responses. Stress is indeed a major risk factor for developing both psychiatric disorders and SUDs.

Several limbic brain regions are critical for managing stress responses and different stages of drug use. For instance, the ventral tegmental area (VTA) and nucleus accumbens (NAc) are involved in reward processing, with VTA dopaminergic neurons releasing dopamine (DA) to the NAc and prefrontal cortex (PFC). Conversely, VTA inhibitory interneurons can reduce reward-seeking in stressed individuals. The amygdala, vital for emotional processing, is highly responsive to stressors and plays a significant role in withdrawal symptoms like anxiety and irritability. Research indicates that stress-induced disruptions in reward responses depend on the amygdala-NAc pathway. The interconnectedness of reward and stress ("anti-reward") systems in SUDs has long been established.

Given the clear link between stress and SUD, it is essential to understand the cellular, molecular, and genetic mechanisms underlying this relationship to identify potential new therapeutic targets. This review will first explore the shared anatomical and neuroendocrine bases of SUD and stress. It will then focus on early life stress (ELS) and cellular stress (e.g., oxidative stress, neuroinflammation) as they relate to SUD. Finally, the review will examine the genetic factors of stress and HPA-axis regulation involved in SUD.

Anatomical and Neuroendocrine Features

The progression from initial drug use to a Substance Use Disorder can be explained by a three-stage model: binge/intoxication, withdrawal/negative effects, and preoccupation/anticipation. The binge/intoxication stage is typically associated with the activating effects of drugs on D1 dopamine receptors in the mesolimbic pathway and the inhibition of D2 receptors in the striatocortical pathway, leading to reinforcing and positive drug effects. However, ongoing drug use leads to dynamic brain changes, increasing the risk of SUD and relapse, a process described by the allostatic theory of addiction. This leads to the withdrawal/negative effects stage, characterized by a reduced ability to experience natural rewards (anhedonia) due to downregulation of the dopaminergic system. Other systems, including CRF, dynorphin, and hypocretin, are also affected by chronic drug intake and contribute to negative withdrawal feelings. The CRF system, in particular, contributes to HPA-axis dysfunction and changes in the extended amygdala, a brain region involved in stress and emotion. The dynorphin-κ opioid system also modulates the extended amygdala, while hypocretin influences various neurotransmitter systems and HPA axis regulation. The preoccupation/anticipation stage is linked to prefrontal cortex (PFC) dysfunction, which impairs decision-making and self-regulation, leading to compulsive drug-taking and loss of control. Studies have shown that stimulating the dorsolateral prefrontal cortex can reduce drug craving, and individuals with SUDs often exhibit reduced activation in certain frontal brain areas compared to healthy individuals.

Crucially, the brain regions and neurotransmitter systems involved in SUD overlap significantly with those governing stress responses. For instance, blocking glucocorticoid receptors can prevent alcohol intake. Both stress and GCs increase dopamine synthesis and reduce its clearance, which can enhance sensitivity to psychomotor stimulants, increase conditioned preferences for substances, and promote drug self-administration and relapse for substances like cocaine, amphetamine, and heroin. Since contextual memory relies on hippocampal glucocorticoid receptors, this mechanism might explain the intense craving and anxiety reported by SUD patients when exposed to stress or drug-related cues. Furthermore, stress and stimulant use can lead to maladaptive decision-making through changes in gene expression in the dorsal striatum. Therefore, stress profoundly impacts various aspects of substance use, from maintaining consumption through modulating neurotransmitter systems to establishing contextual associations that trigger relapse.

Early Life Stress and SUD

Early life stress (ELS) is a major risk factor for developing psychiatric disorders, including SUDs, mood disorders, anxiety, and PTSD. ELS, such as neglect, trauma, family dysfunction, or abuse, affects millions of children annually. For some, substance use may emerge as a way to alleviate suffering, anxiety, or the lingering effects of childhood trauma, potentially leading to substance dependence as a coping mechanism and establishing a harmful cycle.

Proper development of the central nervous system (CNS) requires precise cellular processes. Substance use during adolescence can alter the structure and function of serotonergic and dopaminergic neurons, making the developing brain highly vulnerable to the neurotoxic effects of drug exposure. Brain activation and volume in cortical areas during adolescence can predict future alcohol consumption and related problems. On the other hand, ELS itself can impact neurons and glial cells during neurodevelopment, including structures of the brain's reward system. A significant link exists between ELS and SUD development, often mediated by substance use during adolescence. Rodent studies demonstrate that various stressors during adolescence or pre-adolescence can increase drug consumption in adulthood. Maternal separation, a form of ELS early in life, has also been shown to increase self-administered alcohol drinking and morphine preference in adulthood. This type of stress can alter gene expression and activate the HPA axis. The HPA axis's influence on substance use is so significant that it is considered a potential indicator for assessing relapse risk in cocaine-dependent individuals. ELS occurring at any point from weaning to early adulthood can impact substance use, highlighting that multiple periods during early life are sensitive to stress effects with crucial implications for SUD development.

Cellular Stress in SUD

Stress manifests not only psychologically and physiologically but also at the cellular level, notably as oxidative stress and neuroinflammation. Recent research highlights these cellular processes as critical factors in drug-induced disruptions of brain function. For instance, anti-inflammatory agents have been shown to reduce methamphetamine-induced neuroinflammation in mice. Prolonged use of various addictive substances elevates inflammatory responses in both the peripheral and central nervous systems. This can trigger an inflammatory response through increased reactivity of microglia and astrocytes, which are immune cells of the brain. These cells can detect changes in the cellular environment and initiate inflammation via specific receptors, such as Toll-like receptors (TLRs). Microglia respond to pro-inflammatory signals by altering their activity and gene expression, leading to increased production of oxidative enzymes like NADPH oxidase (NOX) and inducible nitric oxide synthase (iNOS), which generate reactive oxygen species (ROS) and reactive nitrogen species (RNS). Substances like cocaine and opioids induce the release of pro-inflammatory cytokines (e.g., TNF-α, IL-1β) through the activation of microglial and astrocytic TLR4, and via NF-κB and NLRP3 inflammasome pathways.

Studies in animal models indicate that chronic alcohol use increases pro-inflammatory cytokines, inhibits neurogenesis (the formation of new neurons), and induces long-term behavioral changes. Furthermore, excessive dopamine released in response to methamphetamine can undergo oxidation, forming toxic compounds. This process generates oxidative stress, impairs mitochondrial function, and damages presynaptic membranes through the production of free radicals. Oxidative stress in the brain can result from an overproduction of free radicals, reduced activity of antioxidant enzymes, or lower concentrations of protective reducing agents, leading to toxic effects on CNS cells and even neuronal death. Many studies demonstrate a clear link between SUDs and oxidative stress, where the presence of one often correlates with the development of the other. For example, cannabis smoke exposure increases oxidative stress, similar to tobacco, and reduces antioxidant enzyme activity in brain tissue. Amphetamines damage mitochondrial membranes and oxidize lipids and proteins through increased ROS production. Cocaine depletes protective antioxidants in organs and reduces enzyme activity in brain regions. Heroin also increases ROS production and oxidative damage to proteins and lipids in the brain and liver, while decreasing the activity of antioxidant enzymes.

Genetic Factors in SUD

Fundamental questions persist regarding why some individuals are more vulnerable to SUDs and how stress influences this vulnerability. Epigenetic modulation, changes in gene expression without altering the underlying DNA sequence, offers a possible mechanism for stress-induced substance use vulnerability. There is substantial evidence that ELS can induce epigenetic changes that influence substance use in adulthood. For instance, ELS appears to lead to increased DNA methylation of the glucocorticoid receptor gene (NR3C1), which is associated with major depressive disorder. Notably, substance use itself also induces epigenetic changes, including various modifications to proteins associated with DNA and changes in DNA methylation. Several small RNA molecules, known as microRNAs (miRNAs), are regulated after drug exposure, with some affecting drug-related behaviors through their expression in specific brain neurons.

Additionally, subtle genetic variations within the population, known as single nucleotide polymorphisms (SNPs), correlate with varying risks for disorder development. SNPs in genes linked to the HPA axis can modify the risk for drug abuse and withdrawal symptoms. For example, an SNP in the NR3C2 gene, which codes for the mineralocorticoid receptor (MR), has been identified as a risk factor for cocaine and heroin abuse. Regarding ELS, an association exists between childhood physical neglect and a specific SNP (rs5522-Val allele) that modulates crack/cocaine abuse.

The glucocorticoid receptor (GR) is encoded by the NR3C1 gene. Atypical GR sensitivity underlies the pathology of drug abuse, its continuation, and relapse. A particular SNP (rs41423247) in the NR3C1 gene has been linked to depression, and its minor allele is a risk factor for more severe depressive symptoms during early abstinence from crack/cocaine abuse. The homozygous mutation for this SNP appears to correlate with late abstinence. When combined with another specific SNP (rs10052957), the rs41423247 minor allele is associated with an increased risk for cocaine abuse and a greater burden of depression.

Discussion and Conclusion

This review examined how substance use alters brain circuits involved in reward processing and stress response, often termed the "anti-reward" system. These changes are linked to the three-stage model of SUD and its associated anatomical and neuroendocrine features. The review also integrated the concept of cellular stress, which is intimately connected to SUD. Stress, depending on its nature, intensity, and duration, significantly impacts HPA axis modulation, brain plasticity, and cellular processes. Early life stress (ELS) was specifically highlighted due to strong research evidence linking it to blunted stress responses and an increased risk of SUD initiation, maintenance, and relapse, mediated by ELS-induced changes in reward and stress pathways. Finally, individual vulnerability to SUD was explored through genetics and epigenetics, emphasizing how drug use and life experiences can modify gene expression, thereby increasing SUD risk in susceptible individuals.

In conclusion, substance use can profoundly disrupt major brain circuits and neuroendocrine systems, leading to altered behavioral responses to reward and stress. Furthermore, exposure to stress, particularly early-life stress, can heighten an individual's susceptibility to developing substance use disorder during adolescence and adulthood. Cellular stress, whether induced by general stress or substance use, plays a critical role in this process and represents a promising area for therapeutic interventions. Additionally, genetic factors offer valuable insights for identifying individuals at higher risk, which could facilitate early intervention and prevention strategies for SUD.

Introduction

Substance Use Disorders (SUDs) are recognized as brain diseases, marked by a strong urge to seek and use drugs despite serious negative effects. This compulsion involves a loss of control and the emergence of negative emotional states. According to mental health guidelines, SUDs can be classified as mild, moderate, or severe. In 2022, approximately 64 million people worldwide were affected by SUDs, representing a 3% increase over five years. It is notable that SUDs frequently occur alongside other mental health conditions; for instance, 25% of individuals with major depressive disorder and 33% of those with bipolar disorder also experience SUD. There is also strong evidence linking SUD with generalized anxiety disorder and post-traumatic stress disorder (PTSD).

Stress is a natural and necessary response that helps sustain life. It can be understood as any event or situation that alters the body's physical or mental state. When stress occurs, a specific part of the brain releases a substance called corticotropin-releasing factor (CRF). This sets off a chain reaction, leading to the release of hormones called glucocorticoids (GCs), such as cortisol in humans. GCs are crucial stress mediators, influencing arousal, thought processes, mood, and the immune system. They also play a significant role in SUD. Depending on its type, intensity, and how long it lasts, stress can sometimes overwhelm the body's resources, leading to harmful responses. Severe stress can be a major risk factor for developing both mental health conditions and SUDs.

Certain brain areas, including the ventral tegmental area (VTA), nucleus accumbens (NAc), prefrontal cortex (PFC), amygdala, and bed nucleus of the stria terminalis (BNST), are vital in controlling both stress responses and different stages of drug use. For example, the VTA releases dopamine, a chemical associated with reward, into areas like the NAc and PFC. The amygdala, involved in processing emotions, reacts strongly to stress and plays a key role in withdrawal symptoms such as anxiety and irritability. The close connection between stress and SUD means it is important to understand the cellular, molecular, and genetic changes that link them, which could help identify new treatment approaches.

Anatomical and neuroendocrine features of stress and SUD

The progression from casual drug use to a Substance Use Disorder is often explained by a three-stage model: binge/intoxication, withdrawal/negative effects, and preoccupation/anticipation. Initially, drugs activate brain pathways linked to pleasure and reward. However, continued drug use leads to long-term brain changes, increasing the risk of SUD and relapse. This process, known as the allostatic theory of addiction, explains how the body constantly adjusts to drug presence, eventually leading to the negative feelings experienced during withdrawal. During withdrawal, there is often a reduced ability to feel pleasure from natural rewards. Beyond dopamine, other systems involving CRF, dynorphin, and hypocretin are also affected by chronic drug use and contribute to negative withdrawal feelings. In the preoccupation/anticipation stage, the prefrontal cortex, which is important for decision-making and self-control, shows reduced function, leading to a loss of control and compulsive drug taking.

The brain structures and chemical systems involved in SUD greatly overlap with those that control the body's stress response. For example, stress and glucocorticoids increase dopamine levels, which can make individuals more sensitive to stimulants and increase the likelihood of drug use and relapse. Since a part of the brain called the hippocampus, which contains glucocorticoid receptors, is important for remembering contexts, it may contribute to the intense craving and anxiety reported by individuals with SUD when they encounter stress or drug-related cues. Additionally, both stress and stimulant use can lead to poor decision-making due to changes in gene activity within the brain. Therefore, stress affects many aspects of substance use, from maintaining drug consumption through changes in brain chemistry to creating associations with certain environments that can trigger a return to drug use.

The early-life stress implications for SUD

Early life stress (ELS), such as neglect, trauma, or abuse during childhood, is a major risk factor for developing various psychiatric disorders, including SUDs, mood disorders, and anxiety disorders. Often, individuals may turn to substance use as a way to cope with suffering, anxiety, or past trauma, creating a harmful cycle of dependence to manage their emotions.

Proper brain development is crucial, and early substance use can significantly alter the structure and function of brain cells, making the developing brain highly vulnerable to the harmful effects of drugs. Studies show that brain activity and volume in adolescents can predict future alcohol use and related problems. Similarly, ELS can negatively affect brain cells, including those in the reward system, during development. There is a clear connection between ELS and the development of SUD through substance use during adolescence. Research in animal models indicates that various stressors during youth increase drug consumption in adulthood. Even early life stressors, like maternal separation, can lead to increased alcohol consumption and morphine preference later in life. The body's stress response system, known as the HPA axis, is significantly influenced by ELS and plays a key role in substance use, suggesting it could be a target for assessing the risk of relapse in individuals with cocaine dependence. This highlights that any period during early life can be sensitive to the effects of stress, with profound implications for the development of SUD.

SUD and stress at cellular level

Stress does not only affect individuals mentally and physically; it also occurs at a cellular level, involving processes like oxidative stress and neuroinflammation. Recent research shows that these cellular stresses are key factors in how drugs disrupt the brain's normal balance. For example, anti-inflammatory drugs have been shown to reduce drug-induced brain inflammation in studies. Long-term use of various addictive substances increases inflammatory responses both in the body and in the central nervous system, potentially leading to increased activity of brain cells called microglia and astrocytes.

These brain cells can detect changes in the cellular environment and trigger inflammatory responses. When activated, they produce more oxidative enzymes, which increase the generation of harmful molecules known as reactive oxygen species (ROS) and reactive nitrogen species (RNS). Cocaine and opioids, for instance, trigger the release of inflammatory proteins and activate certain pathways within these brain cells, leading to widespread inflammation and oxidative stress in the brain. Animal studies show that chronic alcohol use increases these inflammatory proteins, hindering the growth of new brain cells and causing long-lasting behavioral changes. Moreover, certain drugs like methamphetamine cause dopamine to oxidize, creating toxic substances that lead to oxidative stress, damage to energy-producing parts of cells (mitochondria), and harm to brain cell membranes. Oxidative stress can occur due to an excess of these harmful molecules, a reduction in the body's antioxidant defenses, or both, leading to damage and even death of brain cells. Research consistently links SUDs with oxidative stress, with the presence of one often correlating with the development of the other. Cannabis smoke and other substances like amphetamines, cocaine, and heroin have all been shown to increase oxidative stress and cause damage to cells and proteins in various organs, including the brain and liver.

Genetic hallmarks of SUD

A key question is why some individuals are more susceptible to SUDs than others, and whether stress influences this vulnerability. One possible explanation involves epigenetic modulation, which refers to changes in gene activity without altering the underlying DNA sequence. There is strong evidence that early life stress causes epigenetic changes that affect substance use in adulthood. For example, early life stress can lead to changes in the DNA of a gene that influences how the body responds to stress, which is linked to major depressive disorder. Interestingly, substance use itself can also cause epigenetic changes, affecting how genes are expressed.

Furthermore, small genetic differences among people, known as single nucleotide polymorphisms (SNPs), are linked to varying risks for developing disorders. SNPs in genes associated with the body's stress response system (HPA axis) can alter the risk for drug abuse and withdrawal symptoms. For example, certain SNPs in the NR3C2 gene, which helps regulate stress hormones, have been identified as risk factors for cocaine and heroin abuse. Similarly, SNPs in the NR3C1 gene, another key stress-related gene, are associated with an atypical response to stress hormones. This atypical response can contribute to drug abuse, continued use, and relapse. Specific SNPs in NR3C1 have also been linked to an increased risk for depression and higher depressive symptoms during recovery from crack/cocaine abuse, especially when combined in certain genetic patterns.

Discussion and conclusions

This review examines how substance use changes the brain's reward and stress systems, explaining these alterations through a three-stage model of Substance Use Disorder and highlighting their anatomical and hormonal aspects. The discussion integrates the role of cellular stress, which is closely tied to SUD. Stress, depending on its nature, intensity, and duration, affects the body's stress response, brain flexibility, and cellular processes. Early life stress (ELS) was specifically emphasized due to strong evidence linking it to altered stress responses and an increased risk for SUD, including its onset, continuation, and relapse, all mediated by changes in brain pathways related to reward and stress. Finally, individual vulnerability to SUD was explored through the lens of genetics and epigenetics, showing how drug use and life experiences can change gene expression and increase SUD risk in susceptible individuals.

In summary, substance use can significantly disrupt key brain circuits and hormonal systems, leading to altered responses to both reward and stress. Exposure to stress, particularly early in life, can heighten the risk of developing SUD during adolescence and adulthood. Cellular stress, whether caused by general stress or by substance use itself, plays a crucial role in this process, offering potential targets for treatment. Moreover, understanding genetic factors may help identify individuals at higher risk, allowing for earlier interventions and prevention strategies to reduce the development of SUD.

Introduction

Substance Use Disorders, or SUDs, are brain illnesses. People with SUDs feel a strong need to find and use drugs, even when it causes many problems. These problems can be mild, medium, or serious. In 2022, about 64 million people worldwide had SUDs. This number went up by 3% in just five years. Many people with SUDs also have other mental health issues. For example, about 1 in 4 people with serious sadness (depression) also have SUDs, and 1 in 3 people with bipolar disorder do. SUDs are also often seen with general worry (anxiety) and stress from bad past events (PTSD).

Stress is a normal way the body reacts to things around it. It can change how a person feels in their body or mind. When stressed, the brain releases chemicals. These chemicals help the body react, but too much stress can cause problems. Certain brain chemicals play a big part in how people feel and react. These chemicals also affect how the body handles stress and drug problems. If a person is under too much stress for too long, it can lead to harmful body changes. This is why stress can be a major reason for both mental health problems and SUDs.

Some parts of the brain are very important for how a person handles stress and uses drugs. For example, one part of the brain releases a chemical that makes people feel good, like when they get a reward. Other parts of the brain help control feelings and are very active during stress. They also play a big role when a person is stopping drug use, causing feelings like worry or being upset. Stress can also stop people from feeling good and can make parts of the brain work differently.

This information will help explain how stress and drug use are connected in the body, at the cell level, and through a person's genes. Understanding these links can help find new ways to help people with drug problems. The focus will be on how stress early in life, stress on body cells, and a person's genes affect drug use.

Anatomical and neuroendocrine features of stress and SUD

Drug problems often follow a three-step path: using a lot, feeling bad when stopping, and then only thinking about drugs. When a person first uses drugs, it can activate parts of the brain that make them feel good. Over time, continued drug use changes the brain. This makes the brain work differently and increases the chance of drug problems and starting to use drugs again. For example, it can become harder to feel pleasure from normal things. When a person stops using drugs, they often feel bad, worried, and uncomfortable because of these brain changes. Later, a part of the brain important for making choices and self-control may not work as well, leading to a loss of control over drug use and strong cravings.

The parts of the brain and chemicals that control drug problems are often the same ones that handle stress. Both stress and certain body chemicals can increase the amount of a brain chemical that makes people feel good. This can make someone more likely to use drugs, feel good from them, or start using drugs again after stopping. Stress also affects memory. Since memory is linked to a part of the brain that handles stress, it could explain why people with drug problems feel strong cravings and worry when stressed or when they see things that remind them of drugs. Stress can also cause changes in the brain that make it harder to make good decisions. So, stress affects many parts of drug use, from why someone keeps using to why they start again.

The early-life stress implications for SUD

Stress early in life is a big risk for mental health problems. Things like neglect, trauma, or abuse during childhood can lead to sadness, worry, PTSD, and drug problems later in life. There are many reports each year about children who are abused or neglected. People who faced early life stress might start using drugs to feel better or to cope with their past hurts. This can lead to a cycle where they become dependent on drugs to manage their feelings.

The brain grows and changes a lot during childhood and the teenage years. Drug use during these times can harm how brain cells work and change how the brain is built. This makes the growing brain more open to the bad effects of drugs. Early life stress can also harm brain cells as they develop, including parts of the brain that control how a person feels pleasure. This shows a strong link between early life stress and drug problems during teenage years and adulthood. Studies in animals show that stress during young ages makes them use more drugs when they are older. Also, early life stress can change how the body's stress system works, which is important for drug use. This means any stress during early life can have a big impact on a person's risk for developing drug problems.

SUD and stress at cellular level

Stress happens not just in the mind and body, but also inside the body's cells. Recent studies show that stress inside cells and swelling in the brain are key reasons why drugs harm the brain's balance. For example, giving a medicine that fights swelling to animals reduced brain swelling caused by some drugs. Long-term use of different addictive drugs also increases swelling in the body and brain. This can start a chain reaction that makes certain brain cells too active, leading to more swelling and cell stress.

These brain cells can sense changes and start a swelling response. When they react, they make more harmful chemicals that can damage cells. For example, drugs can cause the release of chemicals that lead to swelling in the brain. They can also harm parts of the cells that make energy, creating more harmful chemicals. This cell stress can cause brain cells to die. Many studies show that drug problems and cell stress are linked, with one often leading to the other. For instance, smoking cannabis, like tobacco, increases cell stress. Different drugs like amphetamines, cocaine, and heroin also cause cell damage by creating harmful chemicals and lowering the body's ability to fight off stress.

Genetic hallmarks of SUD

Important questions remain: Why are some people more likely to develop drug problems than others? And does stress play a role in this? One possible answer is through changes in how genes work. There is much proof that stress early in life can change how genes work, which then affects drug use in adulthood. Also, early life stress seems to change a gene related to stress, which is linked to serious sadness (depression). Interestingly, drug use itself also changes how genes work in many ways.

Small differences in a person's DNA can also affect their risk for drug problems. These small differences in genes linked to the body's stress system can change the risk for drug abuse and problems when someone stops using drugs. For example, one small gene difference has been linked to a higher risk of cocaine and heroin abuse. Another gene difference has been linked to childhood neglect and cocaine abuse. Other gene differences are linked to how the body reacts to stress and have been connected to depression and feelings of sadness when trying to stop crack or cocaine use. These gene differences may even work together to increase the risk for cocaine abuse and depression.

Discussion and conclusions

This summary looked at how drug use changes the brain, affecting how a person feels rewards and handles stress. These changes are linked to the three stages of drug problems and how the brain and hormones are involved. Cell stress, which is closely tied to drug problems, was also discussed. Depending on what kind of stress it is, how strong it is, and how long it lasts, stress affects the body's stress system, how the brain changes, and what happens at the cell level. Stress early in life was highlighted because it strongly increases the risk for drug problems, from starting to use to continuing and relapsing. This happens because early life stress changes how the brain's reward and stress pathways work. Lastly, how a person's genes make them more or less likely to develop drug problems was explored, showing how drug use and life experiences can change how genes work and increase the risk for some people.

In summary, drug use can greatly disturb important brain systems and hormone controls, leading to different ways of reacting to rewards and stress. Also, being exposed to stress, especially early in life, can make a person more likely to develop drug problems during their teenage years and as an adult. Stress at the cell level, caused by either stress or drug problems, is very important in this process and could be a target for new treatments. Finally, looking at a person's genes might help find people who are at higher risk. This could allow for help to be given early to stop drug problems from starting.