Drinking in moderation, is defined by the 2015–2020 Dietary Guidelines for Americans as consumption of up to one drink per day for women and up to two drinks per day for men. Low risk drinking as defined by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) is no more than 3 drinks per day and no more than 7 drinks per week for women, and no more than 4 drinks per day and no more than 14 drinks per week for men. Drinking in moderation and low risk drinking are not associated with a significant increase in risk for alcohol-induced comorbidities. In contrast, binge drinking defined as drinking to elevate blood alcohol concentrations to 0.08% (80 mg/dl) or higher, generally resulting from drinking 4 or 5 drinks over a 2-h time frame is considered at-risk and categorized as extreme when the consumption is twofold or greater than the gender-specific thresholds (i.e., 10 or more standard drinks for men, and 8 or more for women) (Yeomans et al., 2003; Alcohol Research, Current Reviews, and Editorial Staff., 2018). Alcohol consumption is discouraged in certain groups of people including underage individuals (less than 21 years of age), women who are pregnant or trying to become pregnant, those who take medications that interact with alcohol, and those with existing medical conditions, including human immunodeficiency virus (HIV) as discussed in this review (Alcohol Research, Current Reviews, and Editorial Staff., 2018).

While the contribution of at-risk alcohol consumption to organ injury is well recognized, the definition of at-risk drinking is complicated by different patterns of consumption, the types of alcoholic beverages consumed across geographical regions (World Health Organization, 2021), and the inconsistent definition of a standard drink across countries, ranging from 8 g in Iceland to 20 g in Austria (Kalinowski and Humphreys, 2016). In addition, there appears to be wide variability for defining rates of low to moderate-risk drinking across nations, ranging from 98 to 140 g per week for women and 150–280 g per week for men (Kalinowski and Humphreys, 2016). Several factors are considered in the classification of alcohol drinking patterns, including the frequency and amount of alcohol intake, number of episodes of acute intoxication, and number of alcohol binges (Wetterling et al., 1999). According to the World Health Organization (WHO), prevalence of at-risk drinking is measured by heavy episodic drinking, defined as consuming 60 g of alcohol or more on at least one occasion in the past 30 days. In the United States, where a standard drink is 14 g, heavy episodic drinking is defined by consumption of 4.25 standard drinks. Worldwide, approximately 18% of the adult population report heavy episodic drinking (Poznyak, 2018).

Cardiometabolic syndrome is a combination of alterations including glucose intolerance, dyslipidemia, hypertriglyceridemia, central adiposity, and hypertension, that is now recognized by the WHO as a disease entity (Saljoughian, 2016). CMS increases mortality risk due to coronary heart disease, myocardial infarction, stroke, and type 2 diabetes (Castro et al., 2003) and is one of the geriatric comorbidities prevalent in PLWH (Woldu et al., 2020). Lifestyle behaviors including at-risk alcohol use, consumption of diets rich in fat and sugar, low physical activity, and behavioral and psychosocial stressors are associated with increased risk for CMS and type 2 diabetes. Alcohol use impacts risk for CMS following a U or J shape curve (Alkerwi et al., 2009; Baliunas et al., 2009; Koloverou et al., 2015; Lai et al., 2019). However, this is not generalizable across geographical locations or ethnic groups. Moderate alcohol consumption is shown to be protective in studies from the United States (Kerr and Ye, 2010) or Sweden (Rasouli et al., 2013), but not in studies conducted in Japan (Teratani et al., 2012). Data relating alcohol to all-cause and cardiovascular (CV) morbidity and mortality from more than 600,000 current drinkers without a history of CV disease, indicated a much lower threshold for amount of alcohol consumed than currently accepted (Wood et al., 2018). In a prospective, longitudinal study, male sex, being physically active, and in good health status were independently associated with light to moderate drinking. Though there was an apparent protective effect of light to moderate drinking on mortality after adjusting for age, sex, risk factors, and cardiovascular events, the relationship was no longer significant when adjusting for physical activity and perceived health status (Muscari et al., 2015). These results suggest that the protective effect of moderate alcohol use is most prominent among individuals with a healthier lifestyle (Koloverou et al., 2015). Moreover, compelling evidence suggest that risk for CMS increases with increasing alcohol consumption (Vieira et al., 2016). Alcohol-using PLWH have higher odds of displaying lipodystrophy (Cheng et al., 2009; Molina et al., 2014a) and altered adipokine profiles including that of leptin (Srdic et al., 2017) and adiponectin (Lee and Kwak, 2014; Langkilde et al., 2018). Alterations in these adipokines have been linked to metabolic dysregulation in obese subjects (Harwood, 2012; Lee and Kwak, 2014), in PLWH on ART (Jan et al., 2004; Lagathu et al., 2005), and to impaired insulin signaling (Jan et al., 2004; Stankov and Behrens, 2010). CMS is a comorbidity commonly associated with cognitive deficits in PLWH (Pope et al., 2020; Pasipanodya et al., 2021), and cardiometabolic health is linked to improved cognitive function in aging PLWH (Saloner et al., 2019).

Diet quality is influenced by the pattern of alcohol use, being the poorest among subjects who consumed the highest quantity of alcohol (Breslow et al., 2006), among women who were current drinkers, and among both men and women as the amount of alcohol consumption increased (Breslow et al., 2010). The interaction of unhealthy alcohol use with an unhealthy diet is likely to further enhance risk for comorbidities. Diet quality among PLWH (Muhammad et al., 2019; Weiss et al., 2019) is significantly lower than recommended. In a large single-site study among PLWH in the US, dietary recall demonstrated that the average carbohydrate intake was twice the recommended amount and protein consumption was a third of recommendations and was also associated with a trend for increased fat intake (Webel et al., 2017). This dietary pattern, referred to as a Western Diet has been linked to immune and metabolic dysfunction (Childs et al., 2019). PLWH have a lower healthy eating index (HEI) score compared to HIV- subjects, with decreased scores for consumption of seafood and plant proteins and beneficial fatty acids, along with increased consumption of foods with non-nutritional calories including alcohol (Weiss et al., 2019). The HEI assesses dietary patterns and their degree of adherence to the Dietary Guidelines for Americans (Guenther et al., 2008), and scores ≤ 50 are inversely correlated with reduced risk of all-cause mortality in the general population (Sotos-Prieto et al., 2017a,b). Increased insulin, cholesterol, and triglycerides in PLWH are associated with increased total dietary energy intake with high total and saturated fat (Batterham et al., 2000). Chronic binge alcohol in simian immunodeficiency virus (SIV) infected macaques decreases total caloric intake and alters nutrient selection, decreasing nitrogen intake and balance as the disease progresses (Molina et al., 2006). The self-imposed carbohydrate rich, low nitrogen diet likely contributes to decreased muscle mass observed in end stage disease. Changes in dietary intake can influence micronutrient availability and in addition modulate circulating and tissue growth factors (Childs et al., 2019). Hence, direct, and indirect alcohol-mediated effects as well as diet quality and composition can significantly contribute to risk for CMS in PLWH.

Alcohol-induced carbohydrate, lipid, and protein metabolic dysregulation is due to either direct effects of alcohol and its metabolites on liver, adipose tissue, and skeletal muscle (SKM), or due to indirect effects resulting from immune dysregulation (Figure 3). Alcohol consumption significantly decreases gluconeogenesis partly due to impaired hepatic utilization of lactic acid, glycerol, and alanine as gluconeogenic substrates (Steiner et al., 2015a) and a reduction in glycolytic and gluconeogenic hepatic enzyme activity (Baranyai and Blum, 1989; Mokuda et al., 2004). Alcohol impairs insulin signaling including decreased phosphorylation of the insulin receptor, insulin receptor substrate (IRS)-1, and AKT, and decreases GLUT4 membrane translocation in peripheral insulin sensitive tissues (Steiner et al., 2015a). Reports in the literature indicate that chronic alcohol feeding (Kang et al., 2007b) as well as ART (Boccara, 2008) result in the development of insulin resistance, one of the main components of CMS. The mechanisms underlying insulin resistance and dysglycemia; manifested as an increased frequency of glucose intolerance or frank diabetes mellitus in PLWH (Willig and Overton, 2016; Natsag et al., 2017; Noumegni et al., 2017), remain poorly understood. Chronic subclinical inflammation has been proposed as a likely factor contributing to metabolic dyshomeostasis seen in ART-treated PLWH (Longenecker et al., 2013; Beires et al., 2018).

SKM is the major insulin-sensitive tissue in the body and is a major player in maintaining glucose homeostasis. Thus, alcohol-induced alterations in SKM homeostasis can potentially have a significant impact on metabolic dysregulation. The alcohol-mediated decrease in SKM protein synthesis (LeCapitaine et al., 2011; Steiner and Lang, 2019) together with alterations in the mammalian target of rapamycin (mTOR) signaling pathway (Hong-Brown et al., 2012) result in alcoholic myopathy; which together with the alcohol-associated alterations in synthesis and breakdown of carbohydrates and lipids, contribute to metabolic instability and increased risk for CMS (Figure 3). These alcohol-mediated alterations in SKM and adipose mass, and carbohydrate storage, can be reflected in anthropometric changes as well as in alterations of circulating levels of glucose, triglycerides, and cholesterol, as briefly discussed in the next section.

Central or abdominal obesity is associated with increased insulin resistance (Klaus et al., 2009; Govers, 2015; Jankie and Pinto Pereira, 2021). Heavy (20 to less than 60 g/day) and very heavy (60 g/day) alcohol use increases waist circumference and abdominal fat accumulation (Churilla et al., 2014; Hirakawa et al., 2015). Though the exact mechanisms are unclear, proposed alcohol-associated mechanisms include decreased leptin and glucagon like peptide -1, alterations in sex steroid hormones, loss of lean body mass, and increased lipolysis and fatty acid flux (Riserus and Ingelsson, 2007; Sumi et al., 2019). In the post-ART era, obesity is emerging as a critical problem in PLWH (Godfrey et al., 2019), with increased body mass index (BMI) associated with increased risk of CV disease and diabetes mellitus among PLWH (Achhra et al., 2018).

Reports on the effects of alcohol on glycemic control are mixed. Low to moderate alcohol use inhibits hepatic glycogenolysis and gluconeogenesis, decreases fasting insulin and HbA1c, and increases insulin sensitivity (Hong et al., 2009; Koloverou et al., 2015; Schrieks et al., 2015; Vieira et al., 2016). Clinical studies show that alcohol decreases circulating basal insulin secretion (Bonnet et al., 2012) and decreases circulating insulin and c-peptide response to glucose (Patto et al., 1993). Preclinical studies show that chronic binge alcohol significantly impairs endocrine pancreatic response to a glucose load in SIV-infected macaques (Ford et al., 2016; Simon et al., 2021). Similarly, rodents on a chronic alcohol diet have decreased circulating insulin levels (Rasineni et al., 2019), and decreased pancreatic expression of glucokinase, glucose transporter-2 (Kim et al., 2010), and gamma-aminobutyric acid (GABA) receptors (Wang et al., 2014). These alcohol-induced alterations can potentially contribute to decreased insulin release following a glucose load. This is aligned with studies showing that in vitro alcohol exposure decreases glucose-stimulated insulin secretion (GSIS) from human (Dragan et al., 2017) and rodent (Wang et al., 2014; Rasineni et al., 2019) pancreatic islets and increases β-cell apoptosis (Dembele et al., 2009; Kim et al., 2010). These findings support a role for alcohol-mediated impairment of pancreatic endocrine function, particularly of the integrity of β-cell response to glucose as an underlying mechanism of glucose dyshomeostasis. In addition, preclinical studies show that adiponectin, an insulin sensitizing adipokine with anti-inflammatory properties is decreased with at-risk alcohol use (Ford et al., 2016; Steiner and Lang, 2017). A potential factor in alcohol-mediated decrease in adiponectin levels may be increased resistin levels in both clinical studies and animal models of alcohol use. Resistin suppresses adiponectin secretion and stimulates lipolysis, releasing fatty acids and glycerol into circulation (Chen et al., 2014). However, results from clinical studies are inconclusive, with both low to moderate and at-risk alcohol use increasing adiponectin (Steiner and Lang, 2017; Nova et al., 2019). Overall, alcohol-associated alterations in adipocytokine profile may contribute to impaired glucose homeostasis. Moreover, alcohol-mediated impairment of glycolytic pathways is associated with increased formation of advanced glycation end products (AGEs), which together with endothelial dysfunction, inflammatory responses, and oxidative stress discussed below contribute to the development of hypertension and atherosclerosis, important components of CMS (Vasdev et al., 2006). Recent data show that in PLWH at-risk alcohol use increased the likelihood of meeting the clinical criteria for prediabetes/diabetes (Primeaux et al., 2021). Moreover, HOMA-β cell function negatively associated with AUDIT-C, phosphatidyl ethanol (PEth), and Timeline Followback (TLFB), suggesting that alcohol use is associated with impaired endocrine pancreatic function (Simon et al., 2020). Others have also reported a high incidence of diabetes in well controlled PLWH (Bratt et al., 2021), associated with increased oxidative stress (Bastard et al., 2019).

Chronic alcohol use results in a dose-response positive relationship with high density lipoprotein-cholesterol (HDLc) and negative relationship with low density lipoprotein (LDL) (Shuval et al., 2012). The alcohol-mediated biological mechanisms contributing to lowering of cholesterol levels include increased transport of lipoproteins and lipoprotein lipase activity (Shuval et al., 2012), and increased eNOS activity that helps transport of HDL-C (Hirakawa et al., 2015; Wakabayashi, 2019). At-risk alcohol use increases triglyceride levels especially among women (Hirakawa et al., 2015; Vieira et al., 2016) and moderate alcohol is associated with lower triglyceride levels (Kovar and Zemankova, 2015). Alcohol-mediated mechanisms that contribute to increased triglycerides include adipose tissue lipolysis, and hepatic synthesis of large very low density lipoprotein (VLDL) particles through the increased expression of microsomal triglyceride transfer protein (Klop et al., 2013). The interactions of alcohol with high fat diet further exacerbate hypertriglyceridemia by regulating hypothalamic peptides that increase appetite and energy intake (Barson et al., 2010).

Alcohol directly and indirectly alters the balance of lipogenesis and lipolysis and thus dysregulates lipid metabolism (Figure 3). Loss in adipose tissue mass resulting from chronic alcohol consumption is partly due to an increase in triglyceride turnover without significant alteration in triglyceride synthesis (Kang et al., 2007a; Zhong et al., 2012). Alcohol-induced activation of lipolysis and release of free fatty acids (FFAs) that are taken up by the liver has been proposed as a central mechanism of alcohol-induced steatohepatitis. Overall, alcohol alters hepatic lipid flux by increasing free fatty acid uptake from the diet and from adipose tissue lipolysis; stimulating lipogenesis from glycolytic end products; and dysregulating β- oxidation. Moreover, alcohol upregulates expression of fatty acid transporters particularly CD36/FAT promoting fatty acid uptake, and esterification of free fatty acids into triglycerides (You and Arteel, 2019). Alcohol dysregulates lipolysis through inhibitory effects on insulin action (Yki-Jarvinen et al., 1988), but not through enhanced adrenergic effects (Lang et al., 2014). In addition, alcohol increases plasma and adipose tissue expression of fibroblast growth factor 21 (FGF21), a known stimulus for lipolysis (Zhao et al., 2015). In contrast, alcohol decreases expression and activation of several lipogenic enzymes (Steiner and Lang, 2017). Thus, alcohol-associated dysregulation of lipid homeostasis results from an imbalance between lipolysis and lipogenesis. Dyslipidemia is highly prevalent among PLWH (Grunfeld et al., 1992), and this has been attributed to the infection itself, and some types of ART drugs. Early following HIV seroconversion, total, HDL, LDL cholesterol levels decrease. Following the initiation of ART, the profile shifts to increased total and LDL cholesterol to pre-infection levels, with persistent low HDL levels (Riddler et al., 2003). Alcohol-using PLWH have higher odds of presenting with lipodystrophy (Cheng et al., 2009). CVD risk factors, including dyslipidemia and hypertension, are determinants of reduced life expectancy in PLWH (Freiberg and Kraemer, 2010).

In addition to alcohol-induced metabolic dysregulation or instability, alcohol-associated risk for hypertension is also an important contributor to CMS (Saljoughian, 2016). Some studies report higher prevalence of hypertension in PLWH than in uninfected individuals, with a higher frequency in individuals 50 years of age or older (Xu et al., 2017; Fahme et al., 2018). Furthermore, hypertension in PLWH is associated with heavy alcohol use (Ikeda et al., 2013). Multiple mechanisms affected by alcohol and HIV infection can contribute to blood pressure dysregulation. Alcohol-induced dysregulation of vasoconstrictor levels, vasoreactivity, and endothelial integrity are all possible mechanisms contributing to altered blood pressure regulation. Alcohol at low doses produces transient vasodilation. In contrast, at higher doses and with binge drinking, alcohol leads to vasoconstriction (Rekik et al., 2002; Kloner and Rezkalla, 2007) and chronic heavy alcohol use increases the risk of hypertension (Kahl and Hillemacher, 2016; Vieira et al., 2016). Several mechanisms contribute to alcohol-associated hypertension including genetic predisposition for an ALDH2 polymorphism (Hu et al., 2014), activation of renin angiotensin aldosterone system (RAAS), central adrenergic activity, increased sympathetic flow, vascular smooth muscle tone, shifts in baroreceptor reflex sensitivity, and decreased nitric oxide (NO) release (Husain et al., 2014; Kahl and Hillemacher, 2016). In addition, alcohol increases both cytosolic free calcium (Ca²⁺) and cellular Ca²⁺ uptake by direct upregulation of voltage-gated Ca²⁺ channels, inhibits Ca²⁺-adenosine triphosphatase, and sodium-potassium ion pumps, thus increasing sensitivity to endogenous vasoconstrictors and exacerbating hypertension (Altura and Altura, 1982; Husain et al., 2014). The magnitude of increase in blood pressure with heavy alcohol use averages about 5–10 mm Hg with greater increases in systolic than diastolic pressure (Clark, 1985). The association between alcohol use and hypertension is stronger among older individuals (Burke et al., 1992; Riserus and Ingelsson, 2007), which may be due to enhanced sensitivity to sympathoadrenal activation (Husain et al., 2014). Thus, alcohol-associated risk for hypertension results from alterations in endothelial function and in the levels and activity of endogenous mediators of vasoreactivity as discussed in the next section.

Several alterations in vascular integrity and responsiveness may contribute to increased risk for hypertension and vascular instability. The vascular endothelium integrates humoral and hemodynamic signals modulating vasomotor tone and adjusting blood flow to the local tissue needs. Alcohol exerts biphasic effects on endothelial function (Puddey et al., 2001; Figure 4). Acute alcohol consumption produces immediate and transient vasodilation (Bau et al., 2005; Oda et al., 2020) followed by increased blood pressure later after alcohol consumption resulting in a biphasic effect of alcohol on blood pressure. The acute alcohol-induced vasodilation is mainly attributed to the increased expression of endothelial nitric oxide synthase (eNOS) and NO (Venkov et al., 1999). This mechanism has been proposed in cardioprotective benefits of moderate alcohol consumption (Abou-Agag et al., 2005; Toda and Ayajiki, 2010). Chronic and at-risk alcohol use is associated with hyperactivation of the hypothalamo-pituitary-adrenal (HPA) axis and increased glucocorticoid release. Excess glucocorticoid action can also contribute to endothelial dysfunction and accelerate the atherogenic process (Bau et al., 2005). Overall, at-risk alcohol use increases the risk of coronary artery disease, and hemorrhagic and ischemic stroke. Endothelial dysfunction is a predictor of CV disease and precedes atheromatous plaque formation (Schachinger and Zeiher, 2000). In addition, cytotoxicity resulting from at-risk alcohol use through generation of peroxynitrite, resulting from reaction of NO with superoxide; a product of alcohol-induced oxidative stress (Pacher et al., 2007), may also contribute to endothelial dysfunction. PLWH have significant impairment in endothelial function reflected in significantly lower flow-mediated vasodilation compared to uninfected controls, and present with elevated levels of markers of endothelial dysfunction (Rethy et al., 2020). Though evidence supports a deleterious effect of HIV infection on endothelial function, definitive studies remain limited and inconclusive.

At-risk alcohol use may alter the balance of endogenous vasoconstrictor levels including angiotensin II, endothelins, and norepinephrine (Tsuji et al., 1992), contributing to the increased risk for hypertension. Studies demonstrate that alcohol consumption increases overall activity of RAAS (Jing et al., 2008; Yarlioglues et al., 2019). Plasma renin activity is increased in individuals with heavy alcohol consumption (Husain et al., 2014) and angiotensin converting enzyme (ACE) activity in serum of hospitalized individuals with history of chronic alcohol consumption is higher than that of healthy controls (Okuno et al., 1986). Similarly, some evidence supports a role for increased RAAS activation in development of hypertension and metabolic syndrome in PLWH (Srinivasa et al., 2015; Masenga et al., 2020). The importance of increased activation of the Ang II type 1 receptor (AT1) to the development of alcoholic cardiomyopathy has been shown in preclinical studies (Cheng et al., 2006). Furthermore, activation of the AT1 receptor by chronic alcohol activates NADPH oxidase producing endothelial injury (Warnholtz et al., 1999; Gonzaga et al., 2018; Assis et al., 2020). Alcohol increases levels of renin, aldosterone, and angiotensin II (Jing et al., 2008), circulating renin and ACE activity, and left ventricular myocyte AT1 receptor expression in individuals with at-risk alcohol use (Husain et al., 2014). In addition, at-risk alcohol use results in increased plasma vasopressin levels indicating increased sympathetic stimulation (Chan and Sutter, 1983). Together with alterations in endothelial function, the alcohol-induced dysregulation of circulating levels of endogenous vasoactive mediators and their respective receptors promotes alterations in blood pressure regulation, increasing the risk for hypertension.

In addition to the direct and indirect alcohol-mediated peripheral tissue injury implicated in pathophysiology of CMS, at-risk alcohol use also impacts both peripheral and central nervous system physiology. This is perhaps best represented by alcohol’s ability to regulate the conscious experience of pain through its interactions with both ascending and descending nociceptive circuitry (Egli et al., 2012). Importantly, chronic pain affects approximately 20% of adults worldwide and approximately 100 million Americans (Nahin, 2015), a number that will likely increase over the next few decades given an aging U.S. population. Chronic or neuropathic pain is prevalent in approximately 57% of PLWH, significantly impairing quality of life (Ellis et al., 2010). PLWH with HIV-related pain also have higher rates of depression, anxiety, and insomnia, compared to those without neuropathy symptoms (Phillips et al., 2014), indicating that neurological pain symptoms may ultimately transform into CNS pathophysiology including cognitive dysfunction and psychiatric illness. Preclinical studies show significant heightened pain sensitivity in response to systemic injection of HIV viral particles (Guindon et al., 2019; Bagdas et al., 2020). SIV infection in pigtail macaques induces inflammatory cell infiltration in the spinal cord, a frequent finding in chronic pain conditions (Mangus et al., 2015).

Evidence also suggests that diet and metabolic factors influence the development and chronicity of pain symptoms. Diets containing high amounts of omega-6 fatty acids (common in Western diets) exacerbate nociceptive sensitivity in preclinical animal models of neuropathic and inflammatory pain (Boyd et al., 2021). Importantly, Western diets appear to prolong recovery from a pain-related injury in animals, although recovery was accelerated by switching animals to an anti-inflammatory diet (Totsch et al., 2018). Similar dietary interventions have also demonstrated efficacy in reducing pain symptoms in humans (Lattanzio and Imbesi, 2018). A review of global studies also highlighted links between affective disorders, metabolic syndrome, and chronic pain (Bica et al., 2017), strongly suggesting that negative affect serves as a moderator of these relationships. Convergent evidence suggests a strong underlying influence of chronic inflammation in these integrated disease processes, providing a mechanistic basis for how HIV and alcohol use promotes and sustains these conditions.

While the analgesic effects of alcohol have been known for some time (Thompson et al., 2017; Cucinello-Ragland and Edwards, 2021), excessive alcohol exposure damages elements of the peripheral nervous system producing a characteristic small fiber painful neuropathy (Maiya and Messing, 2014), and the resulting increased nociceptive sensitivity (termed hyperalgesia) is hypothesized to contribute to an increased motivational drive to drink (Egli et al., 2012). In addition to the direct effects of alcohol, abstinence from heavy drinking can also increase affective pain sensitivity (termed hyperkatifeia) as part of a larger motivational withdrawal syndrome (Edwards et al., 2012; Koob, 2021) that may also promote the use of alcohol for affective/emotional pain management. Indeed, self-reports of alcohol use specifically for pain are common. Problem drinkers of both sexes report more severe pain symptoms compared to non-drinkers, and also a higher incidence of using alcohol to manage their pain (Brennan et al., 2005). Interestingly, use of alcohol to manage pain symptoms presaged a worsening of alcohol drinking-related comorbidities, including diabetes (Brennan et al., 2005).

Acute pain represents an adaptive sensory process vital to protecting our bodies from damage. In contrast, chronic or unrelieved pain represents a profound negative emotional experience that can have a powerful influence on brain reinforcement mechanisms, possibly facilitating the transition to AUD in vulnerable individuals (Zale et al., 2021). As support for this conceptualization, there are strong associations among alcohol consumption, chronic pain, and pain-related disability (Witkiewitz et al., 2015a,b; Yeung et al., 2020). Evidence suggests that chronic pain may be predictive of future at-risk alcohol use. In one prospective epidemiological study, self-reported pain interference (or how pain disrupts daily life activities) was predictive of AUD development (McDermott et al., 2018). Additional preclinical research suggests that the relationships between individual levels of alcohol drinking and resultant chronic pain relief may change over time (Adrienne McGinn et al., 2020), although the neurobiological basis of these links is currently unknown.

In addition to chronic pain, important bi-directional relationships exist between at-risk alcohol drinking and other negative affective conditions (e.g., stress, anxiety, depression) that represent additional risks for psychiatric co-morbidities. Importantly, people with chronic pain and high negative affect report higher pain severity and pain interference compared to people with only one of the two disorders (Arnow et al., 2006). Such symptoms may precede or emerge within the development of more severe forms of AUD (Gilpin et al., 2015). For example, the development of negative affective states comprises a portion of the constellation of symptoms of alcohol withdrawal, and as such, likely contribute to negative reinforcement processes that drive continued or escalated drinking over time (Tolomeo et al., 2021). Another intense line of preclinical and clinical investigation concerns factors that precede and may presage the development of at-risk drinking. These range from neurological conditions including traumatic brain injury (Phillips et al., 2014; Mayeux et al., 2015; Adams et al., 2020; Schindler et al., 2021) to pre-existing psychiatric disorders such as post-traumatic stress disorder (Whitaker et al., 2014; Langdon et al., 2016; Livingston et al., 2021).