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The Paradoxical and Pervasive Nature of Alcohol Use to Reduce Anxiety: Understanding Underpinning Neurobiology for Efficacious Treatment Approaches

"When there is plenty of wine, sorrow and worry take wing."—Ovid.

Introduction: Many consume alcohol to reduce anxiety.  Paradoxically, anxiety increases at baseline, and continued drinking predisposes one to alcohol use disorder (AUD). The relationship between alcohol and anxiety is noted as a “potent marker” for AUD (Anker & Kushner, 2019, p.15), and “research provides increasing support for the neuroscientific perspective that these conditions share underlying, mutually exacerbating, neurobiological processes” (Anker & Kushner, 2019, p. 15). As a recovering alcoholic and alcohol and drug counselor, the writer finds this intriguing, because self-medicating with alcohol, he experienced heightened anxiety (after two tours of duty in Iraq).  Sadly, he watched both his mother and sister experience progressive alcoholism and anxiety to their untimely deaths.  At a micro level for social work, clinicians must understand the relationship between anxiety and alcohol. From a macro level, mental health and substance abuse treatments are not integrated, bureaucratic turf battles for funding exist, and legislation for standardization in funding and provision of these services would facilitate better treatment (Fisher & Harrison, 2018).

Pervasiveness:  How pervasive is the connection?  Ubiquitously, anxiety disorders and AUD are co-occurring, and “acute alcohol exposure produces anxiolytic effects, whereas withdrawal after protracted exposure leads to the development of anxiety-like symptoms” (Sakharkar, Zhang, Tang, et. al., 2014, p 1207).   “Many people suffering from AUD also suffer from one or more other psychiatric disorders, including…anxiety disorders” (Falk & Yi, 2008, p.100), and over half “of individuals receiving treatment for problematic alcohol use also met diagnostic criteria for one or more anxiety disorders” (Anker & Kushner, 2019, p. 15).  NESARC cites “an estimated 17.6 million American adults (8.5 percent) meet standard diagnostic criteria for an alcohol use disorder” (Archives of General Psychiatry [Volume 61, August 2004: 807-816), and robust studies note that both conditions progressively increase, causing persons to return to drinking within 4 months of abstinence (Anker & Kushner, 2019). Why?

Conceptualization: There’s no reductionistic explanation for unidirectional links between the co-occurring disorders, but data reflect that in three-fourths of individuals diagnosed with AUD, anxiety disorders were first present.  This paper isn’t a post hoc, ergo propter hoc explanation of etiology or cause, but rather is concerned with the phenomenon of increased anxiety and persistent use. Conceptually, our focus is on the bidirectional nature of the conditions. That is, dysregulation in the stress response system predisposes one to alcohol and anxiety disorders.  One helpful way to consider this relationship is understanding the evolution of the psychiatric, psychological, and neurobiological disciplines (Anker & Kushner, 2019). 

Psychiatry:  For over 200 years typologies categorizing alcohol abuse and anxiety were used. Comparison between the Apollonian (anxious) and Dionysian (rule breakers) types introduced the concept of ‘comorbidity.’  Nearly 40 years ago, two or more distinct psychiatric disorders were realized and codified in the third edition of the DSM (Anker & Kushner, 2019).  Unfortunately, these typologies persist today.

Psychology:  Tension reduction and operant-behavioral approaches concomitantly developed within psychology.  Ostensibly, this hypothesis purported that alcohol use reduced anxiety and resulted in negative reinforcement through the removal of distressing emotions, thus perpetuating the behavior, and much research conducted in the later part of the 20th century deemed this as inconclusive (Anker & Kushner, 2019). 

Neurobiology:  Notwithstanding psychiatric and psychological explanations, “studies have examined the neurobiological aspects of co-morbid alcohol and other drug use, seeking to identify shared mechanisms through which the different drug classes may act on the brain” (Falk & Yi et. al, 2008, p.101), and the 1990s focused on the dysregulation of the stress response (i.e., craving, binge, relapse). Allostatic changes in stress response occur via neurochemical messengers (i.e., adrenalin, cortisol, GABA, dopamine, glutamate, etc.) in the system’s attempt to regain balance.  Perhaps the most comprehensively accurate way of explaining the connection between alcohol and anxiety, is through an ‘opponent process model’ which integrates the above disciplines, and explains addiction through the lens of a progressive cycle (i.e. binge/intoxication, negative affect/withdrawal, craving/preoccupation) involving motivation as the primary link between learning, operant conditioning, and overlapping neurobiology affected by anxiety/stress for coping (Anker & Kushner, 2019).  What biological changes occur?

Neuroadaptations:  Neuroadaptations reset baseline operations (allostasis).  Chronic alcohol use results in long term, plastic changes, cause anxiety, potential relapse (Somkuwar & Vendruscolo, 2017), and “in this opponent process model, the term addiction refers to the neurobiological and motivational changes that occur as a consequence of chronic substance use” (Anker & Kushner, 2019 p. 20).  Binge/intoxication and preoccupation/anticipation is here briefly explained, but import is on withdrawal/ negative affect.  In binge/intoxicationreward circuits are activated by alcohol.  Motivation (incentive salience), via the mesolimbic dopaminergic system, produces positive reinforcement and ongoing/increased substance use (pleasure principle). There’s unmistakable evidence for the role of the mesolimbic dopamine pathway in mediating expected rewards and pathological training that reinforces alcohol use.  Rat assays show dopamine receptors to be implicated through motivational learning, but “human data are available to demonstrate that elevated stress reactivity during early withdrawal from both cocaine and alcohol predicts relapse” (Helig & Egli et. al., 2010, p.178).  Long term memory is encoded for rewards through cues, and the “the dendrites, the branches off the neuron, become longer and more numerous in the response to high dopamine rewards” (Lembke, 2021, p. 62).  This is less about avoiding displeasure, more about increasing pleasure, and the chronic use of alcohol between systems causes the brain to seek balance.  Moderate alcohol blood levels produce a release of dopamine that may eventually, at higher levels, cause a person to lose control of their drinking.  These “adaptive changes in dopamine systems contribute to dependence and craving for alcohol and the low mood seen in withdrawal. Endorphins are the brain’s internal endogenous opioid system, which dampens down pain and also produces feelings of euphoria. Their release also contributes to the pleasurable effects of alcohol but at the same time can promote loss of control and so lead to bingeing. It seems likely that both dopamine and endorphins contribute to the propensity of some people to become dependent on alcohol” (Nutt & Tyacke, 2022, pp. 2-3).  When scientists examined the rats’ brains in a cited study, they saw changes in the reward pathways after chronic use, and sensitization of the substance which can change the brain forever through a process called dependent neuroplasticity (Lembke, 2021).  So, “while alcohol is initially consumed for its positive reinforcing effects, the later stages of AUD are characterized by drinking to alleviate the withdrawal-induced “hyperkatifeia” or negative emotional state, via a negative reinforcement mechanism” (Ferragud & Velazquez-Sanchez et. al., 2021, p. 509).

Withdrawal/negative affect occurs when the brain’s stress systems (e.g., corticotropin-releasing factor, norepinephrine, serotonin, etc.) are recruited by the bed nucleus of the stria terminalis (BNST).  Part of the amygdala and aiding in control of autonomic and behavioral responses through negative reinforcement caused by excessive alcohol (Ferragud & Velazquez-Sanchez et. al., 2021), the BNST is thought to be relay center between other limbic systems (e.g., hippocampus, hypothalamic and brainstem regions) for reward, stress, and anxiety.  The “pituitary adenylate cyclase-activating polypeptide (PACAP), a highly conserved neuropeptide which exerts its effects mainly through the PAC1 receptor (PAC1R), has been suggested to be one of the mediators of the effects of drugs of abuse and alcohol” (Ferragud & Velazquez-Sanchez, 2021, p. 509).  “Intermittent ethanol exposure has been shown to increase PACAP in the paraventricular nucleus of the thalamus and acute ethanol exposure to increase PAC1R mRNA expression in cell lines” (Ferragud & Velazquez-Sanchez, 2021, p. 510). This system is implicated in the motivational role for emotional regulation. “Chronic alcohol exposure and withdrawal have been shown to alter the function and plasticity of neurons of the BNST (which) has also been shown to play a role in the sensitization of ethanol withdrawal-induced anxiety-like behavior” (Ferragud & Velazquez-Sanchez, 2022, p. 509). GABA (gamma aminobutyric acid), an amino acid, molecularly like alcohol (and causing the same relaxing effects), is the primary way that alcohol exerts itself.  GABA is synthesized through glutamate (excitatory and precursory) via an enzyme called glutamate decarboxylase (GAD). Social anxiety can accompany events (i.e., meeting new people, occasions, etc.), and historically, there is much evidence that alcohol (like benzodiazepines, barbiturates, and anti-convulsants) has been used for decreasing anxiety, and in low amounts (0.02% and 0.04%) alcohol has a calming effect “due to an enhancement of GABA activity in the brain” (Nutt & Tyacke, 2022, p 2).  Increased GABA is released, enhancing activity of GABA receptors, and affecting the levels of brain neurosteroids.  Hypersensitization of the GABA system manifests as euphoria, relaxation, lowered anxiety, lowered inhibitions, etc., and at higher doses, the inhibitory effects of GABA take over and lead to a suppression of the CNS (drowsiness, slurred speech, etc.).  Supplying a mild high, GABA is the key part of alcohol’s addictive potential, and is believed to underly cravings in abstinence. In connection with the dopaminergic circuit of the brain, alcohol can hijack the reward circuit into overstimulation, and the brain tries hard to achieve a state of balance to be rid of the toxic acetaldehyde (converted ethanol).  Continued assault trains our brains, predicting the next wave of ethanol, and lowers endogenous activity of the GABA system. This “disruption of neurochemical homeostasis not only facilitates symptoms of alcohol-related disease (including anxiety), but also augments the sensitivity to harmful drinking behavior” (Wang, 2022, p. 3).  This downregulation of the GABA system counteracting ingested alcohol increases glutamate activity in a process called upregulation.  At higher blood alcohol levels (> 0.15%), due to alcohol blocking glutamate receptors, an individual is unsteady, falls, slurs speech, and can even black out.  Chronic alcohol consumption results in malfunction of the system orchestrating the body response to stressful challenges (Nutt &Tyacke, 2022). Measured by proton magnetic resonance spectroscopy, “alcohol‐induced suppression of brain GABA levels may be mediated by the suppressing effects of alcohol on glutamic acid decarboxylase activity in both preclinical and clinical studies, the most dramatic disturbances in glutamate levels have been found in states of acute alcohol withdrawal, and alcohol withdrawal symptoms themselves have been proposed to primarily be the direct result of a hyper‐glutamatergic state caused by acute abstinence in individuals with moderate‐severe AUD”  (Prisciandaro & Schacht, et. al., pp. 7-8).  Abstinence causes the imbalanced system to manifest with anxiety, restlessness, irritation, insomnia, agitation, and depression. This cycle takes 18 days to 5 weeks of abstinence to restore balance, but chronic alcohol use leads to more use to feel better.

Preoccupation/anticipation undermines attempts to abstain.  “At this point, chronic alcohol or other drug use becomes an integral, exogenous input for maintaining equilibrium in the brain’s mood and stress regulation systems… (and) epidemiological data and the opponent process model both support the concept that this motive is a primary link between the neurobiological and subjective manifestations of negative affect and drinking behavior” (Anker & Kushner, 2019   p. 21).    

Substrates: Neurobiologically, “the amygdaloid brain circuitry…has been shown to serve as a neuroanatomical substrate for negative reinforcement mechanisms associated with development of alcoholism” (Sakharkar, Zhang, Tang, et. al., 2014, p. 2008).  “Alcohol increases GABAergic synaptic transmission by increasing presynaptic GABA release from vesicles, especially in the central amygdala” (Wang, Zhu, Ni et. al., 2022, p. 3), and “human imaging and animal research show abnormal central amygdala function in individuals with alcohol or anxiety disorders” (Anker & Kushner, 2019, pp. 22-23).  In one study with rats, “following withdrawal from a single large alcohol dose, there was increased release of Corticotropin-releasing hormone (CRH) within the central amygdala” (Helig & Egli et. al., 2010, p. 175), they voluntarily chose an ethanol solution over plain water.  A dysfunctional hypothalamic-pituitary-adrenal (HPA) axis, the endocrine stress response, occurs with chronic alcohol use, and the amygdala activates the HPA in this process.  “Cortisol (the predominant glucocorticoid in humans) links anxiety and alcohol use; for example, elevated plasma cortisol and blunted stress-induced cortisol response were associated with higher anxiety in individuals with alcohol use disorder” (Somkuwar & Vendruscolo, 2017, p. 17).  This stress hormone, increased with alcohol consumption, activates the HPA axis, modulates neuronal function, and this dysregulation can underlie anxiety and perpetuating alcohol use.  In clinical/experimental studies heightened anxiety in alcohol withdrawal led to neuroadaptive changes which caused an experience of exaggerative sensitivity to stress and self-medicative behavior (Helig & Egli et. al., 2010).

“Pro-inflammatory cytokines can impact the brain through vagal and humoral routes” (Santoft, Hedman-Lagerlöf, Salomonsson et. al., 2020, p.1), and one study “showed that alcohol withdrawal after chronic consumption significantly increased the expression of pro-inflammatory cytokines” (Villas, Gustavo, Marina, 2022, p. 32).  “Several lines of research have suggested that dysregulation of the immune system, particularly the pro-inflammatory cytokines, play a vital role in the pathogenesis of these disorders” (Kang & Bae, 2020, p.1).  Sustained levels of cytokines, and resultant anxiety symptoms occur for weeks into abstinence, and “there is evidence that ethanol withdrawal after acute intermittent or chronic exposure may prolong or even exacerbate the proinflammatory response” (Cruz, et. al., 2017, p.108).  “While the sources of this phenomenon are not completely clear, we know that environmental factors are culpable, and that when macrophages are exposed to alcohol or its metabolites, such as acetaldehyde, they produce inflammatory cytokines and reactive oxygen species (ROS), which are primary contributors to the pathogenesis of alcohol-induced diseases” (Kang & Bae, 2020, p.1).   Ergo, alcoholism, as a primary, chronic, and relapsing disease, must be treated with multifaceted modalities. 

Treatment/research:  As AUD and anxiety disorders are complex and multifaceted, and data show that persons with these comorbidities have poor treatment responses (Anker & Kushner, 2019), it is imperative that “effective treatment attends to multiple needs of the individual” (United States Public Health Service. Office of the Surgeon General, 2016, Ch. 4, p. 14) through proper screening, assessment, and diagnosis.  A trial with astaxanthin (naturally in marine life), inhibited oxidative stress and inflammation caused by alcohol consumption, and “repressed ethanol induced expression of proinflammatory genes and ROS accumulation” (Kang & Bae et. al., 2022, pp.1-2).  Botanical treatments can provide the relaxation effects of alcohol “by using molecules that specifically target the GABA system and so are free from the other neurotransmitter interactions” (Nutt & Tyacke, 2022, p. 3).  Historically, herbal drinks to create alcohol like relaxing effects, and specific plants/herbs have this GABAergic effect by helping transport of small molecules (e.g., borneol) across the blood brain barrier (BBB) to potentiate the anxiety reducing GABA neurotransmitter.  Sentia-Red, a mix of “blackberry juice, aronia, magnolia, linden, passionflower, liquorice, ashwagandha, hawthorn, damiana, rose, tulsi, hibiscus, and spice/pepper extracts” (Nut, 2022, pp. 6-7), has shown helpful in increasing GABA effects with no negative effects as with alcohol.

Naltrexone (opioid receptor antagonist), acamprosate (glutamate system regulator), and disulfiram (adverse alcohol/acetaldehyde metabolism) are the conventional, non-addictive FDA treatments used in Medically Assisted Treatment (MAT). “Research studies on the efficacy of medications to treat alcohol use disorders have demonstrated that most patients show benefit, although individual response can be difficult to predict” (United States Public Health Service Ch.4, pp 24-25).  Other promising drugs, such as paroxetine (SSRI) and prazosin (Alpha Blocker), have shown to be efficacious in the treatment of co-occurring anxiety and AUD.  “Metanalysis of 15 randomized controlled trials, in which medication or cognitive behavioral therapy for co-occurring anxiety or depressive disorder was added to standard treatment for AUD, showed results similar to the paroxetine study” (Anker & Kushner, 2019, p. 19).  One PTSD trial “found clinical benefit from prazosin, an alpha1 antagonist, in participants with an alcohol dependence diagnosis” (Anker & Kushner, 2019, p. 21).  In a research trial with rat models, “administration of the PAC1R antagonist PACAP decreased excessive alcohol drinking, motivation to drink, and cue-maintained alcohol seeking” (Ferragud et. al., 2021, p. 518).  This neuropeptide can regulate alcohol consumption.  Other rat studies have shown the efficacy of trichostatin (TSA) to inhibit “histone deacetylases (HDAC which are enzymes that remove acetylaldehyde) was able to attenuate both anxiety-like and alcohol-drinking behaviours… (suggesting) that inhibition of HDAC2 may serve as a potential therapeutic target for developing the future treatment of anxiety and alcoholism” (Sakharkar, Zhang, Tang, et. al., 2018, pp. 1207 and 1217).  While pharmacological interventions are efficacious, psychosocial treatments focus on the individual’s motive for using alcohol to cope with anxiety.  

Yoga and exercise significantly affect neurochemistry.  A study comparing a 60-minute reading session to a 60-minute yoga session measured a 27% increase of GABA levels reported in the yoga participants in comparison to the readers.  Yoga can measurably increase GABA levels naturally (Streeter, Jensen, Perlmutter,, (2007).

Stress response systems of the body (e.g., HPA, corticotropin releasing factor, and alpha1-noradrenergic systems) need more research to “shed needed light on the relationships between alcohol, anxiety, and stress reactivity and regulation. Such studies have the potential to reveal the trajectory of re-regulation of the stress response during abstinence and how it relates to anxiety symptoms and relapse risk. Understanding these parameters could make a valuable contribution toward using the stress system as a recovery biomarker” (Anker & Kushner, 2019, pp. 23-24).     

Screening assessments for alcohol and anxiety: A comprehensive clinical interview is invaluable, and assessment tools which this therapist has used are the SASSI 4 (statistical analysis) and the DSM V Cross Cutting Measure (and the DSM V Anxiety Screening).  The Surgeon General’s Report cites a plethora of screening tools that may be used (United States Public Health Service, 2016, Ch. 4 p 7), effectively detecting AUD and anxiety symptomatology.

Conclusion:  Alcohol and anxiety disorders call for comprehensive approaches with assessment, diagnosis, and treatment.  Attempts to reduce anxiety through more consumption, produces more anxiety through allostatic biological changes, the inability to find pleasure in natural rewards, and predisposes the individual for continued alcohol misuse.  Psychosocial, pharmacological, and biological treatments have proven to be efficacious for treatment in the paradoxical, pervasive, and comorbid nature of alcohol and anxiety.  


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