Health
Treating Alcohol Use Disorder: GLP-1s Emerge as a Promising New Therapy
Alcohol use disorder (AUD) is a multifaceted disease that causes over 140,000 deaths annually.1 AUD, if untreated, is a constantly relapsing condition associated with severe health complications and may interfere with an individual’s daily responsibilities and relationships.2 Despite 29.5 million Americans aged 12 and older being diagnosed with AUD, only 7.6% of individuals will be treated in their lifetime, ranking it as 1 of the top 5 preventable causes of death in the US.1,3 These findings emphasize the urgent need for more research into effective treatment options to address AUD.
Alcohol’s Effect on the Brain
Alcohol influences nearly every neurochemical pathway in the brain, eventually causing chronic users to develop a neuronal dependence on the substance.1 The mesolimbic system is the reward network of the brain and is critical in the development of alcohol’s desirable and addictive qualities.4 The ventral tegmental area (VTA) contains the mesolimbic system, which then connects to the nucleus accumbens (NAc), the primary region of the brain’s positive reinforcement circuitry. Multiple hormones act on these areas to impact an individual’s behavioral and emotional responses to stimuli. When a person is exposed to a reward-related stimulus such as alcohol, the VTA releases dopamine, which travels via the mesolimbic system to activate the nucleus accumbens.4
Glucagon-like peptide-1 (GLP-1) is a hormone that regulates the reward response in this complex pathway. GLP-1 hormones interact with receptors in multiple brain regions to induce various physiological responses affecting an individual’s reward regulation. The hormone is synthesized in the nucleus of the solitary tract (NTS) in the hindbrain, and it regulates the release of several neurotransmitters associated with rewards, such as dopamine, gamma-aminobutyric acid (GABA), glutamate, and serotonin.5
Chronic alcohol exposure activates multiple neurochemical pathways that accumulate to a euphoric feeling and contribute to the vicious cycle of dependence and abuse.
Risk Factors
Genetics
Various factors contribute to an individual’s risk of developing AUD, with genetics comprising 40% to 60% of this risk.6 Researchers have pinpointed a region on chromosome 4p linked that contains genes for the risk of alcohol dependence and affecting brain oscillations in the beta frequency range (13-28 Hz). This region includes 4 GABAA receptor genes—GABRG1, GABRA2, GABRA4, and GABRB1—involved in alcohol’s effects and beta frequency modulation. The strongest association with alcohol dependence was found in a section of GABRA2 (alpha-2 subunit) where 43 consecutive 3-SNP haplotypes reached statistically exceptional significance (P = .000000022). The association of GABRA2 with both alcohol dependence and beta EEG frequencies highlights its potential role in influencing dependence by affecting neural excitation levels.7 Additionally, a variety of alleles that encode for serotonin receptors may affect mood regulation and contribute to alcohol dependence, as well as alleles determining dopamine receptors and transporters, which can influence the rewarding effects of alcohol.8,9
Environmental
It is essential to note that while genetic factors are significant, environmental, social, and psychological components can also be influential in the development of AUD. Several factors over a person’s lifetime may affect an individual’s susceptibility to the development of AUD and can influence the level of severity of the disorder. Early onset of alcohol consumption, family history of substance abuse, trauma, and low socioeconomic status increase the risk of AUD development.8 Stress and pain are significant motivators for alcohol consumption, and individuals experiencing social anxiety are notably more vulnerable.8 Gender disparities are reflected in AUD prevalence with 7% of men and 4% of women affected.10 Environmental influences include cultural acceptance of heavy drinking, positive expectations of alcohol’s social benefits, and limited parental oversight. Lack of family and social support, mood and conduct disorders, and poor self-control further increase susceptibility.11
Clinical Presentation and Diagnosis
Both behavioral and physical symptoms are notable in AUD. Patients frequently consume large amounts of alcohol because of intense cravings and can develop a high tolerance, requiring more alcohol to become intoxicated. AUD can cause an individual to neglect work, school, or home responsibilities, and result in social and interpersonal problems.2 Chronic alcohol consumption also negatively impacts various organ systems, particularly the liver and pancreas, leading to jaundice, ascites, and potentially pancreatitis.3 However, AUD is not only limited to gastrointestinal complications and may contribute to a variety of other adverse outcomes and affect other organ systems (Table 1).3
| Table 1. Systemic Changes Seen in Chronic Alcohol Users 3 | |
| Cardiovascular system | Atrial fibrillation, dilated cardiomyopathy, acceleration of coronary artery disease, hypertension |
| Endocrine system | Osteoporosis, hypothyroidism |
| Gastrointestinal system | Hepatotoxicity, hepatitis, cirrhosis, pancreatitis, upper gastrointestinal bleeding because of esophageal varices, gastritis, acid reflux |
| Hematologic system | Bone marrow suppression, leukocytosis, thrombocytopenia, anemia, macrocytosis with or without anemia due to B12 and folate deficiencies |
| Immune system | Impaired B and T cell functioning, increased susceptibility to infections |
| Neuropsychiatric system | Korsakoff syndrome secondary to thiamine deficiency, peripheral neuropathy, worsening psychiatric disorders (e.g., depression), increased risk of stroke and dementia |
| Oncologic system | Increased risk of cancers |
| Pulmonary system | Worsening sleep apnea, increased pneumonia, and other pulmonary infections |
Symptoms of alcohol withdrawal are a defining characteristic of AUD, typically peaking at around 72 hours after reducing or stopping prolonged, heavy alcohol consumption. A patient may experience insomnia, agitation, tachycardia, seizures, hypertension, and diaphoresis. Some patients may present with hallucinations and altered mental status.12 The most severe manifestations requiring medical attention include delirium tremens (DTs), hallucinations, and seizures.13 These intense and uncomfortable symptoms often drive individuals to continue drinking to avoid or alleviate them.2
Screening
Screening should be conducted in patients exhibiting signs or symptoms of AUD. While there are multiple screening methods, the AUDIT-C (Alcohol Use Disorders Identification Test-Consumption), Single Alcohol Screening Question (SASQ), and CAGE questionnaire are the 3 most commonly used tools.14 The AUDIT-C, created by the World Health Organization (WHO), is generally regarded as the primary tool for screening AUD. This 10-question tool assesses the frequency and amount of alcohol an individual consumes and provides high diagnostic accuracy for screening at-risk individuals across various settings.15
If patients screen positive for AUD, they should undergo evaluation using DSM-5 criteria (Table 2). Diagnosis requires meeting at least 2 out of 11 criteria within a 12-month period.2
Table 2. DSM-5 Diagnostic Criteria of Alcohol Use Disorder 2
| 1. | Alcohol is often taken in larger amounts or over a longer period than was intended. |
| 2. | There is a persistent desire or unsuccessful efforts to cut down or control alcohol use. |
| 3. | A great deal of time is spent in activities necessary to obtain alcohol, use alcohol, or recover from its effects. |
| 4. | Craving, or a strong desire or urge to use alcohol. |
| 5. | Recurrent alcohol use resulting in a failure to fulfill major role obligations at work, school, or home. |
| 6. | Continued alcohol use despite having persistent or recurrent social or interpersonal problems caused by or exacerbated by the effects of alcohol. |
| 7. | Important social, occupational, or recreational activities are given up or reduced because of alcohol use. |
| 8. | Recurrent alcohol use in situations in which it is physically hazardous. |
| 9. | Alcohol use is continued despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by alcohol. |
| 10. | Tolerance as defined by either of the following: A need for markedly increased amounts of alcohol to achieve intoxication or desired effect. A markedly diminished effect with continued use of the same amount of alcohol. |
| 11. | Alcohol (or a closely related substance, such as a benzodiazepine) is taken to relieve or avoid withdrawal symptoms. |
| Levels of severity: Mild: Presenting with 2-3 symptoms Moderate: Presenting with 4-5 symptoms Severe: Presenting with 6 or more symptoms | |
Pharmacologic Treatments for AUD
Currently approved pharmacologic treatments for AUD are designed to create aversive reactions to alcohol, reducing its positive reinforcement and emotional effects.16 While researchers are still investigating the potential utilization of drugs like antidepressants and antipsychotics, the US Food and Drug Administration (FDA) currently recognizes only 3 medications for the treatment of AUD: acamprosate, disulfiram, and naltrexone (Table 3). 16
These drugs work primarily by affecting different pathways in alcohol metabolism. Disulfiram irreversibly inhibits aldehyde dehydrogenase and alcohol dehydrogenase, the enzymes responsible for converting alcohol into acetaldehyde; naltrexone is an opioid receptor antagonist, reducing relapse rates by blocking opioid receptors; and while still not fully understood, acamprosate is suspected to function as an agonist of N-methyl-D-aspartate (NMDA), a type of glutamate receptor. A systematic review of 24 randomized controlled trials (n = 6915) found that acamprosate significantly reduced the risk of any drinking (RR = 0.86; 95% CI, 0.81-0.91; NNT = 9.09) and increased cumulative abstinence duration by an average of 10.94 days (95% CI, 5.08-16.81) compared with placebo.17
Table 3. FDA-Approved Pharmacologic Treatments for AUD16,17
| Medication | How They Work |
| Acamprosate | Unclear. Thought to be a modulator of hyperactive glutamatergic states, possibly an NMDA receptor agonist, effective in relapse prevention. |
| Disulfiram | Aversion reaction. Inhibition of acetaldehyde results in symptoms such as headache, nausea, vomiting, and tachycardia, which discourage the patient from consuming alcohol. |
| Naltrexone | Blocks opioid receptors. Results in less alcohol cravings, improved patient adherence, and ultimately reduced relapse rates. |
GLP-1s in AUD Treatment
Glucagon-like peptide-1 (GLP-1s) agonists have become increasingly popular medications, initially approved for treating type 2 diabetes mellitus (T2DM) and, more recently, recognized for their efficacy in managing obesity. Many types of GLP-1s are available with varying structures, dosing regimens, and administration methods. Examples of GLP-1s include dulaglutide, exenatide, liraglutide, and semaglutide.18
These medications work in T2DM and obesity by acting as incretin hormone mimetics, boosting the effects of the hormone in the gastrointestinal tract. They lower blood sugar levels without significantly increasing the risk of hypoglycemia, suppress glucagon secretion, delay gastric emptying, induce feelings of satiety, and offer other therapeutic benefits.19
As noted, in addition to playing a key in the pancreas and stomach, GLP-1s are also present in the brain.20 These drugs act on the reward center in the brain, specifically those associated with food reward-seeking behaviors, which has prompted research into GLP-1s as a potential treatment option for other disease states related to reward-seeking behaviors such as addiction and AUD.21
Most research on GLP-1 agonists as a potential therapy for AUD focuses on the capacity of GLP-1s to modulate reward and pleasure-seeking mechanisms, much like they do in regulating food intake. Glucagon-like peptide-1 receptors (GLP-1Rs) are expressed in the mesolimbic region, which relays dopaminergic signals. GLP-1s modulate the pathways involving the NAc, an area associated with motivation, and the VTA, an area linked with reward, by reducing dopamine release and activating these areas. They also act in the amygdala to affect emotional and motivational behaviors and in the lateral hypothalamus, which coordinates communication to peripheral organs that affect reward signaling.5
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Most research on GLP-1 agonists as a potential therapy for AUD focuses on the capacity of GLP-1s to modulate reward and pleasure-seeking mechanisms, much like they do in regulating food intake.
While more research is needed, preclinical and clinical studies have demonstrated that GLP-1s work in these areas to regulate alcohol-mediated behaviors, neurochemistry, and motivation.20 Both animal and human research demonstrate that the administration of GLP-1s decreases an individual’s preference for alcohol and the amount consumed.22 Moreover, due to the chronicity and frequent recurrence of AUD, pharmacological treatments must interrupt the cycle of use, abstinence, and recurrence. The growing demand for GLP-1 agents for managing type 2 diabetes and obesity has led to increased demand, reducing availability and rising costs.22
Behavioral Interventions for AUD
Behavioral interventions frequently complement pharmacological treatment to enhance compliance and efficacy. Research demonstrates that combining pharmacological treatment with therapy yields superior outcomes compared to either approach in isolation.16 A variety of psychological treatments are available for individuals, including cognitive behavioral therapy, guided self-control training, and motivational enhancement therapy. Additionally, mutual support groups, such as Alcoholics Anonymous, have demonstrated effective support through encouragement, accountability, and an expanded social network, particularly for those participating in alcohol abstinence or attempting to reduce their drinking.23 Furthermore, multiple empirical studies indicate that behavioral and psychological interventions may be equally effective as medication in treating AUD.23
Case Lessons
- AUD significantly burdens individuals, families, workplaces, and the health care system.
- As rates of alcohol abuse remain high, early identification and intervention for individuals showing signs of potential addiction are crucial.
- Research has demonstrated that GLP-1 agonists affect alcohol-seeking behavior through activity in reward-related areas.
- Treatment for AUD should include psychosocial and pharmacologic interventions.
- GLP-1s as a potential therapy for AUD offer promising new options, especially for patients who have not succeeded with conventional first-line treatments.
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Sources 2/ https://www.clinicaladvisor.com/features/treating-alcohol-use-disorder-glp-1s-emerge-as-a-promising-new-therapy/ The mention sources can contact us to remove/changing this article |
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