Treatment of alcohol use-related disorders

Abstract

The disclosure provides a treatment for alcohol use disorder and related acetaldehyde toxicity, comprising repleting intracellular NAD+, and which may further comprise the administration of a GLP- 1 or dual GLP-1 / GIP receptor against.

Description

TREATMENT OF ALCOHOL USE-RELATED DISORDERS

[0001] All patents, patent applications, and publications cited herein are hereby incorporated by reference in their entirety. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described and claimed herein.

[0002] A portion of the disclosure of this patent document contains material that is subject to copyright protection. The copyright owner has no objection to the reproduction of the patent document or the patent disclosure, as it appears in the U.S. Patent and Trademark Office patent file or records, but otherwise reserves all copyright rights whatsoever.CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority to U.S. Provisional Application No. 63 / 759,976, entitled “TREATMENT OF ALCOHOL USE-RELATED DISORDERS,” filed February 18, 2025, the contents of which is incorporated herein by reference in its entirety.FIELD OF THE INVENTION

[0004] The present invention is in the field of medicine, and more particularly pertains to treatment of alcohol abuse-related disorders.BACKGROUND

[0005] Alcohol Use Disorder (AUD) is a pervasive and relapsing condition affecting millions worldwide, with profound impacts on physical health, mental well-being, and socioeconomic status. In the United States, the incidence of AUD has been growing for the past two decades, and in 2013 approximately 30 million Americans (about 12.7% of the total population) were estimated to qualify forthe AUD diagnosis. Chronic alcohol consumption disrupts numerous biological systems, leading to alterations in cellular metabolism, redox balance, neurotransmitter abundance and receptor function, and immune responses. Treatment of AUD is physically difficult, as withdrawal from alcohol addiction can be physically and mentally severe and life-threatening

[0006] AUD is a complex condition that involves a wide range of biochemical and physiological alterations affecting multiple organ systems. The limitations of current treatments become clearer when viewed through the lens of AUD's complex pathophysiology. Far from being solely a disorder of reward and behavior, AUD represents a systems-wide disruption affecting multiple organs and cellular processes.

[0007] There are currently several FDA-approved medications in the US for the pharmacological intervention of AUD, and each works through distinct mechanisms. Naltrexone, available in both oral and injectable forms, works through p-opioid receptor antagonism. This drug may be effective in patients with high craving levels, and has been found to reduce heavy drinking days by 25% to 50%. Acamprosate, works through NMDA receptor modulation and GABA-B agonism. This drug is said to addresses anxiety-related symptoms and improves abstinence rates by approximately 25%. Disulfiram, while reported to be capable of reducing drinking days by up to 50% under supervised conditions, remains limited by compliance challenges because of its aversive mechanism that is rooted in acetaldehyde toxicity.

[0008] More recent therapeutic development has focused on neuromodulation and anti-inflammatory approaches. Medications in advanced clinical development, such as gabapentin and topiramate, target GABA / glutamate pathways, and has been reported to reduce “heavy” drinking by 25%> to 45%, while offering additional benefits for sleep and mood regulation. Anti-inflammatory agents such as apremilastand ibudilast have also been used to address both craving and neuroinflammation through PDE4 inhibition.

[0009] Metabolic modulators such as glucagon-like peptide receptor agonist s(GLP-l RAs) and dual GIP / GLP-1 RAs have recently been shown to reduce alcohol consumption in model organisms and humans. These receptor agonists are a class of medications primarily used to treat type 2 diabetes and obesity by enhancing insulin secretion and inhibiting glucagon release.

[0010] Despite these advances, AUD treatment outcomes remain suboptimal, with relapse rates exceeding 60% to 70% within the first year of recovery. Even with optimal implementation, existing medications typically reduce heavy drinking days by only 25% to 50%, and individual patient outcomes show significant heterogeneity. Thus, despite the availability of pharmacological and behavioral interventions, patients struggle with persistent cravings and high relapse rates, and long-term abstinence remains challenging. Thus. AUD and related disorders including withdrawal from AUD still remain difficult problems in acute management settings, and improved methods of its treatment are urgently needed.SUMMARY OF THE INVENTION

[0011] It has been discovered that nicotinamide adenine dinucleotide (NAD+) repletion treats AUD and many of the physiological ramifications of AUD. It has also been discovered that NAD+ repletion, in combination with treatment with GLP-1 RAs or with GLP-l / GIP RAs provide synergistic benefits in treating both the metabolic and neurob ehavi oral aspects of AUD and its side effects and ramifications. These discoveries have been exploited to provide the present disclosure, which in part, is related to treatments for AUD and its related disorders.

[0012] In one aspect, the present disclosure is directed to a method of treating AUD in a patient in need thereof, comprising repleting an intracellular level of NAD+ in the patient such that at least one symptom of AUD is reduced, alleviated, or prevented.

[0013] In some examples, the method comprises repleting an intracellular blood level of NAD+.

[0014] In certain examples, repleting an intracellular level of NAD+ is accomplished by administering an enhanced NAD+ formulation to the patient in an amount effective to reduce, alleviate, or prevent a symptom of AUD.

[0015] In particular examples, the enhanced NAD+ formulation comprises UNAD.

[0016] In some examples, the UNAD is administered orally.

[0017] In yet other examples, the method further comprises administering a GLP-1 or GUP-l / GIP receptor agonist to the patient in an amount effective to reduce a symptom of AUD, the combination of repleting the intracellular level of NAD+ and administering the GUP-1 or GLP-l / GIP receptor agonist results in a synergistic therapeutic response to AUD relative to a response obtained by repleting the intracellular NAD+ or administering the GUP-1 or GLP-l / GIP receptor agonist administration alone.

[0018] In some examples, the GLP-1 or GLP-l / GIP receptor agonist comprises exenatide, liraglutide, semaglutide, tirzepatide, dulaglutide, dxenatide, liraglutide, lixisenatide, or a combination thereof.

[0019] In certain examples, the GLP-1 or GLP-l / GIP receptor agonist comprises semaglutide.

[0020] In particular examples, the GLP-1 or GLP-l / GIP receptor agonist is administered via injection.

[0021] In another aspect, the present disclosure is directed to a method of treating acetaldehyde toxicity in a patient in need thereof, comprising repleting an intracellular level of NAD+ in the patient, such that at least one symptom of acetaldehyde toxicity AUD is reduced, alleviated, or prevented.

[0022] In some examples, the method comprising repleting an intracellular blood level of NAD+.

[0023] In particular examples, repleting an intracellular level of NAD+ is accomplished by administering an enhanced NAD+ formulation to the patient in an amount effective to reduce, alleviate, or prevent a symptom of acetaldehyde toxicity.

[0024] In certain examples, the enhanced NAD+ formulation comprises LNAD.

[0025] In some examples, the enhanced NAD+ formulation is administered orally.

[0026] In still other examples, the method further comprises administering a GLP-1 or GLP-l / GIP receptor agonist to the patient in an amount effective to reduce a symptom of acetaldehyde toxicity, the combination of repleting the intracellular level of NAD+ and administering the GLP-1 or GLP-l / GIP receptor agonist results in a synergistic therapeutic response to acetaldehyde toxicity relative to a response obtained by repleting the intracellular NAD+ or administering the GLP-1 or GLP-l / GIP receptor agonist administration alone.

[0027] In some examples, the GLP-1 or GLP-l / GIP receptor agonist comprises exenatide, liraglutide, semaglutide, tirzepatide, dulaglutide, dxenatide, liraglutide, lixisenatide, or a combination thereof.

[0028] In particular examples, the GLP-1 or GLP-l / GIP receptor agonist comprises semaglutide.

[0029] In certain examples, the GLP-1 or GLP-l / GIP receptor agonist is administered via injection.DESCRIPTION OF EXEMPLARY EMBODIMENTS

[0030] The disclosures of these patents, patent applications, and publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described and claimed herein. The instant disclosure will govern in the instance that there is any inconsistency between the patents, patent applications, and publications and this disclosure.

[0031] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The initial definition provided for a group or term herein applies to that group or term throughout the present specification individually or as part of another group, unless otherwise indicated.

[0032] For the purposes of explaining the invention features of alcohol abuse disorder- technology known to those skilled in the art of medicine have been omitted or simplified in order not to obscure the basic principles of the invention. Parts of the following description will be presented using terminology commonly employed by those skilled in the art of optical design. It should also be noted that in the following description of the invention repeated usage of the phrase “in one embodiment” does not necessarily refer to the same embodiment.

[0033] As used herein, the articles “a” and “an” refer to one or to more than one (z.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element. Furthermore, use of the term “including” as well as other forms, such as “include,” “includes,” and “included,” is not limiting.

[0034] As used herein, the term “about” will be understood by persons of ordinary skill in the art and will vary to some extent on the context in which it is used. As used herein when referring to a measurable value such as an amount, a temporal duration, and the like, the term “about” is meant to encompass variations of ±20% or ±10%, including ±5%, ±1%, and ±0.1% from the specified value, as such variations are appropriate to perform the disclosed methods.

[0035] The terms “substance”, “formulation”, and “drug” are used interchangeably throughout.

[0036] The terms “substance” and “drug” are used interchangeably throughout.

[0037] Wherever any of the phrases “for example,” “such as,” “including” and the like are used herein, the phrase “and without limitation” is understood to follow unless explicitly stated otherwise. Similarly, “an example,” “exemplary” and the like are understood to be nonlimiting.

[0038] The term “substantially” allows for deviations from the descriptor that do not negatively impact the intended purpose. Descriptive terms are understood to be modified by the term “substantially” even if the word “substantially” is not explicitly recited.

[0039] The terms “comprising” and “including” and “having” and “involving” (and similarly “comprises”, “includes,” “has,” and “involves”) and the like are used interchangeably and have the same meaning. Specifically, each of the terms is defined consistent with the common United States patent law definition of “comprising” and is therefore interpreted to be an open term meaning “at least the following,” and is also interpreted not to exclude additional features, limitations, aspects, etc. Thus, for example, “a process involving steps a, b, and c” means that the process includes at least steps a, b and c. Wherever the terms “a” or “an” are used, “one or more” is understood, unless such interpretation is nonsensical in context.

[0040] Embodiments as described herein can involve isolating, collecting, or obtaining a biological sample from a subject. As used herein, the term “collecting a sample” or “isolating a sample”, for example, can refer to any process for directly or indirectly acquiring a biological sample from a subject. For example, a biological sample may be obtained (e.g., at a point-of-care facility, e.g., a physician's office, a hospital, laboratory facility) by procuring a tissue sample (such as a skin biopsy) from a subject. Alternatively, a biological sample may be obtained by receiving the biological sample (e.g., at a laboratory facility) from one or more persons who procured the sample directly from the subject. The biological sample may be, for example, a tissue (e.g., biopsy), fluid (e.g., cerebrospinal fluid, plasma, blood, serum) or cell (e.g., skin fibroblast cells, peripheral blood cells) of a subject.

[0041] The term “sample” can refer to a biological sample obtained or derived from a source of interest, as described herein. In some embodiments, a source of interest comprises an organism, such as an animal or human. In some embodiments, a biological sample comprises biological tissue or fluid. In some embodiments, a biological sample is or comprises bone marrow; spleen, blood; blood cells; blood mononuclear cells; serum; plasma; ascites; tissue or fine needle biopsy samples; cell-containing body fluids; free floating nucleic acids; sputum; saliva; urine; cerebrospinal fluid, peritoneal fluid; pleural fluid; feces; lymph; gynecological fluids; skin swabs; vaginal swabs; oral swabs; nasal swabs; washings or lavages such as a ductal lavages or bronchoalveolar lavages; aspirates; scrapings; bone marrow specimens; tissue biopsy specimens; surgical specimens; feces, other body fluids, secretions, and / or excretions; and / or cells therefrom, etc. In some embodiments, a biological sample is or comprises cells obtained from an individual. In some embodiments, a sample is a “primary sample” obtained directly from a source of interest by any appropriate means. For example, in some embodiments, a primary biological sample is obtained by methods selected from the group consisting of biopsy (e.g., fine needle aspiration or tissue biopsy), surgery, collection of body fluid {e.g., blood, lymph, feces etc ). In some embodiments, the term “sample” refers to a preparation that is obtained by processing (e.g., by removing one or more components of and / or by adding one or more agents to) a primary sample. For example, filtering using a semi-permeable membrane. Such a “processed sample” may comprise, for example nucleic acids or proteins extracted from a sample or obtained by subjecting a primary sample to techniques such as amplification or reverse transcription of mRNA, isolation and / or purification of certain components, etc.

[0042] The term “subject” or “patient” can refer to any organism to which aspects of the disclosure can be performed, e.g., for experimental, diagnostic, prophylactic, and / or therapeutic purposes. Subjects to which methods as described herein are performed comprise mammals, such as primates, for examplehumans. For diagnostic or research applications, a wide variety of mammals are suitable subjects, including rodents (e.g., mice, rats, hamsters), rabbits, primates, and swine such as inbred pigs and the like. The term “living subject” can refer to a subject noted herein or another organism that is alive. The term “living subject” can refer to the entire subject or organism and not just a part excised (e.g., a liver or other organ) from the living subject. The term “normal subject” or “control” can refer to a subject that is not afflicted with a disease or condition, such as a subject that is not afflicted with SUD or PSUD.

[0043] As used herein, the phrase “therapeutic agent” can refer to any agent that elicits a desired pharmacological effect when administered to a subject. In some embodiments, an agent is considered to be a therapeutic agent if it demonstrates a statistically significant effect across an appropriate population. In some embodiments, the appropriate population may be a population of model organisms. In some embodiments, an appropriate population may be defined by various criteria, such as a certain age group, gender, genetic background, preexisting clinical conditions, history of alcohol abuse, history of acetaldehyde toxicity, etc. In some embodiments, a therapeutic agent is any substance that can be used to alleviate, ameliorate, relieve, inhibit, delay onset of, reduce severity of, and / or reduce incidence of one or more symptoms or features of a disease, disorder, and / or condition.

[0044] The term “therapeutically effective amount”, as used herein, can refer to an amount of a therapeutic agent whose administration, when viewed in a relevant population, correlates with or is reasonably expected to correlate with achievement of a particular therapeutic effect. The therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., subject gives an indication of or feels an effect). A therapeutically effective amount is that amount that reduces, alleviates, and / or prevents at least one symptom of AUD or acetaldehyde toxicity.

[0045] “Therapeutic effects” can refer to increasing intracellular NAD+, increasing circulating NAD+, or a combination thereof. In certain embodiments, “therapeutic effects” refers to amelioration of one or more symptoms of withdrawal during detoxification.

[0046] In some embodiments, a therapeutically effective amount of a substance is an amount that, when administered to a subject suffering from or susceptible to a disease, disorder, and / or condition, is sufficient to treat, diagnose, prevent, and / or delay and / or alleviate one or more symptoms of the disease, disorder, and / or condition. Disease progression can be monitored by clinical observations, laboratory and imaging investigations apparent to a person skilled in the art. A therapeutically effective amount is administered in a dosing regimen that can comprise multiple unit doses. For a therapeutic agent, a therapeutically effective amount (and / or an appropriate unit dose within an effective dosing regimen) can vary, for example, depending on route of administration, on combination with other pharmaceutical agents. Also, the specific therapeutically effective amount (and / or unit dose) for a patient can depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific pharmaceutical agent employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and / or rate of excretion or metabolism of the therapeutic agent; the duration of the treatment; and like factors known in the art. Furthermore, an effective amount may be administered via a single dose or via multiple doses within a treatment regimen. In some embodiments, individual doses or compositions are considered to contain a “therapeutically effective amount” when they contain an amount effective as a dose in the context of a treatment regimen. Those of ordinary skill in the art will appreciate that a dose or amount may be considered to be effective if it is or has been demonstrated to show statistically significant effectiveness when administered to a population of patients; a particular result need not beachieved in a particular individual patient in order for an amount to be considered to be therapeutically effective as described herein.

[0047] The word “treating” can mean the medical management of a subject, e.g. an animal or human, with the intent that a prevention, cure, stabilization, or amelioration of the symptoms or condition will result. This term includes active treatment, that is, treatment directed specifically toward improvement of the disorder; palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disorder; preventive treatment, that is, treatment directed to prevention of disorder; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the disorder. The term “treatment” also includes symptomatic treatment, that is, treatment directed toward constitutional symptoms of the disorder. “Treating” a condition with the compounds of the disclosure involves administering such a compound, alone or in combination and by any appropriate means, to a patient. For example, “treating” AUD or acetaldehyde toxicity can refer to (or be indicated by) raising intracellular NAD+ levels in a patient or subject. Treatment can be administered to a subject who does not exhibit signs of a disease, disorder, and / or condition (e g., prior to an identifiable disease, disorder, and / or condition), and / or to a subject who exhibits only early signs of a disease, disorder, and / or condition for the purpose of decreasing the risk of developing pathology associated with the disease, disorder, and / or condition. In embodiments, treatment is administered humans suffering from AUD or acetaldehyde toxicity. In certain embodiments, treatment refers to administration of enhanced NAD+ to a patient who is suffering from AUD or acetaldehyde toxicity. Treatment can refer to administration of enhanced NAD+ to a subject who is at risk of developing AUD or acetaldehyde toxicity. In certain embodiments, treatment includes administering enhanced NAD to a subjection who is recovering from AUD or acetaldehyde toxicity.

[0048] An “enhanced NAD+” comprises a bioavailable form of nicotinamide adenine dinucleotide (NAD+), such as a synthetic, isolated NAD+, which, when administered to a subject, is bioavailable, thereby capable of increasing the intracellular levels of NAD+ in the blood of the subject, and which can also have an increased shelflife relative to other known forms of isolated NAD+. The terms “enhanced NAD+ composition,” “enhanced NAD+,” “enhanced NAD+ formulation,” “enhanced NAD+ pharmaceutical formulation,” “LNAD as used interchangeably in this disclosure encompass compositions and pharmaceutical formulations comprising enhanced NAD+ prepared in accordance with or otherwise disclosed in PCT / US23 / 35557, PCT / US2025 / 035967, or PCT / US25 / 43556, or NAD+ compounds which have substantially the same or similar characteristics as the enhanced NAD+ disclosed in any of the foregoing patent applications, such substantially similar characteristics including, but not limited to any one or more of: an increased shelf-life, increased in vivo half-life, bioavailability greater than other known synthetic or isolated forms of NAD+, is orally bioavailable, and repletes or increases a level of intracellular NAD+ levels and penetrates the blood-brain barrier and enters the CNS in a bioavailable form, in a subject following administration. In certain embodiments, the enhanced NAD+ comprises “LNAD,” “BNAD,” “NADaCell™,” “LathMized NAD+,” or any combination thereof.

[0049] ‘ ‘NAD+ repletion” is used herein refers to the supplementation of NAD+ in an amount and form which results in the increase of intracellular levels of NAD+ which approaches, or achieves “normal“ or physiological levels of intracellular NAD+.

[0050] “ GLP-1 RA” as used herein refers to a glucagon-like peptide-1 (GLP-1) receptor agonist (RAs),

[0051] “ GLP-l / GIP RA” as used herein refers to dual GLP-l / glucose-dependent insulinotropic polypeptide (GIP) receptor agonists.

[0052] A “synergistic response” refers to the therapeutic response obtained in a patient suffering from AUD or a related disorder to whom NAD+ repletion and GLP-1 RA (or GLP-l / GIP RA) administration is provided, that response being an improvement greater than that obtained from administration of either treatment alone or added together.

[0053] The present disclosure is directed to the treatment of alcohol use disorder (AUD) (also known as alcohol abuse), and to treatment of related disorders such as, but not limited to, acetaldehyde toxification.

[0054] Pathophysiology of AUD and Acetaldehyde Toxicity

[0055] AUD is a complex condition that involves a wide range of biochemical and physiological alterations affecting multiple organ systems. AUD involves interactions between alcohol metabolism, cellular energetics, oxidative stress, and multiple signaling and neurotransmitter systems. The metabolic burden of chronic alcohol consumption directly leads to NAD+ depletion through increased utilization in ethanol metabolism and impaired NAD+ biosynthesis. Chronic AUD leads to a cascade of halted ATP production, mitochondrial dysfunction, metabolic imbalances, oxidative stress, inflammatory responses, and NAD+depletion, all of which contribute to the progression and severity of the disease.

[0056] NAD+ can refer to a ubiquitous coenzyme that is involved in diverse biological processes ranging from maintaining mitochondrial redox status and cellular energy homeostasis, to participating in post-translational protein modification and DNA repair and generating second messengers. These processes depend on NAD+ as the electron donor / acceptor in oxidative / reductive reactions, and on its utilization by NAD-consuming enzymes.

[0057] One aspect of AUD pathophysiology is neuroadaptation in the brain's reward and learning circuits and accompanying changes in neurotransmitter balance. Alcohol initially triggers dopamine release in the mesolimbic pathway, particularly in the nucleus accumbens, creating pleasurable effectsthat reinforce behavior. With chronic alcohol use, significant neuroadaptations occur in this system leading to increased alcohol craving and compromising reward sensitivity to natural stimuli. The sustained activation of the reward pathway engages learning circuits in the prefrontal cortex and amygdala, strengthening associations between alcohol -related cues and reward expectations. This neuroadaptation contributes to habitual drinking patterns and increased vulnerability to relapse. These changes interact with stress pathways in profound ways, as alcohol-induced alterations in the HPA axis enhance the salience of alcohol-related cues and exacerbate craving during withdrawal.

[0058] Chronic alcohol consumption leads to a significant reduction in cellular NAD+levels due to increased utilization in ethanol metabolism and impaired NAD+biosynthesis. NAD+is essential for numerous cellular processes, including energy production, antioxidant defenses, DNA repair, and cell signaling. Its depletion disrupts these vital functions, contributing to the cellular dysfunction and organ damage observed in AUD. The usage of NAD+in alcohol metabolism, combined with the inhibition of de novo NAD+ synthesis and compromised salvage pathways, results in a substantial decrease in NAD+availability to NAD+ -dependent enzymes, proteins, and reactions. NAD+ depletion also leads to: impaired energy production due to mitochondrial dysfunction and altered metabolic pathways exacerbates cellular stress and damage; reduced antioxidant capacity, resulting from impaired glutathione regeneration and the accumulation of reactive oxygen species (ROS), leading to oxidative stress and cellular injury; reduced DNA repair, coupled with the activation of p53 pathways, resulting in cell cycle arrest or apoptosis, and inflammation; as well as the disruption of cell signaling, through sirtuin dysfunction and altered calcium homeostasis, contributing to the overall cellular dysfunction observed in AUD.

[0059] In addition, chronic alcohol consumption leads to hepatic steatosis or fatty liver disease. This accumulation results from enhanced lipogenesis, impaired fatty acid oxidation, and altered secretion ofvery -low-density lipoproteins (VLDL). The disruption of these metabolic pathways is mediated by the effects of alcohol on key regulators such as the mammalian target of rapamycin (mTOR), peroxisome proliferator-activated receptor alpha (PPARa), and AMP-activated protein kinase (AMPK). The metabolic alterations in AUD are linked to insulin resistance and inflammation due to lipotoxicity, which can trigger the activation of NF-KB signaling. Ultimately, triGLPceride accumulation in the liver contributes to the development of alcoholic fatty liver disease and can progress to more severe forms of liver damage, including steatohepatitis, fibrosis, and cirrhosis.

[0060] AUD also causes the disruption of the gut microbiome and the gut-brain axis. Chronic alcohol consumption leads changes in microbiome composition and potentially intestinal permeability, enabling bacterial endotoxins such as lipopolysaccharides (LPS) to enter the bloodstream, triggering systemic inflammation through the activation of signaling pathways like NF-KB and JAK-STAT, activated due to persistent endothelial damage. The influx of endotoxins can exacerbate liver inflammation and damage (endotoxemia). Alterations in microbial metabolites affect neurotransmitter synthesis and modulation, impacting mood, behavior, and cognitive function through the gut-brain axis.

[0061] Acetaldehyde toxicity causes tissue and organ damage in AUD. When ethanol is consumed, it is metabolized in the liver by alcohol dehydrogenase (ADH) to form acetaldehyde, a highly reactive and toxic compound. Acetaldehyde is converted to acetate by aldehyde dehydrogenases (ALDH). Both ADH and ALDH require NAD+ as a cofactor, directly linking alcohol metabolism to NAD1availability. Acetaldehyde exerts its toxic effects through various mechanisms, such as, but not limited to, the formation of harmful DNA adducts, modification of proteins, and promotion of lipid peroxidation. These effects can activate stress response pathways, such as p53-mediated apoptosis and NF-KB-driven inflammation, contributing to cellular damage and the development of severe complications associated with chronic alcohol use including neuroinflammation and heart failure.

[0062] Treatment

[0063] The present disclosure provides treatments for AUD, acetaldehyde toxicity, and related disorders, all of which comprise the replenishment or “repletion” of intracellular levels ofNAD+ which are decreased in patients suffering from these disorders. Repletion is accomplished by administering to the patient a form of bioavailable NAD+ which can increase the intracellular levels of NAD+.

[0064] One nonlimiting form of such an enhanced NAD+ is LNAD (Bryleos, Inc.), a synthetic NAD+ which can be administered orally, has an increased shelflife, and has therapeutic bioavailability unlike other known synthetic forms of NAD+, having the ability to increases intracellular blood NAD+ levels by over 50% within five days after oral administration (see PCT / US2023 / 035557).

[0065] On embodiment of the present disclosure relates to administration of LNAD as a treatment for AUD. Briefly, LNAD increases intracellular levels of primary NAD+ metabolites, MeNAM and 2PY, as well as causes changes in a number of multi-omic biomarkers, including, but not limited to, plasma levels of sirtuin 1 (SIRT1) (see PCT / US2023 / 035557). SIRT1 is a regulator of cellular metabolism and stress responses that consumes NAD+ and is significantly repressed in models of AUD. LNAD’s ability to upregulate SIRT1 is relevant to AUD treatment, as SIRT1 activation protects against alcohol-induced liver injury and metabolic dysregulation. LNAD administration can also reduce markers of mitochondrial dysfunction and oxidative stress, both of which are factors in alcohol-induced cellular damage.

[0066] In addition, LNAD+ administration improves liver function and metabolism which are often decreased in AUD patients. LNAD administration supports more efficient alcohol clearance and reduces acetaldehyde toxicity. Not wishing to be held to any particular theory, LNAD may improve alcohol clearance by enhancing drug metabolism pathways involving cytochrome P450 enzymes and aldehyde dehydrogenase (ALDH).

[0067] Alcohol withdrawal is characterized by glutamatergic hyperexcitability, and the ability of LNAD to reduce peripheral glutamate levels systems reduces withdrawal symptoms and excitotoxicity. These effects, combined with the ability of LNAD for serotonergic and immune signaling are therapeutic or both the acute and chronic phases of AUD treatment. LNAD also affects steroid hormone biosynthesis by reducing cortisone levels, and thus modulates the hypothalamic-pituitary-adrenal (HP A) axis. Stress is one of the triggers of relapse, and dysregulation of HP A signaling and elevated cortisol levels both persist over time and are predictive of abstinence.

[0068] As described above, treatment of one suffering from AUD or from acetaldehyde toxicity, according to one embodiment of the present disclosure, comprises repletion of intracellular levels of NAD+, such as intracellular blood levels of NAD+. This can be accomplished by the administration of an enhanced form of NAD+. This enhanced NAD+ can be any synthetic NAD+, such as, but not limited to, LNAD, with equivalent bioavailability and chemical properties and characteristics as LNAD such that it is able to increase intracellular blood NAD+ levels, or to replenish decreased intracellular blood levels of NAD+.

[0069] The amounts of the enhanced NAD+ administered is an amount effective to reduce, alleviate, or prevent at least one symptom of AUD, and can be administered by any route that accomplishes this effect, including, but not limited to sublingual, oral, subcutaneous, ocular, transdermal, rectal vaginal, nasal, or inhalation methods, or by intramuscular, or intravenous injection. In one nonlimiting example, replenishment is accomplished by the oral administration of LNAD in the form of a capsule, tablet, powder, lozenge, liquids, and the like. The enhanced NAD+ can be provided as a bolus, or multiple times a day, for more than one day. The oral formulation of LNAD can comprise The amount administered varies depending on, but not limited to, the weight, age, sex, and physical condition of the patient. For example, from about 1 mg to about 30 mg of LNAD, from about 5 mg to about 25 mgLNAD, from about 10 mg to about 20 mg LNAD, from about 12 mg to about 15 mg LNAD, from about 1 mg to about 5 mg LNAD, or about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about? mg, about 8, mg, about 9 mg, about 10 mg, about 11 mg, or about 12 mg LNAD can be administered daily, In one nonlimiting example, 50 mg of LNAD is administered as a bolus wash as a liquid for about one to about 15 days or from about 3 to about 10 days, or as determined by a physician.

[0070] The AUD or acetaldehyde toxicity treatment can further comprise the administration of an GLP-1 RAs or a dual GLP-l / GIP RA, or combination thereof. This combination treatment provide synergistic results which directly addresses multiple pathophysiological mechanisms of AUD, including acetaldehyde toxicity, while providing benefits in treating both the metabolic and neurob ehavi oral aspects of the disorder.

[0071] GLP-1 RAs and GIP RAs classes of compounds primarily used to treat adult type 2 diabetes and obesity. They are in the drug class of incretin mimetics, and include, but is not limited to, commercially available forms of exenatide, liraglutide, semaglutide, tirzepatide, dulaglutide, dxenatide, liraglutide, and lixisenatide. GLP-1 RAs activate GLP-1 receptors, thereby affecting metabolic regulation, providing neuroprotection, modulating the gut-brain axis, and influencing reward pathways, making them useful for the treatment of AUD. GIP RAs activate GIP receptors, and together with GLP-1 RAs, reduce alcohol and food reward behaviors and may improve mitochondrial health in patients with obesity.

[0072] The GLP-1 RA or a dual GIP / GLP-1 RA to be administered can be any one that has the therapeutic and chemical characteristics of a commercially available GLP-1 RA or a dual GIP / GLP-1 RA effective for treatment of diabetes type 2 and / or obesity. The amount of the GLP-1 RA or a dual GIP / GLP-1 RA to be administered, along with the enhanced NAD+ is that amount re amounts effective to reduce alleviate, or prevent at least one symptom of AUD or acetaldehyde toxicity. Certainformulations of GLP-1 RA or a dual GIP / GLP-1 RA comprise the receptor agonist, or combination thereof, in a physiologically acceptable carrier. These receptor agonists can be administered via subcutaneous injection, but can be administered by any method which provides metabolic regulation, provides neuroprotection, modulates the gut-brain axis, and affects reward pathways, making them useful for the treatment of AUD. The amount administered may vary according to the subjects, size, age, health, and sex. For example, semaglutide (Ozempic) in an amount ranging from about 0.25 mg to about 1 mg (e.g., 1 mg / 0.74 ml of a physiologically acceptable buffer containing, e.g., sodium phosphate dihydrate, propylene glycol, phenol, in water for subcutaneous injection). Administration can be weekly by subcutaneous injection once a week, but can be administered by any known mode and as often as is determined by a physician provider. The enhanced NAD+ and the GLP-1 RA or a dual GIP / GLP-1 RA can be administered simultaneously or at different times and as often as determined by a health care provider.

[0073] In general In various embodiments, the step of administering a pharmaceutical composition or therapeutic compound (such as an enhanced NAD+ composition) or GLP-1 RA or dual GLP-l / GIP RA) can be accomplished by any route of administration known in the art. Exemplary routes of administration include but are not limited to oral, subcutaneous, parenteral (such as, intravenous, intraperitoneal), intramuscular, rectal, epidural, intratracheal, intranasal, dermal, vaginal, buccal, intraperitoneal, intravenous, ocular, or pulmonary. The compositions and preparations can appear in conventional forms, for example, solutions and suspensions for injection, capsules and tablets, in the form of enteric formulations, e.g. as disclosed in U.S. Pat. No. 5,350,741, and for oral administration.

[0074] Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such asethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

[0075] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EM™ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, a pharmaceutically acceptable polyol like glycerol, propylene glycol, liquid polyethylene glycol, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by tire maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of tire action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, and thimerosal. In many cases, it can be useful to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.

[0076] Sterile injectable solutions can be prepared by incorporating the compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated herein, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated herein. In the case of sterile powders for the preparation of sterile injectable solutions, examples of useful preparation methods are vacuum drying and freeze-dryingwhich yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

[0077] Oral compositions can include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed.

[0078] This enhanced NAD+ and GLP-1 RA or GLP-l / GIP RA combined treatment provides synergistic results which directly addresses multiple pathophysiological mechanisms of AUD, including acetaldehyde toxicity, while providing benefits in treating both the metabolic and neurob ehavi oral aspects of the disorder. It provides a synergistic result that is more effective in treating AUD and acetaldehyde toxicity than is the treatment administration of an enhanced NAD+ or the administration of a GLP-1 RA or dual GIP / GLP-1 RA, alone, or when the resulted are added together. Nonlimiting representative synergistic results are described below in EXAMPLE 2.

[0079] One result concerns joint metabolic regulation. Both NAD+ and GLP-1 / GIP RAs influence cellular energy metabolism, though distinct mechanisms. While NAD+ serves as a fundamental coenzyme in energy production pathways, GLP-1 and GIP / GLP-1 RAs modulate metabolic signaling through receptor-mediated effects. Together, they offer comprehensive metabolic support.

[0080] Another nonlimiting synergist result of the combination treatment comprises reduced oxidative stress. The antioxidant and acetaldehyde toxicity modulating effects of NAD+ repletion complement GLP-1 RA’s and GLP-1 / GI P RAs' ability to reduce oxidative stress through improved metabolic efficiency. This dual approach to managing oxidative damage represents a key synergistic opportunity.

[0081] Additionally, the combination therapy provides enhanced neuroplasticity. The role of NAD+ in cellular repair mechanisms (see U.S. Prov. Ser. No. 63 / 665,794) parallels neuroprotective effects of GLP-1 RA and GLP-l / GIP RA by providing synergy in promoting neural recovery and resilience.

[0082] Reference will now be made to specific examples illustrating the disclosure. It is to be understood that the examples are provided to illustrate exemplary embodiments and that no limitation to the scope of the disclosure is intended thereby.EXAMPLESEXAMPLE 1LNAD Treatment of Patient with AUD

[0083] A 50-year-old male who suffered from life-long alcohol use disorder. This was exacerbated by the COVID- 19 pandemic and subsequent professional work-life stressors. Over the last 3 years, his alcohol intake has been at its highest point - about 750 ml of vodka per day. Per the patient’s report, he would develop withdrawal symptoms including nausea, vomiting, headache, tremor and severely increased blood pressure at the 4 hr to 6 hr mark of not consuming any alcohol. Over the last 6 months, he has become aware of the negative impact this is having on his life and health and no longer has the desire to drink. He is now solely consuming alcohol to prevent withdrawal symptoms and cannot remember the last time he felt “intoxicated.”

[0084] The patient is married with 2 children and has a strong support system in his wife and church community. He does not have any sign of significant underlying psychiatric disorder that would compromise this process, both by his admission and through multiple hours of discussion with me.Given the above, the patient is a candidate for at-home alcohol detox utilizing the NADaCell NAD+ (LNAD) oral swish with remote management and virtual oversight.

[0085] The patient is on two blood pressure medications, hydrochlorothiazide and atenolol, and takes 0.5mg Ativan as needed usually at night but not every day. As the patient has significant GERD with a hiatal hernia, he takes Nexium daily. He sees his PCP regularly and had bloodwork drawn two days prior to the present evaluation which did reveal significant liver enzyme elevation.

[0086] The patient was administered LNAD (as a “swish” containing! g in 4 oz. (about 118 ml) dH2O,) gabapentin 300 mg (initially 3 times a day, but then only once a day at bed time), clonidine 0.1 mg as needed for high blood pressure and Zofran as needed for nausea. He was a bit sensitive to the gabapentin so only ended up taking it at night for sleep but this helped a lot. He did not require the clonidine or Zofran during the 7-day detox process.

[0087] Throughout the week of detox, the patient performed extremely well. He is very regimented and communicates directly with the principal investigator multiple times a day via text and phone call. He is diligent about monitoring his blood pressure and did so after every 4-hour dose of LNAD). The subject notes significant improvement in his energy and mood, his sleep has been significantly improved, and he feels motivated. His maximum CIWA score for the entire week was 4, which was a single occurrence and he never complained of any significant symptoms related to withdrawal. Both blood pressure medications were reduced throughout the week, starting with HCTZ and then the atenolol, as his BP began normalizing. After multiple days off of both medications, his blood pressure was consistently 120s / 70s, down from 160s / l 10s on the meds. His resting heart rate also gradually decreased from the 90s to being consistently 58-62. During the peak of the detox (days 2-3), the patient was able to be a productive member of society and care for his family and be present for events more than he has in years. Specifically on day 2, starting 24 hours after his last use of alcohol, he woke at 6 a.m. andcleaned his whole house, spent time with his daughter shopping, made food, and was up until 12 a.m. feeling wonderful the whole time with no self-reported or observed withdrawal symptoms.

[0088] The patient also noted an increased appetite, desire to exercise and tolerance to do much more physical activity than his baseline as well as a profound ability to function at a high level for prolonged periods of time. The patient was diligent about strictly following the process, which helped make this detox smooth and effortless in comparison to any traditional detox process.

[0089] All of these positive feelings have persisted throughout the process, even through the end of the detox week when his LNAD dose has been tapering. This patient had a tremendous response to the LNAD swish detox. In the 30 days following his detox, he remained off his blood pressure and GERD medications, lost 13 pounds, and had a monumental increase in his productivity, sleep, appetite, and energy.EXAMPLE 2MCDA of AUD Mechanisms

[0090] Without being bound by theory, the combination of LNAD administration and GLP-1 RA administration synergistically treats AUD by targeting multiple pathways involved in the pathophysiology of AUD. This was determined using a multi-criteria decision analysis (MCDA) to rank the pathways and mechanisms involved in AUD based on predefined criteria applied to specific molecular mechanisms and biological pathways.

[0091] The evaluation criteria include relevance to AUD (R), strength of evidence (E), impact of NAD+repletion (N), impact of GLP-1 RAs (G), potential for synergy (S), and feasibility of targeting (F). Each pathway was assessed on a scale of 1-5 for each criterion, with 1 being low or weak and 5 being high orstrong. The total score was calculated as the average of all criteria scores, while the weighted score assigns greater importance to relevance to AUD and strength of evidence:

[0092] Total Score = (R + E + N + G+ S + F) / 6

[0093] Weighted Score = (2R + 2E + 1 ,5N + 1 ,5G + S + F) / 8

[0094] The results are shown in Table 1.

[0095] TabletTotal Weighted Rank Pathway / Mechanism (R) (E) (N) (G) (S) (F)Score Score12 Glu Neurotransmission 4 4 2 3 2 3 3.00 3.25

[0096] As summarized in Table 2, both interventions influence major cellular signaling mechanisms, such as, but not limited to, AMPK activation, SIRT1 modulation, and HPA axis regulation, thus resulting in a synergistic, comprehensive, and more effective AUD treatment compared to either treatment alone.Table 2General NAD+ LNAD+ Specific Evidence GLP-1 RA EffectsPathway / System Subcategory Synergistic Benefits Repletion Effects (Bryleos) (Literature)SIRTl-mediated _ .• Comprehensive Lipid Increased FABP1 and Direct inhibition ofinhibition of ,, reduction in Metabolism RBP2 hpogenesisSREBP-lc , , hepatic fat• Improved Increased PGC-la Reduced cholesterol Reduced triGLPceridemetabolic activation levels accumulationflexibility Enhanced Enhanced fatty acid . .. • Enhanced lipid Improved lipid profilesoxidation utilizationclearance< < &• Improved Increased NADPH Modulation of NF-KBReduced SOD2 levels .. .. . . , cellular availability signalingresilience• Reduced Enhanced DNA Improved gut barrierAltered JAK-STAT signaling. . . . systemic repair via PARP functioninflammation ModulationModulation of „ .• Reduced of Increased plasma HTR1A Reduced dopamine releaseNeurological dopamine .. . . , , substtance activity / neuro receptor levels in NAcsynthesiscravings -transmittersEnhancedReduced peripheral Decreased reward *lmpr°Vedserotonin, . . . reward system glutamate sensitivityproduction .regulation Improved ., . . ,.r. , • Enhanced Increased activity of Modified VTA neuronneurotransmitter , ,, , , . . behavioral sleep-wake pathway activitybalance .controlEnhanced stress Altered steroid „ . . .„ , . . . • Reduced relapse Reduced stress sensitivityresilience biosynthesis . .risk• Improved Improved energy Modulated cellular stressemotional homeostasis response pathways Improved anxiety controlregulation

[0097] The combination of NAD+ repletion (with administered LNAD) and GLP-1 RA or GIP / GLP-1 RA administration reduces triGLPceride accumulation. Through AMPK-mediated effects, both interventions promote fatty acid oxidation and inhibit lipogenesis, which can lead to a reduction in hepatic steatosis and improved lipid profiles. Furthermore, the activation of PGC-la by NAD+and by GLP-1 RAs can synergistically enhance mitochondrial biogenesis.

[0098] While not being held to any particular mechanism, NAD+repletion enhances ALDH activity perhaps through increased NAD+availability to mitigate acetaldehyde toxicity, while GLP-1 RA or GIP / GLP-1 RA may support this process through metabolic improvements. Together, they improve acetaldehyde clearance and reduce toxic effects. Additionally, the combined approach offers comprehensive protection against alcohol-induced oxidative damage by enhancing antioxidant defense systems.

[0099] Without being bound by theory, the combined approach also provides neuroprotection and promotes neuroplasticity through the modulation of the mTOR pathway and NF-KB signaling. NAD+repletion inhibits mTOR through AMPK activation, while GLP-1 RAs modulate mTOR signaling. Together, they provide balanced regulation of cellular growth, autophagy, and neuroprotection.Additionally, both interventions exhibit anti-inflammatory effects through the inhibition of NF-KB signaling, potentially reducing neuroinflammation and oxidative stress.

[0100] NAD+repletion and GLP-1 RAs or GIP / GLP-1RA interventions activate FOXO transcription factors, which can enhance cellular stress resistance and regulate metabolic genes in thegut. Furthermore, NAD+repletion modulates the p53 pathway through SIRT1 -mediated deacetylation and PARP regulation, affecting DNA repair, while GLP-1 RAs or GIP / GLP-1 RAs may indirectly influence overall cellular health.

[0101] SIRT1 activation underlies many of the effects of NAD+ and / or interact with many of the listed pathways. SIRT1 activity is directly linked to enhanced lipid metabolism as well as neuroprotection.

[0102] In conclusion, the synergistic potential of NAD+repletion and GLP-1 RAs or GIP / GLP-1 RAs in the treatment of AUD is supported by their complementary actions on pathways involved in the disorder's pathophysiology. By targeting metabolic regulation, detoxification processes, neuroprotection, and behavioral modulation, this integrated approach provides a more effective and sustainable treatment for AUD.EQUIVALENTS

[0103] Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments described specifically herein. Such equivalents are intended to be encompassed in the scope of the following claims.

Claims

CLAIMS1.A method of treating AUD in a patient in need thereof, comprising repleting an intracellular level AD+ in the patient such that at least one symptom of AUD is reduced, alleviated, or prevented.2 The method of claim 1, wherein an intracellular blood level of NAD+ is repleted.3 The method of any one of claims 1-2, wherein repleting an intracellular level of NAD+ is accomplished by administering an enhanced NAD+ formulation to the patient in an amount effective to reduce, alleviate, or prevent a symptom of AUD.3 The method of claims 3, wherein the enhanced NAD+ formulation comprises LNAD.4 The method of claim 4, wherein the LNAD is administered orally.5 The method of any one of claims 1-5, further comprises administering a GLP-1 or GLP-l / GIP receptor agonist to the patient in an amount effective to reduce a symptom of AUD, the combination of repleting the intracellular level of NAD+ and administering the GLP-1 or GLP-l / GIP receptor agonist resulting in a synergistic therapeutic response.6 The method of claim 5, wherein the GLP-1 or GLP-l / GIP receptor agonist comprises exenatide, liraglutide, semaglutide, tirzepatide, dulaglutide, dxenatide, liraglutide, lixisenatide, or a combination hereof.

7. The method of claim 6, wherein the GLP-1 or GLP-l / GIP receptor agonist comprises semaglutide.8 The method of any one of claims 5-7, wherein the GLP-1 or GLP-l / GIP receptor agonist is administered via subcutaneous injection.9 A method of treating acetaldehyde toxicity in a patient in need thereof, comprising repleting an intracellular level of NAD+ in the patient, such that at least one symptom of acetaldehyde toxicity AUD is reduced, alleviated, or prevented.10 The method of claim 9, wherein an intracellular blood level of NAD+ is repleted.1 l The method of any one of claims 9-10, wherein repleting an intracellular level of NAD+ is accomplished by administering an enhanced NAD+ formulation to the patient in an amount effective to reduce, alleviate, or prevent a symptom of acetaldehyde toxicity.12 The method of claim 11, wherein the enhanced NAD+ formulation comprises LNAD.13 The method of any one of claims 11 - 12, wherein the enhanced NAD+ formulation is administered orally.14 The method of any one of claims 9-12, further comprising administering a GLP-1 or GLP-l / GIP receptor agonist to the patient in an amount effective to reduce a symptom of acetaldehyde toxicity, thecombination of repleting the intracellular level of NAD+ and administering the GLP-1 or GLP-l / GIP receptor agonist results in a synergistic therapeutic response.

15. The method of claim 14, wherein the GLP-lor GLP-l / GIP receptor agonist comprises exenatide, liraglutide, semaglutide, tirzepatide, dulaglutide, dxenatide, liraglutide, lixisenatide, or a combination hereof.

16. The method of claim 15, wherein the GLP-1 or GLP-l / GIP receptor agonist comprises semaglutide.

17. The method of any one of claims 14-16, wherein the GLP-1 or GLP-l / GIP receptor agonist is administered via injection.

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