Use of 5-methoxy-2-aminoindan ("MEAI") in methods for weight loss and treating fatty liver disease

Abstract

The disclosure relates to methods for losing weight by administering a therapeutically effective amount of 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof to a subject in need thereof for a period of time sufficient to increase basal energy expenditure. The disclosure also relates to methods for treating fatty liver disease by administering a therapeutically effective amount of 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof to a subject in need thereof.

Description

[0001] USE OF 5-METHOXY-2-AMINOINDAN ( “MEAI”) IN

[0002] METHODS FOR WEIGHT LOSS AND TREATING FATTY LIVER DISEASE

[0003] Cross-Reference to Related Applications

[0004]

[0001] This application claims the benefit of priority to U.S. Provisional

[0005] Application No. 63 / 668,632, filed on July 8, 2024, and claims the benefit of priority to U.S. Provisional Application No. 63 / 671 ,385, filed on July 15, 2024, the contents of which are incorporated by reference herein in their entireties.

[0006] Technical Field

[0007] [2] The present disclosure relates, inter alia, to methods for losing weight by administering to a subject in need thereof a therapeutically effective amount of 5- methoxy-2-aminoindan (“MEAI”) or a pharmaceutically acceptable salt thereof for a period of time sufficient to increase basal energy expenditure. The present disclosure also relates to methods for treating fatty liver disease by administering to a subject in need thereof a therapeutically effective amount of MEAI or a pharmaceutically acceptable salt thereof. In some embodiments, the methods of treatment comprise administering MEAI or a pharmaceutically acceptable salt thereof in combination with one or more additional compounds. In some embodiments, the methods of treatment comprise administering MEAI or a pharmaceutically acceptable salt thereof in combination with one or more N-acylethanolamines, for example, palmitoylethanolamide (“PEA”).

[0008] Introduction

[0009] [3] Obesity is a chronic disease reaching epidemic proportions, with more than one-third (34.9% or 78.6 million) of U.S. adults considered obese. Obesity has been described as a catalyst for a number of conditions, most notably cardiovascular disease, type 2 diabetes mellitus (T2DM) and liver disease (e.g., metabolic dysfunction- associated steatotic liver disease (MASLD)). While several metabolic factors have been linked to the development of obesity, the exact molecular mechanisms involved are not fully understood.

[0010] [4] The etiologies of obesity have been attributed to eating behavior or fast food, personality issues, depression, or genetics. Food addiction is currently one of the emerging hypotheses for the epidemic spread of obesity, which is often associated with both substance-related disorders and eating disorders (most prominently binge-eating). There is evidence that bingeing on sugar-dense, palatable foods increases extracellular dopamine in the striatum and thereby possesses an addictive potential. Moreover, there appear to be several biological and psychological similarities between food addiction and drug dependence including craving and loss of control.

[0011] [5] Nevertheless, because there are limited options for treating obesity and other metabolic disorders, a need remains for improved treatment options.

[0012] Summary of the Disclosure

[0013] [6] In some embodiments, provided herein is a method for losing weight comprising administering to a subject in need thereof a therapeutically effective amount of 5-methoxy-2-aminoindan (MEAI) or a pharmaceutically acceptable salt thereof for a period of time sufficient to increase basal energy expenditure in the subject. In some embodiments, the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof increases caloric burning without increasing physical activity of the subject. In some embodiments, the period of time sufficient to increase basal energy expenditure is about 5 days, about 10 days, about 15 days, about 20 days, about 25 days, about 30 days, about 45 days, about 60 days, about 90 days, or about 120 days. In some embodiments, the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof is administered as a dose of from about 0.5 mg to about 520 mg. In some embodiments, the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof comprises from about 10 mg to about 520 mg, from about 10 mg to about 520 mg, from about 20 mg to about 520 mg, from about 20 mg to about 250 mg, from about 20 mg to about 200 mg, from about 20 mg to about 175 mg, from about 20 mg to about 150 mg, from about 20 mg to about 125 mg, from about 20 mg to about 100 mg, or from about 20 mg to about 50 mg. In some embodiments, the therapeutically effective amount of the 5-methoxy-2-aminoindan or pharmaceutically acceptable salt thereof is administered as a dose of from about 20 mg to about 250 mg, from about 20 mg to about 200 mg, from about 20 mg to about 175 mg, or from about 20 mg to about 150 mg.

[0014] [7] In some embodiments, the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof is formulated in a single dose or as more than one divided dose. In some embodiments, the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof is administered daily. In some embodiments, the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof is administered once daily. In some embodiments, the single dose is administered once daily. In some embodiments, the more than one divided dose is administered once daily. In some embodiments, the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof is administered twice daily.

[0015] [8] In some embodiments, the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof may be determined for a human equivalent dose by referencing a 60 kg human body weight. In some embodiments, the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof comprises from about 0.0083 mg / kg body weight per day to about 8.67 mg / kg body weight per day, from about 0.042 to about 8.67 mg / kg body weight per day, from about 0.167 mg / kg body weight per day to about 8.67 mg / kg body weight per day, from about 0.33 mg / kg body weight per day to about 8.67 mg / kg body weight per day, from about 0.33 mg / kg body weight per day to about 4.167 mg / kg body weight per day, from about 0.33 mg / kg body weight per day to about 3.33 mg / kg body weight per day, from about 0.33 mg / kg body weight per day to about 2.92 mg / kg body weight per day, from about 0.33 mg / kg body weight per day to about 2.5 mg / kg body weight per day, from about 0.33 mg / kg body weight per day to about 2.08 mg / kg body weight per day, from about 0.33 mg / kg body weight per day to about 1 .67 mg / kg body weight per day, or from about 0.33 mg / kg body weight per day to about 0.83 mg / kg body weight per day.

[0016] [9] In some embodiments, the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof may be determined for a human equivalent dose by referencing a 70 kg human body weight. In some embodiments, the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof comprises from about 0.007 mg / kg body weight per day to about 7.43 mg / kg body weight per day, from about 0.036 mg / kg body weight per day to about 7.43 mg / kg body weight per day, from about 0.142 mg / kg body weight per day to about 7.43 mg / kg body weight per day, from about 0.29 mg / kg body weight per day to about 7.43 mg / kg body weight per day, from about 0.29 mg / kg body weight per day to about 3.57 mg / kg body weight per day, from about 0.29 mg / kg body weight per day to about 2.86 mg / kg body weight per day, from about 0.29 mg / kg body weight per day to about 2.5 mg / kg body weight per day, from about 0.29 mg / kg body weight per day to about 2.14 mg / kg body weight per day, from about 0.29 mg / kg body weight per day to about 1 .79 mg / kg body weight per day, from about 0.29 mg / kg body weight per day to about 1 .43 mg / kg body weight per day, or from about 0.29 mg / kg body weight per day to about 0.71 mg / kg body weight per day.

[0010] In some embodiments, the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof comprises at least about 0.007 mg / kg body weight per day, at least about 0.036 mg / kg body weight per day, at least about 0.142 mg / kg body weight per day, at least about 0.29 mg / kg body weight per day, at least about 0.71 mg / kg body weight per day, at least about 1 .43 mg / kg body weight per day, at least about 1 .79 mg / kg body weight per day, at least about 2.14 mg / kg body weight per day, at least about 2.5 mg / kg body weight per day, at least about 2.86 mg / kg body weight per day, at least about 3.57 mg / kg body weight per day, or at least about 7.43 mg / kg body weight per day.

[0017]

[0011] In some embodiments, the method for losing weight further comprises administering a therapeutically effective amount of MEAI or a pharmaceutically acceptable salt thereof, and administering separately, sequentially, concurrently, or simultaneously a therapeutically effective amount of an N-acylethanolamine or a pharmaceutically acceptable salt thereof. The N-acylethanolamine or pharmaceutically acceptable salt thereof may be in the same or a separate pharmaceutical composition as the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof and the N-acylethanolamine or pharmaceutically acceptable salt thereof are formulated in a single pharmaceutical composition. In some embodiments, the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof and the N-acylethanolamine or pharmaceutically acceptable salt thereof are formulated in separate pharmaceutical compositions.

[0018]

[0012] In some embodiments, the therapeutically effective amount of N- acylethanolamine or pharmaceutically acceptable salt thereof comprises from about 200 to about 1800 mg. In some embodiments, the therapeutically effective amount of the N- acylethanolamine or pharmaceutically acceptable salt thereof comprises from about 250 mg to about 1550 mg, from about 300 mg to about 1200 mg, from about 350 mg to about 950 mg, from about 400 mg to about 800 mg, from about 450 mg to about 700 mg, or from about 500 mg to about 600 mg. In some embodiments, the therapeutically effective amount of the N-acylethanolamine or pharmaceutically acceptable salt thereof comprises about 400 mg. In some embodiments, the therapeutically effective amount of the N-acylethanolamine or pharmaceutically acceptable salt thereof comprises about 800 mg. In some embodiments, the therapeutically effective amount of the N- acylethanolamine or pharmaceutically acceptable salt thereof is administered simultaneously with the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount of the N-acylethanolamine or pharmaceutically acceptable salt thereof is formulated in a single dose or as more than one divided dose. In some embodiments, the therapeutically effective amount of the N-acylethanolamine or pharmaceutically acceptable salt thereof is formulated as a single dose or as more than one divided dose. In some embodiments, the therapeutically effective amount of the N-acylethanolamine or pharmaceutically acceptable salt thereof is administered twice a day.

[0019]

[0013] In some embodiments, the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof and the therapeutically effective amount of N- acylethanolamine or pharmaceutically acceptable salt thereof may be administered at a molar ratio ranging from about 1 :0.2 to about 1 :2000.

[0020]

[0014] In some embodiments, the N-acylethanolamine is selected from N- palmitoylethanolamine (PEA), Me-palmitoylethanolamide (Me-PEA), palmitoylcyclohexamide, palmitoylbutylamide, oleoylethanolamine (OEA), palmitoylisopropylamide (PIA), pharmaceutically acceptable salts thereof, and any combination thereof. In some embodiments, the N-acylethanolamine is PEA or a pharmaceutically acceptable salt thereof. In some embodiments, the N- acylethanolamine comprises PEA or a pharmaceutically acceptable salt thereof. In some embodiments, the N-acylethanolamine comprises PEA.

[0021]

[0015] In some embodiments, the therapeutically effective amount of the N- acylethanolamine or pharmaceutically acceptable salt thereof may be determined for a human equivalent dose by referencing a 60 kg human body weight. In some embodiments, the therapeutically effective amount of N-acylethanolamine or pharmaceutically acceptable salt thereof comprises from about 3.33 mg / kg body weight per day to about 30.0 mg / kg body weight per day, from about 4.17 mg / kg body weight per day to about 25.83 mg / kg body weight per day, from about 5.0 mg / kg body weight per day to about 20.0 mg / kg body weight per day, from about 5.83 mg / kg body weight per day to about 15.83 mg / kg body weight per day, from about 6.67 mg / kg body weight per day to about 13.33 mg / kg body weight per day, from about 7.50 mg / kg body weight per day to about 12.50 mg / kg body weight per day, or from about 8.33 mg / kg body weight per day to about 10.0 mg / kg body weight per day.

[0022]

[0016] In some embodiments, the therapeutically effective amount of N- acylethanolamine or pharmaceutically acceptable salt thereof comprises at least about 3.33 mg / kg body weight per day, at least about 4.17 mg / kg body weight per day, at least about 5.0 mg / kg body weight per day, at least about 5.83 mg / kg body weight per day, at least about 6.67 mg / kg body weight per day, at least about 7.50 mg / kg body weight per day, at least about 8.33 mg / kg body weight per day, at least about 10.0 mg / kg body weight per day, at least about 12.50 mg / kg body weight per day, at least about 13.33 mg / kg body weight per day, at least about 15.83 mg / kg body weight per day, at least about 20.0 mg / kg body weight per day, at least about 25.83 mg / kg body weight per day, or at least about 30.0 mg / kg body weight per day.

[0023]

[0017] In some embodiments, the therapeutically effective amount of the N- acylethanolamine or pharmaceutically acceptable salt thereof may be determined for a human equivalent dose by referencing a 70 kg human body weight. In some embodiments, the therapeutically effective amount of N-acylethanolamine or pharmaceutically acceptable salt thereof the therapeutically effective amount of the N- acylethanolamine or pharmaceutically acceptable salt thereof comprises from about 2.86 mg / kg body weight per day to about 25.71 mg / kg body weight per day, from about

[0024] 3.57 mg / kg body weight per day to about 22.14 mg / kg body weight per day, from about

[0025] 4.29 mg / kg body weight per day to about 17.14 mg / kg body weight per day, from about

[0026] 5.0 mg / kg body weight per day to about 13.57 mg / kg body weight per day, from about 5.71 mg / kg body weight per day to about 11 .43 mg / kg body weight per day, from about

[0027] 6.43 mg / kg body weight per day to about 10.71 mg / kg body weight per day, or from about 7.14 mg / kg body weight per day to about 8.57 mg / kg body weight per day.

[0028]

[0018] In some embodiments, the therapeutically effective amount of N- acylethanolamine or pharmaceutically acceptable salt thereof comprises at least about 2.86 mg / kg body weight per day, at least about 3.57 mg / kg body weight per day, at least about 4.29 mg / kg body weight per day, at least about 5.0 mg / kg body weight per day, at least about 5.71 mg / kg body weight per day, at least about 6.43 mg / kg body weight per day, at least about 7.14 mg / kg body weight per day, at least about 8.57 mg / kg body weight per day, at least about 10.71 mg / kg body weight per day, at least about 11 .43 mg / kg body weight per day, at least about 13.57 mg / kg body weight per day, at least about 17.14 mg / kg body weight per day, at least about 22.14 mg / kg body weight per day, or at least about 25.71 mg / kg body weight per day.

[0029]

[0019] In some embodiments, the therapeutically effective amount of the MEAI or pharmaceutically acceptable salt thereof and / or the N-acylethanolamine or pharmaceutically acceptable salt thereof are formulated in a pharmaceutical composition further comprising at least one pharmaceutically acceptable carrier and / or excipient. In some embodiments, the pharmaceutical composition is a free-flowing powder, a tablet, a capsule, a lozenge, a liquid, a liquid concentrate, suspension, or a syrup. In some embodiments, the pharmaceutical composition is a unit dosage form composition.

[0030]

[0020] In some embodiments, administration of the pharmaceutical composition is oral, sublingual, buccal, vaginal, rectal, parenteral, transdermal, or by inhalation. In some embodiments, parenteral administration is intravenous, intramuscular, or subcutaneous.

[0031]

[0021] In some embodiments, administration is oral, mucosal, nasal, sublingual, inhalational, topical, rectal, vaginal, or parenteral. In some embodiments, parenteral administration is intravenous, intramuscular, or subcutaneous.

[0032]

[0022] In some embodiments, the subject receiving the therapeutically effective amount of MEAI or a pharmaceutically acceptable salt thereof has a healthy body weight or healthy body mass index. In some embodiments, the subject has at least one metabolic disorder. In some embodiments, the metabolic disorder results from chronic consumption of a high-fat diet. In some embodiments, the metabolic disorder is selected from obesity, dyslipidemia, diabetes, hyperglycemia, hyperlipidemia, hypercholesterolemia, insulin-resistance, hyperinsulinemia, glucose intolerance, and hepatic steatosis. In some embodiments, the metabolic disorder is selected from obesity and diabetes. In some embodiments, the subject is sedentary, unable to exercise, or not on an exercise regimen. In some embodiments, the subject is on a weight loss regimen. In some embodiments, the subject is on a weight loss regimen prior to administering the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof and where the weight loss regimen alone led to a plateau in weight loss, at least one adverse side effect, or a combination thereof. In some embodiments, the weight loss regimen comprises a diet regimen, an exercise regimen, a medication, or a combination thereof. In some embodiments, combining the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof with the weight loss regimen further increases weight loss in the subject relative to weight loss prior to administering the therapeutically effective amount of MEAI or a pharmaceutically acceptable salt thereof. In some embodiments, combining the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof with the weight loss regimen prevents or alleviates at least one adverse side effect caused by the medication in the weight loss regimen. In some embodiments, combining the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof with the weight loss regimen increases an amount of time spent on the weight loss regimen. In some embodiments, the medication comprises a GLP-1 receptor agonist. In some embodiments, the GLP-1 receptor agonist and the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof increase metabolism and decrease caloric intake.

[0033]

[0023] In some embodiments, provided herein is a method for preventing or treating fatty liver disease comprising administering to a subject in need thereof a therapeutically effective amount of 5-methoxy-2-aminoindan (MEAI) or a pharmaceutically acceptable salt thereof.

[0034]

[0024] In some embodiments, administering the therapeutically effective amount of MEAI or a pharmaceutically acceptable salt thereof alters a level of at least one biomarker associated with lipid metabolism. In some embodiments, the at least one biomarker comprises a protein and / or an mRNA level of a gene associated with lipid metabolism. In some embodiments, the gene associated with lipid metabolism comprises peroxisome proliferator-activated receptor alpha (Ppara), cluster of differentiation 36 (Cd36), lipoprotein lipase Lpl), stearoyl-CoA desaturase 1 (Scoff), acetyl-CoA carboxylase alpha (Acaca), fatty acid synthase (Fas / i), fatty acid-binding protein 1 Fabpl), glucose-6-phosphate dehydrogenase (G6pdx), and / or phosphorylated AMP-activated protein kinase (p-AMPK).

[0035]

[0025] In some embodiments, administering the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof decreases fatty acid oxidation, lipolysis, or fatty acid synthesis in the subject compared to a level prior to administering the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof.

[0036]

[0026] In some embodiments, the subject has a genetic risk for developing fatty liver disease. In some embodiments, the subject has a genetic mutation that alters a level of the at least one biomarker associated with lipid metabolism.

[0037]

[0027] In some embodiments, the fatty liver disease is a metabolic dysfunction- associated steatotic liver disease (MASLD) or an alcoholic fatty liver disease.

[0038] Brief Description of the Drawings

[0039]

[0028] The foregoing summary, as well as the following detailed description of the disclosure, will be better understood when read in conjunction with the appended drawings. For the purpose of illustrating the present disclosure, the attached drawings illustrate some, but not all, alternative embodiments. It should be understood, however, that the disclosure is not limited to the precise arrangements and instrumentalities shown. These figures, which are incorporated into and constitute part of the specification, assist in explaining the principles of the disclosures.

[0040]

[0029] Figure 1 shows acute effects of MEAI administration on food intake patterns and energy utilization. Shown are experimental design (FIG. 1 A), cumulative food intake and sum of food intake (FIGs. 1 B and 1 C), cumulative water intake and sum of water intake (FIGs. 1 D and 1 E), respiratory exchange rate (RER) (FIG. 1 F), rate of oxygen consumption (FIG. 1G), rate of carbon dioxide emission (FIG. 1 H), total energy expenditure (TEE) and daily TEE (FIGs. 11 and 1 J), energy balance (FIG. 1 K), fat oxidation (FIG. 1 L), and carbohydrate oxidation (FIG. 1 M). Data represent mean ± SEM from 6-8 mice per group. *P < 0.05 relative to Vehicle-treated group.

[0041]

[0030] Figure 2 shows acute alterations in the activity profile following MEAI administration. Shown are total ambulatory activity (FIG. 2A), pedestrian locomotion (FIG. 2B), pedestrian speed (FIG. 2C), wheel running distance (FIG. 2D), total pedometer count (FIG. 2E), and activity energy expenditure (FIG. 2F). Data represent mean ± SEM from 6-8 mice per group. *P < 0.05 relative to Vehicle-treated group.

[0042]

[0031] Figure 3 shows the acute effects of MEAI on sweet tase preference. Shown are sucrose preference percentages compared to sterile water over a test period of 48 hours. Data represent mean ± SEM from 8 mice per group. *P < 0.05 relative to Vehicle-treated group.

[0043]

[0032] Figure 4 shows the chronic administration of MEAI attenuates weight gain and body composition changes associated with obesity. Shown are the experimental design to test efficacy of MEAI in a HFD-induced obesity model (FIG. 4A), time course changes of body weight (FIG. 4B), total body weight at the end of the experiment (FIG. 4C), total body weight change at the end of the experiment (FIG. 4D), lean mass percentage of the overall body weight (FIG. 4E), lean mass in grams (FIG. 4F), fat mass percentage of overall body weight (FIG. 4G), fat mass in grams (FIG. 4H), leptin levels (FIG. 4I), and serum serotonin levels (FIG. 4J). Data represent mean ± SEM from 8-11 mice per group. *P < 0.05 relative to STD vehicle; #P < 0.05 relative to HFD vehicle.

[0044]

[0033] Figure 5 shows the effect of chronic MEAI administration on food consumption and energy metabolism. Shown are hourly food consumption rate (FIG. 5A), cumulative food consumption (FIG. 5B), thermic effect of food (FIG. 5C), cumulative water intake (FIG. 5D), respiratory exchange rate (RER) (FIG. 5E), rate of oxygen consumption (FIG. 5F), rate of carbon dioxide emission (FIG. 5G), total energy expenditure rate (FIG. 5 H), total energy expenditure rate compared using analysis of covariance (ANCOVA) using lean mass as covariant, provided by the NIDDK Mouse Metabolic Phenotyping Centers (FIG. 51), energy balance (FIG. 5J) , energy flux (FIG. 5K), Basal energy expenditure (FIG. 5L), fat oxidation (FIG. 5M), and carbohydrate oxidation (FIG. 5N). Data represent mean ± SEM from 8-11 mice per group. *P < 0.05 relative to STD vehicle; #P < 0.05 relative to HFD vehicle.

[0045]

[0034] Figure 6 shows locomotive activity following chronic MEAI administration in HFD-induced obesity. Shown are 24-hour time course changes of ambulatory activity (FIG. 6A), pedestrian locomotion (FIG. 6B), pedestrian locomotion speed (FIG. 6C), total distance traveled (FIG. 6D), wheel running distance (FIG. 6E), wheel speed (FIG. 6F), and a chart indicating percentages of time spent by mice engaging in various activities (FIG. 6G). Data represent mean ± SEM from 8-11 mice per group. *P < 0.05 relative to STD vehicle; #P < 0.05 relative to HFD vehicle.

[0046]

[0035] Figure 7 shows effects of chronic MEAI administration on glucose tolerance and insulin sensitivity. Shown are blood glucose levels in a glucose tolerance test (FIG. 7A), area-under-curve (AUC) values of the glucose tolerance test (FIG. 7B), blood glucose percentages in an insulin tolerance test (FIG. 7C), AUC values of the insulin tolerance test (FIG. 7D), fasting blood glucose levels (FIG. 7E), serum insulin levels (FIG. 7F), homeostasis model assessment insulin resistance (HOMA-IR) values (FIG. 7G), insulin sensitivity index (ISI) values (FIG. 7H), and adiponectin levels (FIG. 7I). Data represent mean ± SEM from 8-11 mice per group. *P < 0.05 relative to STD vehicle; #P < 0.05 relative to HFD vehicle.

[0047]

[0036] Figure 8 shows a circulating lipids profile following MEAI treatment. Shown are HDL levels (FIG 8A), LDL levels (FIG. 8B), HDL-to-LDL ratio (FIG. 8C), cholesterol levels (FIG. 8D), triglyceride levels (FIG. 8E), and free fatty acid levels (FIG. 8F). Data represent mean ± SEM from 8-11 mice per group. *P < 0.05 relative to STD vehicle; #P < 0.05 relative to HFD vehicle.

[0048]

[0037] Figure 9 shows the effects of MEAI on kidney weight and function. Shown are Kidney weight (FIG. 9A), Kidney weight to body weight ratio (FIG. 9B), and BUN as measured by the COBAS Chemistry analyzer (FIG. 9C). Data represent mean ± SEM from 8-11 mice per group. *P < 0.05 relative to STD vehicle; #P < 0.05 relative to HFD vehicle.

[0049]

[0038] Figure 10 shows the effects of MEAI on obesity-associated liver steatosis. Shown are weight of liver samples after chronic treatment with MEAI compared to vehicle (FIG. 10A), liver weight to body weight ratio (FIG. 10B), ALT levels (FIG. 10C), AST levels (FIG. 10D), ALP levels (FIG. 10E), hepatic triglyceride content (FIG. 10F), hepatic cholesterol content (FIG. 10G), Oil Red O staining area percentage (FIG. 10H), and Oil Red O stained samples demonstrating lipid vacuoles in hepatocytes (FIG. 101). Data represent mean ± SEM from 8-11 mice per group. *P < 0.05 relative to STD vehicle; #P < 0.05 relative to HFD vehicle.

[0050]

[0039] Figure 11 illustrates the molecular mechanism of MEAI in hepatic lipid metabolism. Shown is mRNA expression of key genes involved in hepatic lipid metabolism using qRT-PCR with or without MEAI administration (FIG. 11 A), protein levels of CD36 (FIG. 11 B), protein levels of SCD1 (FIGs. 11 C and 11 D), protein levels of FASN (FIGs. 11 E and 11 F), phosphorylated AMPK levels (FIG. 11 G), and phosphorylated ACC levels (FIG. 11 H).

[0051]

[0040] Figure 12 illustrates MEAI binding affinity to serotonin receptors and calcium influx agonists. Shown are binding affinities of MEAI to several serotonin and serotonin-related receptors (FIG. 12A) and calcium influx via HTR2B following serotonin administration and MEAI administration (FIG. 12B).

[0052] Detailed Description of the Disclosure Definitions

[0053]

[0041] “Metabolic Syndrome” refers to a cluster of symptoms (which may occur together), which may increase a subject’s risk of having or which are associated with a metabolic condition such as obesity, heart disease, stroke, or type 2 diabetes. These symptoms, alone or in combination, include increased blood pressure, high blood sugar, and / or insulin resistance (type-2 diabetes), excess body fat around the waist, and abnormal cholesterol (low HDL and / or high LDL) triglyceride levels with or without fatty liver disease, obesity, overweight, excess body weight, excess fat mass, excess adiposity, decreased energy expenditure, abnormal glycemic control, increased hepatic steatosis, excess sugar intake, excess food intake or consumption, abnormal glucose homeostasis, increased dyslipidemia, or abnormal liver function. In some embodiments, a person exhibiting a metabolic syndrome has excess body fat around the waist and / or is obese.

[0054]

[0042] “Metabolic condition” or “metabolic disorder” are used interchangeably and refer to a group of conditions associated with one or more metabolic syndrome. Examples of metabolic conditions include obesity, diabetes, diabetes associated with obesity, cardiovascular disease, metabolic dysfunction-associated steatohepatitis (MASH), dyslipidemia, hyperglycemia, hyperlipidemia, hypercholesterolemia, insulinresistance, hyperinsulinemia, glucose intolerance, or hepatic steatosis. Examples of dyslipidemia may include subjects having elevated cholesterol levels, elevated triglyceride levels, and / or reduced HDL / LDL ratios.

[0055]

[0043] "Metabolic activity” refers to a sum of chemical reactions and changes that occur in a cell or an organism that use energy produced from food or stored energy reserves. “Metabolic activity” may refer to a degree of metabolism in a cell or an organism. For example, an increased metabolic activity may refer to an increased metabolism. Examples of metabolic activity include processes related to cellular respiration, anaerobic digestion, fat oxidation, carbohydrate oxidation, and / or lipid oxidation. In some circumstances, a person exhibiting increased metabolic activity may exhibit reduced excess body fat around the waist, increased caloric burning at rest, a higher ratio of lean mass to fat mass, an increased fat oxidation rate, or reduced body weight.

[0056]

[0044] The term “fatty liver disease” as used herein means a condition characterized by excessive buildup of fat in the liver that results in impairment of the liver. In some embodiments, the impairment is the result of a surplus of triglyceride that accumulates in the liver and forms large vacuoles. The symptoms accompanying fatty liver disease are known from standard textbooks of medicine such as Stedman's Medical Terminology or Pschyrembel Clinical Dictionary. Fatty liver disease may result from alcohol abuse, diabetes mellitus, nutritional defects, and poor diets, toxicity of drugs or genetic predisposition (see Carulli et al. 2009, Dig Liver Dis. 41 (11 ):823-8. Epub 2009 Apr. 28 “Genetic polymorphisms in nonalcoholic fatty liver disease: interleukin-6-174G / C polymorphism is associated with nonalcoholic steatohepatitis”; or Yoneda et al. 2009, Liver Int. 29(7):1078-85. Epub 2009 Mar. 3 “Association between angiotensin II type 1 receptor polymorphisms and the occurrence of nonalcoholic fatty liver disease”). Fatty liver disease as used herein also includes the more severe forms thereof, such as steatosis, alcoholic fatty liver disease, metabolic dysfunction- associated steatohepatitis (MASH), or metabolic dysfunction-associated steatotic liver disease (MASLD). Symptoms accompanying these diseases are also well known and are described in detail in standard textbooks of medicine.

[0057]

[0045] “Overweight” and “obesity” mean an abnormal or excessive fat accumulation that presents a risk to health. “Overweight” refers to a subject with a weight that is higher than what is considered a healthy weight for a given height and a body mass index above a first threshold and below a second threshold. The second threshold may be understood to be larger than the first threshold. For a human subject, the first threshold of a body mass index may be 25.0 and the second threshold of a body mass index may be 30. “Obesity” refers to a subject with a weight that is also higher than what is considered a healthy weight for a given height and a body mass index above the second threshold. For a human subject, “obesity” may refer to a body mass index that is 30 or higher.

[0058]

[0046] “Dyslipidemia” means a condition characterized by altered levels of lipids above a baseline target level of lipids. In some embodiments, dyslipidemia is a condition involving elevated levels of low-density lipoprotein (LDL) cholesterol and triglycerides. In some embodiments, dyslipidemia is a condition involving lowered levels of high-density lipoprotein (HDL) cholesterol. Dyslipidemia can be caused by genetic factors, lifestyle factors (such as diet and exercise), or other medical conditions.

[0059]

[0047] “Hyperglycemia” means a condition characterized by excessive amounts of glucose in the bloodstream compared to a baseline target level.

[0060]

[0048] “Hyperlipidemia” means a condition characterized by excessive lipid levels in the bloodstream. In some embodiments, hyperlipidemia is associated with higher levels of cholesterol and triglycerides in the bloodstream compared to a baseline target level.

[0061]

[0049] “Hypercholesterolemia” means a condition characterized by excessive cholesterol levels in the bloodstream. In some embodiments, hypercholesterolemia is associated with higher levels of LDL cholesterol in the bloodstream compared to a baseline target level.

[0062]

[0050] “Insulin-resistance” means a condition where a greater amount of insulin is required to achieve a desired effect on glucose uptake from the bloodstream.

[0063]

[0051] “Hyperinsulinemia” means a condition characterized by excessive insulin levels are present in the bloodstream.

[0064]

[0052] “Glucose intolerance” means a condition where the body is unable to properly regulate blood glucose levels after eating a meal or during a fasting period. In some embodiments, glucose intolerance is associated with excessive blood glucose levels are eating a meal or during a fasting period.

[0065]

[0053] “Hepatic steatosis” means a condition where excess fat accumulates in the liver. In some embodiments, hepatic steatosis may occur when fat exceeds 5-10% of the liver’s weight.

[0066]

[0054] “Healthy body weight” means a subject does not have excessive fat accumulation that presents a risk to health and the subject exhibits a body fat percentage that falls within a target range for a certain age group, sex, and age compared to muscle mass index and bone. A “healthy body weight” may be refer to a measurement of abdominal fat compared to a measurement of lean muscle mass.

[0067]

[0055] “Healthy body mass index” means a subject has a body weight relative to a height that is within a target range and indicative of lower health risks associated with excess weight. A healthy body mass index may be from 18.5 to 24.9.

[0068]

[0056] “Type 2 diabetes” and “T2DM” are used interchangeably and mean a condition where a subject is unable to process insulin to regulate blood sugar levels. In some embodiments, “Type 2 diabetes” develops from overweight and / or obesity or is associated with overweight and / or obesity. Insulin resistance may be measured by a known assay (e.g., Homeostatic model assessment (HOMA), Glucose / insulin ratio, Insulin sensitivity test, Insulin tolerance test, hyperinsulinemic-euglycemic clamp, or any other known assay to determine insulin resistance).

[0069]

[0057] “High-fat diet” means a diet that contains a disproportionate amount of fat compared to other nutrients, relative to a diet recommended for maintaining or achieving a healthy body weight or healthy body mass index. For example, a high-fat diet is characterized as a diet containing more fat relative to carbohydrates and protein. For example, a high-fat diet contains more fat than what is recommended for daily consumption. As another example, a high-fat diet is characterized by 35% or more of a total daily caloric intake being derived from fats.

[0070]

[0058] “High-carb diet” means a diet that contains a disproportionate amount of carbohydrates compared to other nutrients, relative to a diet recommended for maintaining or achieving a healthy body weight or healthy body mass index. For example, a high-carb diet is characterized as a diet containing more carbohydrates relative to fat and protein. As another example, a high-carb diet is characterized by 65% or more of a total daily caloric intake being derived from carbohydrates. As another example, a high-carb diet contains more carbohydrates than what is recommended for daily consumption.

[0071]

[0059] “High-processed-foods diet” means a diet that contains a disproportionate amount of processed foods compared to other nutrients, relative to a diet recommended for maintaining or achieving a healthy body weight or healthy body mass index. For example, a high-processed-foods diet is characterized as a diet containing more processed foods relative to fruits, vegetables, whole grains, or other organic foods. As another example, a high-processed-foods diet has containing foods that have undergone industrial processing such as sugary drinks, processed meats, sweetened cereals, and trans fats. Examples of high-processed-foods diet include a Western diet and an industrial diet.

[0072]

[0060] “Plateau” in the context of a weight loss regimen (e.g., a diet regimen, an exercise regimen, a medication, or combination thereof) means that a subject on a weight loss regimen has achieved a state of little or no change in weight reduction, relative to a baseline. Then, commencing a method for losing weight comprising administering a therapeutically effective amount of MEAI or a pharmaceutically acceptable salt thereof for a period sufficient to increase BEE in the subject may overcome the plateau from the weight loss regimen. In the context of weight loss, “plateau” means a subject has stopped losing weight relative to a baseline or starting weight and has remained at a same or similar weight while on a weight loss regimen. For example, a subject may reach a plateau in a weight loss regimen when the subject is unable to continue losing weight after losing 10% of their body weight at baseline. In some embodiments, the period of time for a plateau is at least 24 weeks, at least 32 weeks, at least 40 weeks, at least 48 weeks, at least 56 weeks, at least 64 weeks, at least 72 weeks, or at least 80 weeks.

[0073]

[0061] “Isomers” means compounds having the same number and kind of atoms, and hence the same molecular formula and molecular weight, but differing with respect to the arrangement or configuration of the atoms in space.

[0074]

[0062] “Stereoisomer” or “optical isomer” mean a stable isomer that has at least one chiral atom or restricted rotation giving rise to perpendicular dissymmetric planes (e.g., certain biphenyls, allenes, and spiro compounds) and can rotate plane-polarized light. Because asymmetric centers and other chemical structures exist in the compounds of the disclosure, which may give rise to stereoisomerism, the disclosure contemplates stereoisomers and mixtures thereof. The compounds of the disclosure and their pharmaceutically acceptable salts include asymmetric carbon atoms and may therefore exist as single stereoisomers, racemates, and as mixtures of enantiomers and diastereomers. Typically, such compounds will be prepared as mixtures of enantiomers and diastereomers, for example, as a racemic mixture. If desired, however, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. As discussed in more detail below, individual stereoisomers of compounds are prepared by synthesis from optically active starting materials containing the desired chiral centers or by preparation of mixtures of enantiomeric products followed by separation or resolution, such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, use of chiral resolving agents, or direct separation of the enantiomers on chiral chromatographic columns. Starting compounds of particular stereochemistry are either commercially available or are made by the methods described below and resolved by techniques well-known in the art.

[0075]

[0063] It is well-known in the art that the biological and pharmacological activity of a compound can be sensitive to the stereochemistry of the compound. Thus, for example, enantiomers often exhibit strikingly different biological activity including differences in pharmacokinetic properties, including metabolism, protein binding, and the like, and pharmacological properties, including the type of activity displayed, the degree of activity, toxicity, and the like. Thus, one skilled in the art will appreciate that a first enantiomer may be more active or may exhibit beneficial effects when enriched relative to a second enantiomer or when separated from the second enantiomer. Additionally, one skilled in the art would know how to separate, enrich, or selectively prepare enantiomers of the compounds of the disclosure from this disclosure and the knowledge of the prior art.

[0076]

[0064] Thus, although a racemic form of drug may be used, it is often less effective than administering an equal amount of enantiomerically pure drug; indeed, in some cases, one enantiomer may be pharmacologically inactive and would merely serve as a simple diluent. For example, although ibuprofen had been previously administered as a racemate, it has been shown that only the (S)-isomer of ibuprofen is effective as an anti-inflammatory agent (in the case of ibuprofen, however, although the (F?)-isomer is inactive, it is converted in vivo to the (S)-isomer, thus, the rapidity of action of the racemic form of the drug is less than that of the pure (S)-isomer). Furthermore, the pharmacological activities of enantiomers may have distinct biological activity. For example, (S)-penicillamine is a therapeutic agent for chronic arthritis, while (F?)- penicillamine is toxic. Indeed, some purified enantiomers have advantages over the racemates, as it has been reported that purified individual isomers have faster transdermal penetration rates compared to the racemic mixture. See U.S. Pat. Nos. 5,114,946 and 4,818,541.

[0077]

[0065] In some embodiments, the compound is a racemic mixture of (S)- and (Flisomers. In some embodiments, provided herein is a mixture of compounds wherein individual compounds of the mixture exist predominately in an (S)- or (F?)-isomeric configuration. For example, the compound mixture has an (S)-enantiomeric excess of greater than about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, or more. In some embodiments, the compound mixture has an (S)- enantiomeric excess of greater than from about 55% to about 99.5%, greater than from about 60% to about 99.5%, greater than from about 65% to about 99.5%, greater than from about 70% to about 99.5%, greater than from about 75% to about 99.5%, greater than from about 80% to about 99.5%, greater than from about 85% to about 99.5%, greater than from about 90% to about 99.5%, greater than from about 95% to about 99.5%, greater than from about 96% to about 99.5%, greater than from about 97% to about 99.5%, greater than from about 98% to about 99.5%, greater than from about 99% to about 99.5%, or more. In some embodiments, the compound mixture has an ( / ^-enantiomeric purity of greater than about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5% or more. In some other embodiments, the compound mixture has an ( / ^-enantiomeric excess of greater than from about 55% to about 99.5%, greater than from about 60% to about 99.5%, greater than from about 65% to about 99.5%, greater than from about 70% to about 99.5%, greater than from about 75% to about 99.5%, greater than from about 80% to about 99.5%, greater than from about 85% to about 99.5%, greater than from about 90% to about 99.5%, greater than from about 95% to about 99.5%, greater than from about 96% to about 99.5%, greater than from about 97% to about 99.5%, greater than from about 98% to about 99.5%, greater than from about 99% to about 99.5%, or more.

[0078]

[0066] Individual stereoisomers of compounds of the present disclosure can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. These methods of resolution are exemplified by: (1 ) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary; (2) salt formation employing an optically active resolving agent; or (3) direct separation of the mixture of optical enantiomers on chiral chromatographic columns. Stereoisomeric mixtures can also be resolved into their component stereoisomers by well-known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent. Stereoisomers can also be obtained from stereomerically-pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.

[0067] Thus, if a first enantiomer is pharmacologically more active, less toxic, or has a preferred disposition in the body than a second enantiomer, it would be therapeutically more beneficial to administer the first enantiomer preferentially. In this way, the patient undergoing treatment would be exposed to a lower total dose of the drug and to a lower dose of an enantiomer that is possibly toxic or an inhibitor of the other enantiomer.

[0079]

[0068] As used herein, nomenclature for compounds including organic compounds, can be given using common names, IUPAC, IUBMB, or CAS recommendations for nomenclature. One of skill in the art can readily ascertain the structure of a compound if given a name, either by systemic reduction of compound structure using naming conventions, or by commercially available software, such as ChemDraw™ (Revvity Signals Software, U.S.A.). Chemical names were generated using PerkinElmer ChemDraw® Professional.

[0080]

[0069] The compounds of the disclosure may contain one or more chiral centers and / or double bonds and, therefore, exist as stereoisomers, such as geometric isomers, enantiomers or diastereomers. The term “stereoisomers” when used herein consist of all geometric isomers, enantiomers or diastereomers. These compounds may be designated by the symbol “R” or “S,” depending on the configuration of substituents around the stereogenic carbon atom. The present disclosure encompasses various stereoisomers of these compounds and mixtures thereof. Stereoisomers include enantiomers and diastereomers. Mixtures of enantiomers or diastereomers may be designated “(±)” in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly. In some embodiments, an enantiomer or stereoisomer may be provided substantially free of the corresponding enantiomer.

[0081]

[0070] As used herein, a "pharmaceutical composition" refers to a preparation of the active agents described herein with other chemical components such as physiologically suitable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism. As used herein, the phrase "pharmaceutically acceptable carrier" refers to a carrier, an excipient or a diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound. An adjuvant is included under these phrases.

[0082]

[0071] The term "excipient" as used herein refers to an inert substance added to a pharmaceutical composition to further facilitate administration of an active ingredient. Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, oils such as vegetable oils or fish oils, and polyethylene glycols.

[0083]

[0072] The term "carrier" as used herein refers to a diluent, adjuvant, excipient, or vehicle with which the compound is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils. Water or aqueous solution saline solutions and aqueous dextrose and glycerol solutions are preferably employed as carriers, particularly for injectable solutions. Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E. W. Martin, 18th Edition.

[0084]

[0073] The phrase "pharmaceutically acceptable" as used herein refers to molecular entities and compositions that are physiologically tolerable and do not typically produce an allergic or similar toxicity when administered to an individual. Preferably, and particularly where a formulation is used in humans, the term "pharmaceutically acceptable" may mean approved by a regulatory agency (for example, the U.S. Food and Drug Administration or European Medicines Agency) or listed in a generally recognized pharmacopeia for use in humans and animals (e.g., the U.S. Pharmacopeia).

[0085]

[0074] The term "N-acylethanolamine" as used herein generally refers to a type of fatty acid amide, lipid-derived signaling molecules, formed when one of several types of acyl group is linked to the nitrogen atom of ethanolamine. These amides conceptually can be formed from a fatty acid and ethanolamine with the release of a molecule of water, but the known biological synthesis uses a specific phospholipase D to cleave the phospholipid unit from N-acylphosphatidylethanolamines. The suffixes

[0086] -amine and -amide in these names each refer to the single nitrogen atom of ethanolamine that links the compound together: it is termed "amine" in ethanolamine because it is considered as a free terminal nitrogen in that subunit, while it is termed "amide" when it is considered in association with the adjacent carbonyl group of the acyl subunit. Names for these compounds may be encountered with either "amide" or "amine" in the present application. The term "ethanolamine" is used in the generic sense and is meant to include mono-ethanolamine, di-ethanolamine, tri-ethanolamine, and mixtures thereof.

[0087]

[0075] The term “GLP-1 receptor agonist” as used herein means an agent capable of binding to and activating the GLP-1 receptor. Glucagon-like peptide 1 (GLP- 1 ) is an endocrine hormone that increases the insulin response following oral intake of glucose or fat. GLP-1 generally regulates the concentrations of glucagons, slows down gastric emptying, stimulates the biosynthesis of (Pro-)insulin, increases the sensitivity toward insulin, and stimulates the insulin-independent biosynthesis of glycogen (Holst (1999), Curr. Med. Chern 6:1005, Nauck et al (1997) Exp Clin Endocrine Diabetes 105: 187, Lopez-Delgado et al (1998) Endocrinology 139:2811 ).

[0088]

[0076] GLP-1 is a naturally occurring agonist of the GLP-1 receptor. GLP-1 receptor agonists encompass GLP-1 analogs. A GLP-1 receptor agonist is a compound that mimics the effects of GLP-1 and may be used as a medication for type 2 diabetes and weight loss. Specifically, GLP-1 receptor agonists may increase feelings of fullness, reduce overall food intake, control insulin levels, and help lower blood sugar levels. A GLP-1 receptor agonist may be a peptide or a small molecule GLP-1 receptor agonist. In some embodiments, the GLP-1 receptor agonist is a long-acting small molecule GLP- 1 receptor agonist. Unless otherwise noted, GLP-1 receptor agonists may also comprise additional functions, such as a glucagon (GCG) receptor agonist function and / or a glucose-dependent insulinotropic polypeptide (GIP) receptor function. In some embodiments, the GLP-1 receptor agonist is a dual receptor agonist. In some embodiments, the GLP-1 receptor agonist is a GLP-1 / GCG dual receptor agonist. In some embodiments, the GLP-1 receptor agonist is a GLP-1 / GIP dual receptor agonist. In some embodiments, the GLP-1 receptor agonist is a triagonist. In some embodiments, the GLP-1 RA is a GLP-1 / GCG / GIP triagonist. Non-limiting examples of GLP-1 receptor agonists include medications such as semaglutide, tirzepatide, liraglutide, and exenatide.

[0089]

[0077] The term "derivative" as used herein means a compound whose core structure is the same as, or closely resembles that of, another compound, but which has a chemical or physical modification, such as different or additional substituents.

[0090]

[0078] The term "salt" as used herein refers to any form of an active ingredient in which the active ingredient assumes an ionic form and is coupled to a counter ion (a cation or anion) or is in solution. This also includes complexes of the active ingredient with other molecules and ions, in particular complexes which are complexed by ion interaction. Pharmaceutically acceptable salts are known to persons of ordinary skill in the art.

[0091]

[0079] Techniques for formulation and administration of drugs are well known in the art, and may be found, e.g. in "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, Pa. Pharmaceutical compositions of the present disclosure may be manufactured by processes well known in the art, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing processes.

[0080] For oral administration, the pharmaceutical composition can be formulated readily by combining active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the pharmaceutical composition to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for oral ingestion by a patient. Pharmacological preparations for oral use can be made using a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries as desired, to obtain tablets or dragee cores. Suitable excipients are fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, and sodium carbomethylcellulose; and / or physiologically acceptable polymers such as polyvinylpyrrolidone (PVP). If desired, disintegrating agents, such as cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a pharmaceutically acceptable salt thereof, such as sodium alginate, may be added.

[0092]

[0081] The term "oral administration" refers to any method of administration in which an active agent can be administered by swallowing, chewing, sucking, or drinking an oral dosage form. Examples of solid dosage forms include conventional tablets, multi-layer tablets, capsules, caplets, etc., which do not substantially release the drug in the mouth or in the oral cavity.

[0093]

[0082] Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

[0094]

[0083] Pharmaceutical compositions that can be used orally include stiff or soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The capsules may contain active ingredients in admixture with filler such as lactose, binders such as starches, lubricants such as talc or magnesium stearate, and, optionally, stabilizers. In soft capsules, the active ingredients may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for the chosen route of administration. For buccal and sublingual administration, the compositions may take the form of tablets or lozenges formulated in conventional manner or in adhesive carriers. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., a sterile, pyrogen-free, water-based solution, before use.

[0095]

[0084] Pharmaceutical compositions suitable for use in the context of the present disclosure include compositions wherein the active ingredients are contained in an amount effective to achieve the intended purpose. More specifically, a "therapeutically effective amount" means an amount of active ingredients effective to prevent, alleviate, or ameliorate symptoms or side effects of a disease or disorder, or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein. More specifically, a "therapeutically effective amount of a mixture" means an amount of at least two active ingredients, wherein each one of the active ingredients independently may not be in a therapeutically effective amount or wherein both of the active ingredients may not be in a therapeutically effective amount, the mixture is nevertheless effective to prevent, alleviate, or ameliorate symptoms or side effects of a disease or disorder, or prolong the survival of the subject being treated. The term "mixture" as used herein refers to a non-covalent combination of two molecules.

[0096]

[0085] For any preparation used in the methods of the disclosure, the dosage or the therapeutically effective amount can be estimated initially from in vitro, in vivo and cell culture assays. For example, a dose can be formulated in animal models to achieve a desired concentration or titer. Such information can be used to more accurately determine useful doses in humans. The dosage of each compound of the claimed combinations depends on several factors, including: the administration method, the disease to be treated, the severity of the disease, whether the disease is to be treated or prevented, and the age, weight, and health of the person to be treated. Additionally, pharmacogenomic (the effect of genotype on the pharmacokinetic, pharmacodynamic or efficacy profile of a therapeutic) information about a particular patient may affect dosage used. Continuous daily dosing may not be required; a therapeutic regimen may require cycles, during which time a drug is not administered, or therapy may be provided on an as-needed basis during periods of acute disease worsening. Dosage escalation may or may not be required; a therapeutic regimen may require reduction in medication dosage. Toxicity and therapeutic efficacy of the active ingredients described herein can be determined by standard pharmaceutical procedures in vitro, in cell cultures or experimental animals. The data obtained from these in vitro and cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage may vary depending upon the dosage form employed and the route of administration utilized. The exact formulation, route of administration, and dosage can be chosen by the individual physician in view of the patient's condition (See, e.g., Fingl, E. et al. (1975), "The Pharmacological Basis of Therapeutics," Ch. 1 , p. 1 ). Depending on the severity and responsiveness of the condition to be treated, dosing can be of a single or a plurality of administrations, with course of treatment lasting from several days to several weeks, or until cure is affected or until a desired level of diminution of the disease state is achieved.

[0097]

[0086] The term "treating" as used herein, includes, but is not limited to, any one or more of the following: abrogating, ameliorating, inhibiting, attenuating, reducing, blocking, suppressing, reducing, delaying, halting, alleviating, preventing, or slowing the onset of one or more symptoms or side effects of the diseases or conditions of the disclosure.

[0098]

[0087] The term "acute" refers to a condition or treatment with a relatively short time course.

[0099]

[0088] The term "chronic" as used herein means that the length of time of the diseases or conditions or treatment of the disclosure can be weeks, months, or possibly years. The intensity of the diseases or conditions can differentiate according to various conditions such as patient age, temperature, season, type of disease, etc.

[0100]

[0089] The term "about" as used herein in relation to a value, a plurality of values or a range of values defined by a lowest and highest values means a value which is

[0101] 10% lower and / or higher than the corresponding value, plurality of values, or range of values. For example, the phrase "about 1" means "0.9 to 1.1", the phrase "about 1 or 2" means "0.9 to 1.1 or 1 .8 to 2.2", and the phrase "about 1 to about 2" means "0.9 to 2.2".

[0102]

[0090] As used herein, the singular form "a," "an," and "the" include plural references unless the context clearly dictates otherwise. For example, the term "a compound" or "at least one compound" may include a plurality of compounds, including mixtures thereof.

[0103] Compounds

[0104]

[0091] Compounds derived from 2-aminoindan may be used in the methods disclosed herein. Such compounds have been shown to selectively bind to the dopamine D3 receptor. U.S. Pat. No. 5,708,018 discloses some 2-aminoindan derivatives and hypothesizes that these 2-aminoindan derivatives may be useful in treating CNS disorders associated with dopamine D3 receptor. One such compound is 5-methoxy-2-aminoindan (“MEAI”), having the following chemical structure:

[0105]

[0092] Other 2-aminoindan derivatives that may be used in the disclosure herein may be represented by a compound of Formula I:

[0106] (Formula I), wherein

[0107] - each of R1and R2is independently selected from H, (Ci-Cs) alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)cycloalkyl, aryl, heteroaryl, heteroalicyclic, -O(Ci-C8 alky), OH, -OSO2CF3, -OSO2-(Ci-C8)alkyl, -SOR5, -CO2R5, -CONR5R6, -COR5, -CF3, CN, -SR5, -SO2NR5R6, -SO2R5, -OCO-(Ci-C8)alkyl, -NCO-(Ci-Cs)alkyl, -CH2O- (Ci-Cs)alkyl, -(Ci-Ce)alkyl-OH, -NHSO2R5, and halogen, or, alternatively, R1and R2together with two or more of the phenyl carbon atoms to which they are attached form a -X1-(CR5R6)m-X2-ring, wherein each of X1and X2is independently selected from C, O, NH or S and m is 1 , 2, 3, or 4;

[0108] - each of R3and R4is independently selected from H, (Ci-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)cycloalkyl, and -(CH2)P-thienyl, wherein p is 1 , 2, 3, or 4, or alternatively, R3and R4are joined together to form a heterocyclic ring (heteroalicyclic or heteroaryl) containing the nitrogen atom to which they are attached; and

[0109] - each of R5and R6is independently selected from H, (Ci-Csjalkyl, (C2-C8)alkenyl, (Cs-Csjcycloalkyl and aryl.

[0110]

[0093] In some embodiments, the 2-aminoindan derivative represented by Formula I as presented herein, is defined as follows:

[0111] - each of R1and R2is independently selected H, (Ci-Csjalkyl, (C2-C8)alkenyl, (C2- Csjalkynyl, (Cs-Csjcycloalkyl, aryl, -OCH3, OH, -OSO2CF3, -OSO2CH3, -SOR5, - CO2R5, -CONR5R6-COR5, -CF3, -CN, -SR5, -SO2NR5R6, -SO2R5, -CH2-OH, halogen, phthalimidyl, thiophenyl, pyrrolyl, pyrrolinyl, oxazolyl, or, alternatively, R1and R2together with two or more of the phenyl carbon atoms form a - 0(CH2)m0- ring, wherein m is 1 or 2; - R3and R4are joined together to form a heterocyclic ring containing 4 to 8 carbon atoms with the nitrogen atom to which they are attached; and

[0112] - each of R5and R6is independently selected from H, (Ci-Cs) alkyl, (C2-C8)alkenyl, and (Ca-CsjcycloalkyL

[0113]

[0094] Non-limiting examples of 2-aminoindan derivatives include:

[0114] (1 ) 5-methoxy-2-aminoindan;

[0115] (2) 5,6-dimethoxy-2-aminoindan:

[0116] (3) 5-methoxy-2-(N-propylamino)indan;

[0117] (4) 5,6-dimethoxy-2-(N-propylamino)indan;

[0118] (5) 5,6-dimethoxy-2-(di-N-butylamino)indan;

[0119] (6) 5-(trifluoromethylsulfonyloxy)-6-hydroxy-2-(di-N-propylamino)indan;

[0120] (7) 5-(trifluoromethylsulfonyloxy)-2-(N-propylamino)indan ;

[0121] (8) 5,6-(di-trifluoromethylsulfonyloxy)-2-(N-propylamino)indan;

[0122] (9) 5,6-dimethoxy-2(pyrrolidino)indan ;

[0123] (10) 5-(trifluoromethylsulfonyloxy)-6-acetoxy-2-(di-N-propylamino)indan;

[0124] (11 ) 5-trifluromethansulfonyloxy-6-methoxy-2-(di-N-propylamino)indan;

[0125] (12) 5,6-ethylenedioxy-2-(di-N-propylamino)indan;

[0126] (13) 5,6-methylenedioxy-2-(di-N-propylamino)indan;

[0127] (14) 5-hydroxy-2-(n-propylamino)indan;

[0128] (15) 5,6-dihydroxy-2-(n-propylamino)indan;

[0129] (16) 4-methyl-2-aminoindan;

[0130] (17) 4,5-di-methyl-2-aminoindan;

[0131] (18) 5,6-di-mcthyl-2-amninoindan;

[0132] (19) 6-methyl-2-aminoindan;

[0133] (20) 4-fluoro-2-aminoindan;

[0134] (21) 5-( / -propyl)-2-aminoindan;

[0135] (22) 4,6-dimethyl-2-aminoindan;

[0136] (23) 4,7-dimethyl-2-aminoindan;

[0137] (24) 5-(t-butyl)-2-aminoindan:

[0138] (25) 5-propyl-2-aminoindan;

[0139] (26) 5-fluoro-2-(di-N-propylamino)indan;

[0140] (27) 6-methylenedioxy-2-(di-N-propylamino)indan:

[0141] (28) 5 ,6-dimethoxy-2(pyrrolidino)indan;

[0142] (29) 5,6-(di-carbomethoxy)-2-(di-N-propylamino)indan;

[0143] (30) 5-(carbomethoxy)-6-hydroxy-2-(di-N-propylamino)indan; (31 ) 5-bromo-2-(dipropylamino)indan;

[0144] (32) (6-methylsulfanyl-indan-2-yl)-dipropyl-amine;

[0145] (33) (6-methylsulfonyl-indan-2-yl)-dipropyl-amine;

[0146] (34) (6-methylsulfinyl-indan-2-yl)-dipropyl-amine;

[0147] (35) 2-dipropylamino-indan-5-carbaldehyde;

[0148] (36) (5-iodo-indan-2-yl)-dipropyl-amine;

[0149] (37) (4-iodo-indan-2-yl)-dipropyl-amine;

[0150] (38) toluene-4-sulfonic acid 2-dipropylamino-indan-5-yl ester;

[0151] (39) toluene-4-sulfonic acid 2-dipropylamino-6-hydroxy-indan-5-yl ester;

[0152] (40) N- [2-(benzyl-propylamino)-indan-5-yl]-4-methyl benzene-sulfonamide;

[0153] (41 ) N-[2-(benzyl-propyl-amino)-indan-5-yl]methanesulfonamide;

[0154] (42) 2-[2-(benzyl-propyl--amino)-indan-5-yl] -isoindole-1 ,3-dione;

[0155] (43) benzyl-propyl-(6-pyrrol-1 -yl-indan-2-yl)-amine;

[0156] (44) propyl-(6-pyrrol- 1 -yl-indan-2-yl)-amine;

[0157] (45) propyl-(6-pyrrolidin- 1 -yl-indan-2-yl)-amine;

[0158] (46) dipropyl-(6-pyrrolidin- 1 -yl-indan-2-yl)-amine;

[0159] (47) cyclopropanecarboxylic acid-[2-(benzyl-propyl-amino)-indan-5-yl] acetamide;

[0160] (48) N-[2-(benzyl-propyl-amino)-indan-5-yl]propionamide;

[0161] (49) N-[2-(benzyl-propyl-amino)-indan-5-yl]-2,2-dimethyl propionamide;

[0162] (50) 5-(2-propenyloxy)-2-(di-N-propylamino)-indan;

[0163] (51 ) 5,6 di-toluenesulfonyloxy-2-(di-N-propylamino)indan;

[0164] (52) 5-methanesulfonyloxy-2-(di-N-propylamino)indan ;

[0165] (53) 5-carbomethoxy-2-(di-N-propylamino)indan;

[0166] (54) 5-carboxamido-2-(di-N-propylamino)indan;

[0167] (55) 5,6-di-trifluoromethansulfonyloxy-2-(propylamino)indan;

[0168] (56) 4-methyl-2-(di-N-propylamino)indan;

[0169] (57) 4,5-di-methyl-2-(di-N-propylamino)indan;

[0170] (58) 5,6-di-methyl-2-(di-N-propylamino)indan;

[0171] (59) 5-methyl-2-(di-N-propylamino)indan;

[0172] (60) 4-fluoro-2-(N-propyl)aminoindan ;

[0173] (61 ) 5-(i-propyl)-2-(di-N-propylamino)indan;

[0174] (62) 5-(i-propyl)-2-(N-propylamino)indan ;

[0175] (63) 4, 6-dimethyl-2-(di-N-propylamino)indan;

[0176] (64) 4, 7-dimethyl-2-( di-N-propylamino)indan;

[0177] (65) 5-propyl-2-(di-N-propylamino)indan; (66) 5-(t-butyl)-2-( dim-propylamino)indan;

[0178] (67) 5-trifluoromethyl-2-(di-N-propylamino)indan;

[0179] (68) 5-sulfoxamido-2-(di-N-propylamino)indan;

[0180] (69) 5-(3-thiophene)-2-(di-N-propylamino)indan;

[0181] (70) 5-ethynyl-2-(di-N-propylamino)indan ;

[0182] (71 ) 5-acetyl-2-(di-N-propylamino)indan;

[0183] (72) 5-cyano-2-(di-N-propylamino)indan;

[0184] (73) 5-carbomethoxy-6-acetoxy-2-( di-N-propylamino)indan;

[0185] (74) 5-carbomethoxy-6-trifluoromethanesulfonyloxy-2-(di-N-propylamino)indan;

[0186] (75) 5-carbomethoxy-6-methoxy-2-(di-N-propylamino)indan;

[0187] (76) 5-formyl-6-methoxy-2-(di-N-propylamino)indan :

[0188] (77) 5-hydroxymethyl- 6-methoxy-2-(di-N-propylamino)indan;

[0189] (78) 5-carboxy-6-rnethoxy-2-(di-N-propylamino)indan;

[0190] (79) 5-acetyl-6-methoxy-2-(di-N-propylamino)indan;

[0191] (80) 5-carboxamido-6-methoxy-2-(di-N-propylamino)indan;

[0192] (81 ) 5-ethynyl-6-methoxy-2-(di-N-propylamino)indan:

[0193] (82) 5-cyano-6-methoxy-2-(di-N-propylamino)indan; and

[0194] (83) 5,6-di-(hydroxymethyl-2-(di-N-propylamino)indan.

[0195]

[0095] In some embodiments described herein, the 2-aminoindan derivative represented by Formula I is any one of the compounds (1 )-(13) above, in which the phenyl moiety is substituted by one or two -OCH3, or -OSO2CF3 groups, or in which the phenyl moiety bears a -O(CH2)mO- ring, wherein m is 1 or 2, fused thereto. The structural formulas of compounds (1 )-(13) are depicted in Table 1 below.

[0196]

[0096] Table 1

[0197]

[0198]

[0097] N-acylethanolamines (NAEs) are a type of fatty acid amide, lipid-derived signaling molecules. They are formed when one of several types of acyl groups is linked to the nitrogen atom of ethanolamine. These amides conceptually can be formed from a fatty acid and ethanolamine with the release of a molecule of water, but the known biological synthesis uses a specific phospholipase D to cleave the phospholipid unit from N-acylphosphatidylethanolamines. Examples of N-acylethanolamines include anandamide (the amide of arachidonic acid (20:4 omega-6) and ethanolamine), N- palmitoylethanolamine (the amide of palmitic acid (16:0) and ethanolamine), N- oleoylethanolamine (the amide of oleic acid (18:1 ) and ethanolamine), N- stearoylethanolamine (the amide of stearic acid (18:0) and ethanolamine) and N- docosahexaenoylethanolamine (the amide of docosahexaenoic acid (22:6) and ethanolamine).

[0199]

[0098] Palmitoylethanolamide (PEA, also known as N-(2-hydroxyethyl) hexadecanamide; hydroxyethylpalmitamide; palmidrol; N-palmitoylethanolamine; and palmitylethanolamide) is an example NAE and is an endogenous fatty acid amide, belonging to the class of nuclear factor agonists. The chemical structure of PEA is: o . PEA has been demonstrated to bind to a receptor in the cell nucleus (a nuclear receptor) and exerts a variety of biological functions related to chronic pain and inflammation. Studies have shown that PEA interacts with distinct non- CB1 / CB2 receptors, suggesting that PEA utilizes a unique "parallel" endocannabinoid signaling system. This concept was further supported by growing evidence that PEA production and inactivation can occur independently of AEA and 2-AG production and inactivation. Much of the biological effects of PEA on cells can be attributed to its affinity to PPAR (particularly PPAR-alpha and PPAR-gamma). PEA has been shown to have an affinity to cannabinoid-like G-coupled receptors GPR55 and GPR1 19 as well as the transient receptor potential vanilloid type 1 receptor (TRPV1 ). PEA has been shown to have anti-inflammatory, anti-nociceptive, neuro-protective, and anti-convulsant properties.

[0200] Methods of T reatment

[0201]

[0099] In some embodiments, disclosed herein are methods of losing weight comprising administering to a subject in need thereof a therapeutically effective amount of MEAI or a pharmaceutically acceptable salt thereof for a period of time sufficient to increase basal energy expenditure. In some embodiments, administering the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof promotes caloric burning at rest. In some embodiments, administering the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof promotes caloric burning without increasing physical activity of the subject.

[0202]

[0100] In some embodiments, the therapeutically effective amount of MEAI or a pharmaceutically acceptable salt thereof is administered for a period of time sufficient to increase basal energy expenditure, where the period of time is at least about 5 days, at least about 10 days, at least about 15 days, at least about 20 days, at least about 25 days, at least about 30 days, at least about 45 days, at least about 60 days, at least about 90 days, at least about 120 days, at least about 150 days, at least about 180 days, at least about 210 days, at least about 240 days, at least about 270 days, at least about 300 days, at least about 330 days, or at least about 360 days. In some embodiments, the period of time is at least about 120 days, at least about 150 days, at least about 180 days, at least about 210 days, at least about 240 days, at least about 270 days, at least about 300 days, at least about 330 days, or at least about 360 days.

[0203]

[0101] In some embodiments, the basal energy expenditure is increased by about 10% over a baseline, about 15% over a baseline, about 20% over a baseline, about 25% over a baseline, about 30% over a baseline, about 35% over a baseline, about 40% over a baseline, about 45% over a baseline, or about 50% over a baseline, wherein the baseline is a basal energy expenditure of the subject prior to administering the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof. In some embodiments, the basal energy expenditure is increased by at least about 10% over a baseline, at least about 15% over a baseline, at least about 20% over a baseline, or at least about 25% over a baseline. In some embodiments, the basal energy expenditure is increased by from about 10% to 50% over a baseline, from about 15% to about 50% over a baseline, from about 20% to about 50% over a baseline, or from about 25% to about 50% over a baseline. In some embodiments, the basal energy expenditure is increased by from about 10 to 15% over a baseline. In some embodiments, administering the therapeutically effective amount of MEAI or a pharmaceutically acceptable salt thereof does not alter a period of time that the subject is sedentary compared to a period of sedentary time prior to administering the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof.

[0204]

[0102] In some embodiments, the disclosure also provides preclinical evidence for the efficacy of MEAI in regulating energy metabolism and mitigating obesity and its related metabolic abnormalities. In some embodiments, the disclosure provides a method for treating fatty liver disease, comprising administering to a subject in need thereof a therapeutically effective amount of MEAI or a pharmaceutically acceptable salt thereof. MEAI demonstrates remarkable effectiveness in preventing or alleviating various conditions associated with a metabolic syndrome. In some embodiments, MEAI maintains glucose homeostasis, lower dyslipidemia, and preserves liver function, possibly improves fat utilization and oxidation. In some embodiments, MEAI has potential as a novel therapeutic option for fatty liver disease. In some embodiments, MEAI has potential as a therapy for obesity and its related metabolic disorders.

[0205]

[0103] In some embodiments, administering the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof alters a level of at least one biomarker associated with lipid metabolism. The term “biomarker” as used herein may be understood to mean a level or amount of protein and / or mRNA of a gene associated with lipid metabolism, a level or amount of lipid, a level or amount of cell expression, or any other measurable indicator associated with lipid metabolism. In some embodiments, the at least one biomarker comprises a protein and / or an mRNA level of a gene associated with lipid metabolism. In some embodiments, the at least one biomarker is measured by collecting a liver cell sample from the subject. In some embodiments, the liver cell sample is collected by a liver biopsy, from a serum sample, or any other collection method.

[0206]

[0104] In some embodiments, the gene associated with lipid metabolism is associated with fatty acid oxidation, lipolysis, fatty acid synthesis, or cholesterol metabolism. In some embodiments, the gene associated with lipid metabolism comprises peroxisome proliferator-activated receptor alpha Ppara), cluster of differentiation 36 (Cd36), lipoprotein lipase (Lpl), stearoyl-CoA desaturase 1 (Scd1), acetyl-CoA carboxylase alpha (Acaca), fatty acid synthase (Fasn), fatty acid-binding protein 1 (Fabpl), glucose-6-phosphate dehydrogenase (G6pdx), and / or phosphorylated AMP-activated protein kinase (p-AMPK). In some embodiments, the gene associated with lipid metabolism comprises Cd36.

[0207]

[0105] In some embodiments, administering the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof reduces a level of the at least one biomarker. In some embodiments, administering the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof reduces a level of Ppara, Cd36, Lpl, Scd1 , Acaca, Fasn, Fabpl , or G6pdx compared to a baseline, wherein the baseline is a level of Ppara, Cd36, Lpl, Scd1 , Acaca, Fasn, Fabpl , or G6pdx prior to administering the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof. In some embodiments, the method of treating fatty liver disease further comprises administering a further dose of the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof, if a decrease in a level of Ppara, Cd36, Lpl, Scd1 , Acaca, Fasn, Fabpl , or G6pdx compared to the baseline is observed. In some embodiments, administering the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof reduces a level of the at least one biomarker by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90%, compared to a baseline, wherein the baseline is a level of the at least one biomarker of the subject prior to administering the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof. In some embodiments, administering the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof reduces a level of the at least one biomarker by at least about 10%, at least about 20%, at least about 30%, at least about 40%, or at least about 50% compared to a baseline. In some embodiments, administering the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof reduces a level of the at least one biomarker by from about 10% to about 90%, from about 20% to about 90%, from about 30% to about 90%, from about 40% to about 90%, from about 50% to 90%, from about 10% to about 80%, from about 10% to about 70%, from about 10% to about 60%, or from about 10% to about 50% compared to a baseline. In some embodiments, administering the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof reduces a level of the at least one biomarker by about 40%, about 50%, about 60%, about 70%, or about 80% compared to a baseline. In some embodiments, administering the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof reduces a level of the at least one biomarker by about 60% compared to a baseline.

[0208]

[0106] In some embodiments, administering the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof increases a level of p-AMPK compared to a level of p-AMPK in the subject prior to administering the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof. In some embodiments, the method further comprises administering a further dose of the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof if an increase in a level of p-AMPK is observed. In some embodiments, administering the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof increases a level of p-AMPK by about 40% or about 50% compared to a level of p- AMPK in the subject prior to administering the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof.

[0209]

[0107] In some embodiments, administering the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof reduces a protein level of Fasn or Scd1 by about 40% to 60% compared to a baseline, wherein the baseline is a protein level of Fasn or Scd1 in the subject prior to administering the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof.

[0108] In some embodiments, administering the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof decreases fatty acid oxidation, lipolysis, or fatty acid synthesis in the subject compared to a level prior to administering the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof. In some embodiments, administering the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof decreases fatty acid oxidation, lipolysis, or fatty acid synthesis by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90% relative to a level prior to administering the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof. In some embodiments, administering the therapeutically effect amount of MEAI or pharmaceutically acceptable salt thereof decreases fatty acid oxidation, lipolysis, or fatty acid synthesis by at least about 10%, at least about 20%, at least about 30%, at least about 40%, or at least about 50% relative to a level prior to administering the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof. In some embodiments, administering the therapeutically effect amount of MEAI or pharmaceutically acceptable salt thereof decreases fatty acid oxidation, lipolysis, or fatty acid synthesis by from about 10% to 90%, from about 10% to about 80%, from about 10% to about 70%, from about 10% to about 60%, from about 10% to about 50%, from about 20% to about 90%, from about 30% to 90%, from about 40% to about 90%, or from about 50% to about 90% relative to a level prior to administering the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof.

[0210]

[0109] In some embodiments, the subject has a genetic risk for developing fatty liver disease. The term “genetic risk” as used herein is understood to mean that a subject has a diagnosed or undiagnosed genetic condition that makes the subject more susceptible to developing fatty liver disease. In some embodiments, “genetic risk” is understood to mean that the subject has a relative with fatty liver disease and is at an increased risk of developing fatty liver disease compared to a subject that does not have a family member diagnosed with fatty liver disease. In some embodiments, the subject has a genetic mutation that alters a level of the at least one biomarker associated with lipid metabolism.

[0211]

[0110] In some embodiments, the subject has a risk for developing fatty liver disease wherein the risk is associated with a lifestyle. In some embodiments, the subject has a chronic sedentary lifestyle; chronically consumes a high-fat diet, a high- processed-foods diet, and / or a high-carb diet; chronically consumes excessive amounts of alcohol; and / or is overweight or obese.

[0212]

[0111] In some embodiments, the fatty liver disease comprises metabolic dysfunction-associated steatotic liver disease (MASLD) or alcoholic fatty liver disease.

[0213]

[0112] In some embodiments, the subject has a healthy body weight or healthy body weight index. In some embodiments, the subject has at least one metabolic disorder. In some embodiments, the at least one metabolic disorder results from chronic consumption of a high-fat diet. In some embodiments, the at least one metabolic disorder is selected from obesity, dyslipidemia, diabetes, hyperglycemia, hyperlipidemia, hypercholesterolemia, insulin-resistance, hyperinsulinemia, glucose intolerance, and hepatic steatosis.

[0214]

[0113] In some embodiments, the subject is on a weight loss regimen. In some embodiments, the weight loss regiment comprises a diet regimen, an exercise regimen, a medication, or a combination thereof. In some embodiments, the weight loss regimen alone led to a plateau in weight loss, at least one adverse side effect, or a combination thereof. The term “adverse side effect” in the context of a weight loss regimen is understood to mean an undesired side effect associated with the diet regimen, the exercise regimen, the medication, or a combination thereof. In some embodiments, the adverse side effect comprises gastrointestinal distress, increased heart rate, increased blood pressure, nutrient deficiencies, muscle loss, dizziness, or fatigue. In some embodiments, the gastrointestinal distress comprises nausea, vomiting, diarrhea, or constipation. In some embodiments, the medication comprises a GLP-1 receptor agonist. In some embodiments, the medication comprises metformin.

[0215]

[0114] In some embodiments, the method further comprises administering a second active with the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof. In some embodiments, the second active is an N- acylethanolamine, or a pharmaceutically acceptable salt thereof. In some embodiments, the second active is a GLP-1 receptor agonist.

[0216]

[0115] In some embodiments, the GLP-1 receptor agonist is administered once every 7 days. In some embodiments, the GLP-1 receptor agonist is administered at an amount of from about 0.25 mg to about 2.5 mg. In some embodiments, the GLP-1 receptor agonist comprises semaglutide.

[0217]

[0116] In some embodiments, the GLP-1 receptor agonist is administered once daily. In some embodiments, the GLP-1 receptor agonist is administered at an amount of from about 0.5 mg to about 2 mg. In some embodiments, the GLP-1 receptor agonist comprises liraglutide.

[0218] Pharmaceutical Compositions

[0219]

[0117] In some embodiments, a pharmaceutical composition comprises a therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof comprises from about 0.5-520 mg. In some embodiments, the therapeutically effective amount comprises from about 10 mg to about 520 mg, from about 10 mg to about 450 mg, from about 10 mg to about 400 mg, from about 10 mg to about 350 mg, from about 20 mg to about 350 mg, from about 20 mg to about 300 mg, from about 20 mg to about 250 mg, from about 20 mg to about 200 mg, from about 20 mg to about 175 mg, from about 20 mg to about 150 mg, from about 20 mg to about

[0220] 125 mg, from about 20 mg to about 100 mg, or from about 20 mg to about 50 mg MEAI or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount comprises from about 5 mg to about 520 mg, from about 5 mg to about 450 mg, from about 5 mg to about 400 mg, from about 5 mg to about 350 mg, from about 5 mg to about 300 mg, from about 5 mg to about 250 mg, from about 5 mg to about 200 mg, from about 5 mg to about 175 mg, from about 5 mg to about 150 mg, from about 5 mg to about 125 mg, from about 5 mg to about 100 mg, from about 5 mg to about 50 mg, from about 5 mg to about 25 mg, from about 5 mg to about 20 mg, from about 5 mg to about 15 mg, or from about 5 mg to about 10 mg.

[0221]

[0118] In some embodiments, the pharmaceutical composition is formulated to comprise a therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof determined for a human equivalent dose by referencing a 60 kg human body weight. In some embodiments, the pharmaceutical composition is formulated to comprise a therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof from about 0.0083 mg / kg body weight per day to about 8.67 mg / kg body weight per day, from about 0.042 mg / kg body weight per day to about 8.67 mg / kg body weight per day, from about 0.167 mg / kg body weight per day to about 8.67 mg / kg body weight per day, from about 0.33 mg / kg body weight per day to about 8.67 mg / kg body weight per day, from about 0.33 mg / kg body weight per day to about 4.167 mg / kg body weight per day, from about 0.33 mg / kg body weight per day to about 3.33 mg / kg body weight per day, from about 0.33 mg / kg body weight per day to about 2.92 mg / kg body weight per day, from about 0.33 mg / kg body weight per day to about 2.5 mg / kg body weight per day, from about 0.33 mg / kg body weight per day to about 2.08 mg / kg body weight per day, from about 0.33 mg / kg body weight per day to about 1 .67 mg / kg body weight per day, or from about 0.33 mg / kg body weight per day to about 0.83 mg / kg body weight per day.

[0222]

[0119] In some embodiments, the pharmaceutical composition is formulated to comprise a therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof of at least about 0.0083 mg / kg body weight per day, at least about 0.042 mg / kg body weight per day, at least about 0.167 mg / kg body weight per day to about 8.67 mg / kg body weight per day, at least about 0.33 mg / kg body weight per day, at least about 0.83 mg / kg body weight per day, at least about 1 .67 mg / kg body weight per day, at least about 2.08 mg / kg body weight per day, at least about 2.5 mg / kg body weight per day, at least about 2.92 mg / kg body weight per day, at least about 3.33 mg / kg body weight per day, at least about 4.167 mg / kg body weight per day, or at least about 8.67 mg / kg body weight per day.

[0223]

[0120] In some embodiments, the pharmaceutical composition comprising the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof is administered in conjunction with a therapeutically effective amount of an N- acylethanolamine or a pharmaceutically acceptable salt thereof. In some embodiments, administering a pharmaceutical composition comprising an N-acylethanolamine or a pharmaceutically acceptable salt thereof and separately, concurrently, or simultaneously with a pharmaceutical composition comprising 5-methoxy-2-aminoindan improves the therapeutic potency of the separate, concurrent, or simultaneous administration compared to administering a pharmaceutical composition comprising 5- methoxy-2-aminoindan alone. In some embodiments, a required therapeutic dosage of 5-methoxy-2-aminoindan is decreased when administered with an N-acylethanolamine compared to administering 5-methoxy-2-aminoindan alone.

[0224]

[0121] In some embodiments, the molar ratio between the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof and the therapeutically effective amount of N-acylethanolamine or pharmaceutically acceptable salt thereof is from about 1 :0.2 and about 1 :2000. In some embodiments, the molar ratio between the therapeutically effective amount of MEAI and the N-acylethanolamine is from about 1 :0.2 to about 1 :1900, from about 1 : 0.2 to about 1 :1800, from about 1 : 0.2 to about 1 :1700, from about 1 : 0.2 to about 1 :1600, from about 1 : 0.2 to about 1 :1500, from about 1 : 0.2 to about 1 :1400, from about 1 : 0.2 to about 1 :1300, from about 1 : 0.2 to about 1 :1200, from about 1 :0.2 to about 1 :1100, from about 1 :0.2 to about 1 :1000, from about 1 :0.2 to about 1 :900, from about 1 : 0.2 to about 1 :800, from about 1 : 0.2 to about 1 :700, from about 1 : 0.2 to about 1 :600, from about 1 : 0.2 to about 1 :500, from about 1 : 0.2 to about 1 :400, from about 1 : 0.2 to about 1 :300, from about 1 : 0.2 to about 1 :200, from about 1 :0.2 to about 1 :100, from about 1 : 0.2 to about 1 :50, from about 1 :0.2 to about 1 :40, from about 1 :0.2 to about 1 :30, from about 1 :0.2 to about 1 :20, from or about 1 :0.2 to about 1 :10.

[0225]

[0122] In some embodiments, the molar ratio between the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof and the N- acylethanolamine or pharmaceutically acceptable salt thereof is from about 1 :0.5 to about 1 :2000. In some embodiments, the molar ratio between the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof and the N- acylethanolamine or pharmaceutically acceptable salt thereof is from about 1 :0.5 to about 1 :1000, from about 1 : 0.5 to about 1 :900, from about 1 : 0.5 to about 1 :800, from about 1 : 0.5 to about 1 :700, from about 1 : 0.5 to about 1 :600, from about 1 : 0.5 to about 1 :500, from about 1 : 0.5 to about 1 :400, from about 1 : 0.5 to about 1 :300, from about 1 : 0.5 to about 1 :200, from about 1 :0.5 to about 1 :100, from about 1 : 0.5 to about 1 :50, from about 1 :0.5 to about 1 :40, from about 1 :0.5 to about 1 :30, from about 1 :0.5 to about 1 :20, or from about 1 :0.5 to about 1 :10.

[0226]

[0123] In some embodiments, the pharmaceutical composition comprises about 200-1800 mg N-acylethanolamine or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 250-1550 mg, about 300-1200 mg, about 350-950 mg, about 400-700 mg, about 450-600 mg or about 500-550 mg N-acylethanolamine or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises at least about 50 mg, at least about 100 mg, at least about 150 mg, at least about 200 mg, at least about 250 mg, at least about 300 mg, at least about 350 mg, at least about 400, at least about 450 mg, at least about 500 mg, at least about 550 mg, at least about 600 mg, at least about 650 mg, at least about 700 mg, at least about 750 mg, at least about 800 mg, at least about 850 mg, at least about 900 mg, at least about 950 mg, at least about 1000 mg, at least about 1050 mg, at least about 1100 mg, at least about 1150 mg, at least about 1200 mg, at least about 1250 mg, at least about 1300 mg, at least about 1350 mg, at least about 1400 mg, at least about 1450 mg, at least about 1500 mg, at least about 1550 mg, at least about 1600 mg, at least about 1650 mg, at least about 1700 mg, at least about 1750 mg or at least about 1800 mg N-acylethanolamine or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg or about 1800 mg N-acylethanolamine or a pharmaceutically acceptable salt thereof.

[0227]

[0124] In some embodiments, the pharmaceutical composition comprising MEAI also comprises a concentration of N-acylethanolamine or pharmaceutically acceptable salt thereof sufficient to provide a patient with a dose of the N-acylethanolamine or a pharmaceutically acceptable salt thereof of about 2.5 mg / kg / day to about 36 mg / kg / day body weight. In some embodiments, the pharmaceutical composition comprises a concentration of N-acylethanolamine or pharmaceutically acceptable salt thereof sufficient to provide a patient with a dose of about 2.5 to about 5 mg / kg / day, about 5 mg / kg / day to about 7.5 mg / kg / day, about 7.5 mg / kg / day to about 10 mg / kg / day, about 10 mg / kg / day to about 12.5 mg / kg / day, about 12.5 mg / kg / day to about 15 mg / kg / day, about 15 mg / kg / day to about 17.5 mg / kg / day, about 17.5 mg / kg / day to about 20 mg / kg / day, about 20 mg / kg / day to about 22.5 mg / kg / day, about 22.5 mg / kg / day to about 25 mg / kg / day, about 25 mg / kg / day to about 27.5 mg / kg / day, about 27.5 mg / kg / day to about 30 mg / kg / day, about 30 mg / kg / day to about 32.5 mg / kg / day, about

[0228] 32.5 mg / kg / day to about 36 mg / kg body weight / day. In some embodiments, the pharmaceutical composition comprises a concentration of N-acylethanolamine or pharmaceutically acceptable salt thereof sufficient to provide a patient with a dose of N- acylethanolamine or a pharmaceutically acceptable salt thereof of about 2.5 mg / kg / day, about 5 mg / kg / day, about 7.5 mg / kg / day, about 10 mg / kg / day, about 12.5 mg / kg / day, about 15 mg / kg / day, about 17.5 mg / kg / day, about 20 mg / kg / day, about 22.5 mg / kg / day, about 25 mg / kg / day, about 27.5 mg / kg / day, about 30 mg / kg / day, about 32.5 mg / kg / day, or about 36 mg / kg bodyweight / day. In some embodiments, the pharmaceutical composition comprises a concentration of N-acylethanolamine or pharmaceutically acceptable salt thereof sufficient to provide a patient with a dose of N-acylethanolamine or a pharmaceutically acceptable salt thereof of about 2.5 mg / kg / day, less than about

[0229] 2.5 mg / kg / day, less than about 5 mg / kg / day, less than about 7.5 mg / kg / day, less than about 10 mg / kg / day, less than about 12.5 mg / kg / day, less than about 15 mg / kg / day, less than about 17.5 mg / kg / day, less than about 20 mg / kg / day, less than about 22.5 mg / kg / day, less than about 25 mg / kg / day, less than about 27.5 mg / kg / day, less than about 30 mg / kg / day, less than about 32.5 mg / kg / day, or about 36 mg / kg bodyweight / day. In some embodiments, the pharmaceutical composition comprises a concentration of N-acylethanolamine or pharmaceutically acceptable salt thereof sufficient to provide a patient with a dose of N-acylethanolamine or a pharmaceutically acceptable salt thereof of about 2.5 mg / kg / day to about 5 mg / kg / day, about 2.5 mg / kg / day to about 7.5 mg / kg / day, about 2.5 mg / kg to about 10 mg / kg / day, about 2.5 mg / kg / day to about 12.5 mg / kg / day, about 2.5 mg / kg / day to about 15 mg / kg / day, about 2.5 mg / kg / day to about 17.5 mg / kg / day, about 2.5 mg / kg / day to about 20 mg / kg / day, about 2.5 mg / kg / day to about 22.5 mg / kg / day, about 2.5 mg / kg / day to about 25 mg / kg / day, about 2.5 mg / kg / day to about 27.5 mg / kg / day, about 2.5 mg / kg / day to about 30 mg / kg / day, about 2.5 mg / kg / day to about 32.5 mg / kg / day, or about 2.5 mg / kg / day to about 36 mg / kg body weight / day.

[0230]

[0125] In some embodiments, the therapeutically effective amount of the N- acylethanolamine or pharmaceutically acceptable salt thereof comprises from about 2.86 mg / kg body weight per day to about 25.71 mg / kg body weight per day, from about

[0231] 3.57 mg / kg body weight per day to about 22.14 mg / kg body weight per day, from about

[0232] 4.29 mg / kg body weight per day to about 17.14 mg / kg body weight per day, from about

[0233] 5.0 mg / kg body weight per day to about 13.57 mg / kg body weight per day, from about 5.71 mg / kg body weight per day to about 11 .43 mg / kg body weight per day, from about

[0234] 6.43 mg / kg body weight per day to about 10.71 mg / kg body weight per day, or from about 7.14 mg / kg body weight per day to about 8.57 mg / kg body weight per day.

[0235]

[0126] In some embodiments, the therapeutically effective amount of the MEAI or pharmaceutically acceptable salt thereof and / or the N-acylethanolamine or pharmaceutically acceptable salt thereof are formulated in a pharmaceutical composition further comprising at least one pharmaceutically acceptable carrier and / or excipient. In some embodiments, the pharmaceutical composition is a free-flowing powder, a tablet, a capsule, a lozenge, a liquid, a liquid concentrate, suspension, or a syrup. In some embodiments, the pharmaceutical composition is a unit dosage form composition.

[0236]

[0127] In some embodiments, the N-acylethanolamine is N- palmitoylethanolamine (PEA), Me-palmitoylethanolamide (Me-PEA), palmitoylcyclohexamide, palmitoylbutylamide, oleoylethanolamine (OEA), palmitoylisopropylamide (PIA), or pharmaceutically acceptable salts thereof, or any combination thereof. In some embodiments, the N-acylethanolamine is PEA or a pharmaceutically acceptable salt thereof. In some embodiments, the N- acylethanolamine consists of PEA or a pharmaceutically acceptable salt thereof. In some embodiments, the N-acylethanolamine consists of PEA.

[0237]

[0128] In some embodiments, the pharmaceutical composition is formulated for systemic administration. In some embodiments, the pharmaceutical composition is formulated for oral, oral mucosal, nasal, sublingual, inhalational, topical, rectal, vaginal, parenteral, intravenous, intramuscular, or subcutaneous administration. In certain embodiments, the pharmaceutical composition is formulated for oral, oral mucosal, nasal, or sublingual administration. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated for oral mucosal administration. In some embodiments, the pharmaceutical composition is formulated for nasal administration. In some embodiments, the pharmaceutical composition is formulated for sublingual administration.

[0238]

[0129] The present disclosure further provides, in another aspect, a dosage unit comprising or consisting of the pharmaceutical composition described above.

[0239]

[0130] In some embodiments, the dosage unit comprises the pharmaceutical composition described above. In some embodiments, the dosage unit consisting of the pharmaceutical composition described above. In some embodiments, the dosage unit is formulated as a gel, a powder, or a spray. In some embodiments, the dosage unit is formulated as a gel. In some embodiments, the dosage unit is formulated as a powder. In some embodiments, the dosage unit is formulated as a spray.

[0240] Toxicity and Therapeutic Efficacy

[0241]

[0131] Toxicity and therapeutic efficacy can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50 / ED50. Compositions that exhibit large therapeutic indices are preferable.

[0242]

[0132] Data obtained from cell culture assays or animal studies can be used in formulating a range of dosage for use in humans. Therapeutically effective dosages achieved in one animal model may be converted for use in another animal, including humans, using conversion factors known in the art (see, e.g., Freireich et al., Cancer Chemother. Reports 50(4):219-244 (1966) and Table 2 for Equivalent Surface Area Dosage Factors). Table 2. Equivalent Surface Area Dosage Factors.

[0243]

[0133] The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. Generally, a therapeutically effective amount may vary with the subject's age, condition, and gender, as well as the severity of the medical condition in the subject. The dosage may be determined by a physician and adjusted, as necessary, to suit observed effects of the treatment.

[0244]

[0134] One skilled in the art will recognize that, both in vivo and in vitro trials using suitable, known and generally accepted cell and / or animal models are predictive of the ability of a test compound to treat or prevent a given disorder.

[0245]

[0135] One skilled in the art will further recognize that human clinical trials including first-in-human, dose ranging and efficacy trials, in healthy patients and / or those suffering from a given disorder, may be completed according to methods well known in the clinical and medical arts.

[0246]

[0136] While the present disclosure has been described with reference to some embodiments, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the scope of the present disclosure. In addition, many modifications may be made to adapt a particular situation or material to the teachings of the present disclosure without departing from its scope. Therefore, it is intended that the present disclosure is not limited to the particular embodiment disclosed, but that the present disclosure will include all embodiments falling within the scope of the appended claims.

[0247]

[0137] The following examples are presented to more fully illustrate some embodiments of the disclosure. It should in no way be construed, however, as limiting the broad scope of the disclosure. EXAMPLES

[0248] ABBREVIATIONS

[0249]

[0138] The following is a list of abbreviations included in the disclosure:

[0250] SPF Specific pathogen-free

[0251] HFD High fat diet

[0252] DIO Diet induced obesity

[0253] STD Standard laboratory diet

[0254] MEAI 5-methoxy-2-aminoindan

[0255] RER Respiratory Exchange Rate

[0256] TEE Total energy expenditure

[0257] EE Energy expenditure

[0258] AEE Active energy expenditure

[0259] HOMA-IR Homeostasis model assessment insulin resistance

[0260] BUN Blood urea nitrogen

[0261] 5-HT2B 5-Hydroxytryptamine receptor 2B

[0262] ANCOVA Analysis of Covariance

[0263] Example 1 : 5-Methoxy-2-aminoindane (MEAI) Anti-obesity Effect METHODS

[0264]

[0139] Mice. The experimental protocol used was approved by the Institutional Animal Care and Use Committee of the Hebrew University, which is an AAALAC International accredited institute. Male 6-week-old C57BL / 6 mice were obtained from Envigo. Animal studies were conducted in compliance with the ARRIVE guidelines, which aim to improve the transparency and reproducibility of preclinical research. The principle of replacement, refinement, or reduction was followed to minimize the number of animals used in this study. All the animals were housed in specific pathogen-free (SPF) conditions, with no more than five animals of the same gender and dose group per cage, in standard plastic cages, with natural soft sawdust provided as bedding.

[0265]

[0140] Male 6-week-old C57BL / 6 mice (Envigo, Israel) were maintained under a 12-h light / dark cycle and fed ad libitum. A total of 32 animals were divided into four experimental groups (N=8 mice per group) receiving single doses of 40, 60, or 100 mg / kg of MEAI or vehicle (sterile water), which was administered via oral gavage two hours prior to the dark phase. The animals were monitored for 48 hours post-dose for drug tolerability, food and water intakes as well as activity and metabolic parameters. At the end of the experiment, the animals were euthanized, and tissues (brain, liver, fat, and kidney) and blood were collected and stored frozen for future analyses. To generate diet-induced obesity, C57BI6 / J mice were fed either a high-fat diet (HFD) (60% of calories from fat, 20% from protein, and 20% from carbohydrates; Research Diet, D12492) or a standard laboratory diet (STD, 14% fat, 24% protein, 62% carbohydrates; NIH-31 rodent diet) for 18 weeks.

[0266]

[0141] Effect of MEAI on Obesity. Male C57BL / 6 mice were used to establish DIO by feeding them a high-fat diet (HFD; 60% Kcal fat, 20% Kcal protein, and 20% Kcal carbohydrates; Research Diet, D12492) for 18 weeks. After this period, mice were treated with either vehicle (sterile water, N=8) or MEAI (N=1 1 ) daily for 28 days by gavage at a dose of 40 mg / kg / day. Age-matched control mice (N=10) on a standard diet (STD; 14% Kcal fat, 24% Kcal protein, 62% Kcal carbohydrates; NIH-31 rodent diet) and received vehicle daily. The body weight of all mice was monitored daily, and total body fat and lean mass were determined by EchoMRI-100H™ (Echo Medical Systems LLC, Houston, TX, USA). On Day 29, at the end of the experimental period, mice were euthanized by a cervical dislocation under anesthesia. The kidneys, brain, liver, and fat pads were removed and weighed, and samples were either snap-frozen or fixed in buffered 4% formalin. Trunk blood was collected to determine biochemical parameters.

[0267]

[0142] Sucrose Preference Test. Thirteen-week-old male C57BL / 6 mice maintained on a STD and housed individually were habituated to two water bottles in their home cage for 48 h prior to the test. Baseline intake was measured by weighing the bottles. On the test day (Day 1 ), 2 h before the onset of the dark phase, fresh water and a 1 .5% sucrose solution were added to the bottles, and mice were subsequently treated orally with MEAI (40 mg / kg, N = 8) or sterile water (N = 8). The mice were allowed to drink from either bottle freely for 24 h, after which the bottles were weighed to measure consumption. The study was repeated for an additional day (Day 2), with the bottles switched in position (in the cage) to account for side preference. The sucrose and water intake over the two days were averaged, and the sucrose preference index was calculated as the average consumed sucrose solution divided by the average volume of total consumed liquid (average water plus average sucrose solution).

[0268]

[0143] Multi-parameter metabolic assessment. The metabolic profiles and food and water intakes of the mice were assessed by using the Promethion High-Definition Behavioral Phenotyping System (Sable Instruments, Inc., Las Vegas, NV, USA). Data acquisition and instrument control were performed using MetaScreen software version 2.2.18.0, and the obtained raw data were processed using ExpeData version 1 .8.4 using an analysis script detailing all aspects of data transformation. Mice with free access to food and water, housed at temperatures of (22-23qC) were subjected to a standard 12 h light / 12 h dark cycle, which consisted of a 48 h acclimation period followed by 24 h of sampling. Respiratory gases were measured by using the GA-3 gas analyzer (Sable Systems, Inc., Las Vegas, NV, USA) using a pull-mode, negative pressure system. Air flow was measured and controlled by FR-8 (Sable Systems, Inc., Las Vegas, NV, USA), with a set flow rate of 2000 mL / min. Water vapor was continuously measured and its dilution effect on O2 and CO2 was mathematically compensated. Respiratory exchange rate (RER) was calculated as the ratio of CO2 produced (VCO2) to O2 consumed (VO2) using Equation (1 ):

[0269] RER = VCO2 / VO2(1 )

[0270]

[0144] Total energy expenditure (TEE) was calculated using VO2 and RER, according to Equation (2):

[0271] TEE = VO2 x (3.815 + 1 .232 x RER) (2)

[0272]

[0145] Fat oxidation (FO) and carbohydrate oxidation (CHO) were calculated using VO2 and VCO2 based on Equations (3) and (4), respectively:

[0273] FO = 1 .69 x VO2 - 1 .69 x VCO2 (3) CHO = 4.57 x VCO2 - 3.23 x VO2 (4)

[0274]

[0146] Energy balance and Energy flux were derived from Equations (5) and (6):

[0275] Energy balance = TEE - Food intake (kcal) (5) Energy flux = TEE + Food intake (kcal) (6)

[0276]

[0147] The thermic effect of food for each animal was calculated based on its individual food intake in a period of 24 hours according to the specific percentage of carbohydrates, fats, and proteins in the consumed diet. The basal energy expenditure was calculated based on the mean energy expenditure (EE) during the lowest EE in a 30-minute period, in kilocalorie per hour (kcal / hr). This calculated represented the animal’s basal metabolic rate.

[0277]

[0148] The activity energy expenditure was calculated based on equation (7): Activity energy expenditure (AEE) = TEE - (Basal energy expenditure + thermic effect of food) (7)

[0278]

[0149] Wheel running and locomotive activity. The assessment of wheel running and locomotor activity was performed using the Promethion High-Definition Behavioral Phenotyping System (Sable Instruments, Inc., Las Vegas, NV, USA). Wheel revolutions were measured with a monitor that recorded voluntary wheel running activity, and locomotor activity was quantified using disruptions of infrared XYZ beam arrays, with a beam spacing of 0.25 cm. Pedestrian locomotion represented the sum of all directed ambulatory locomotion within the beam break system, using a speed cut off of 1 cm / s. Total distance represented the sum of all distances traveled within the beam break system, not including any distance run on the wheel in meters (m). This included fine movements (such as grooming and scratching).

[0279]

[0150] Glucose Tolerance Test (IpGTT) and the Insulin Tolerance Test (IpITT). On day 25 of the experiment, mice were subjected to an overnight fasting and then injected with glucose (1 .5 g / kg i.p.) on the following day (day 26). Blood glucose levels were determined at 0, 15, 30, 45, 60, 90, and 120 min after injection using the Contour® glucometer (Bayer, Pittsburgh, PA, USA). The mice were then fasted for 6 h on the next day (day 27) before being administered insulin (0.75 U / kg, i.p.; Actrapid vials, Novo Nordisk A / S, Bagsvaerd, Denmark). Blood glucose levels were determined at the same intervals as described above. To assess insulin resistance, the homeostasis model assessment insulin resistance (HOMA-IR) was calculated as fasting serum insulin ([pU / mL] x fasting plasma glucose [mmol / L] / 22.5). The relative insulin sensitivity index (ISI) was calculated as 1 / (glucose x insulin) x 1000, with glucose expressed as mg / dL and insulin as mU / L.

[0280]

[0151] Blood and urine biochemistry. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), cholesterol, triglycerides, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) were determined by using the Cobas C-1 11 chemistry analyzer (Roche, Switzerland). Blood urea nitrogen (BUN) was calculated based on serum urea levels as follows: BUN (mg / dL) = Urea (mg / dL) / 2.1428. Fasting blood glucose was measured using the Contour® glucometer (Bayer, Pittsburgh, PA). Serum insulin was determined using an Ultra-Sensitive Mouse Insulin ELISA kit (Crystal Chem, Inc., Elk Grove Village, IL, USA). Serum free fatty acid content was determined using a Free Fatty Acid Assay Kit (Cat #ab65341 , Abeam, Cambridge, UK). Serum leptin (Cat # EZML-82K, MilliporeSigma, Burlington, MA, USA), serotonin (Cat # ab133053, Abeam, Cambridge, UK), and adpidonectin (Cat # 80569, Crystal Chem, Inc., Elk Grove Village, IL, USA) levels were quantified by ELISAs.

[0281]

[0152] Hepatic T riglyceride and Cholesterol Content. Liver tissue was extracted as described in (Tam et aL, 2012), and its cholesterol and triglycerides contents were determined using a Cobas C-11 1 chemistry analyzer (Roche, Switzerland).

[0153] Histopathology. First, 5 pm paraffin-embedded liver sections from 5 animals per group were stained with hematoxylin-eosin staining. Liver images were captured using a Zeiss Axio Scope A1 light microscope (Carl Zeiss AG, Jena, Germany equipped with a Zeiss AxioCam ICc5 color camera. Ten random 40x fields of view were taken from each animal to obtained representative images.

[0282]

[0154] Oil Red O staining. Liver cryosections (8 pm) were stained with Oil Red O (Cat# ab150678; Abeam, Cambridge, UK) following the manufacturer’s protocol. Images were acquired as described above. For quantitative analysis of Oil Red O staining, the area of lipid droplets in the liver cryosections was measured using the Imaged software.

[0283]

[0155] Ligand binding assays. MEAI at 0.1 M was tested in ligand binding assays at Eruofins Inc. as described previously (Bender, et aL, “Identification of Potent, Selective, and Peripherally Restricted Serotonin Receptor 2B Antagonists from a High- Throughput Screen,” Assay Drug Dev. TechoL 2023, 21 (3) 89-96). Compound binding was calculated as a % inhibition of the binding of a ligand specific for each target. Results showing an inhibition or stimulation higher than 50% are considered to represent significant effects of MEAI. In each experiment, and if applicable, the respective reference compound was tested concurrently with MEAI, and the data were compared with historical values determined at Eurofins. The experiment was accepted in accordance with Eurofins validation Standard Operating Procedure.

[0284]

[0156] 5-HT2B-Calcium Influx Assay. This assay was performed using the screening services of Eurofins. Evaluation of the agonistic activity of MEAI at the human 5-HT2B receptor expressed in BA / F3 cells was determined by measuring its effect on cytosolic Ca2+ ion mobilization using a fluorimetric detection method. The cells were suspended in HBSS buffer (Invitrogen) complemented with 20 mM Hepes and then distributed in microplates at a density of 5 x 104 cells / well. The fluorescent probe (Fluo8, AAT Bioquest, San Francisco, CA) mixed with probenicid in HBSS buffer (Invitrogen) complemented with 20 mM Hepes (Millipore, Burlington, MA) (pH 7.4) was then added into each well and equilibrated with the cells for 60 min at 30 °C. Thereafter, the assay plates were positioned in a microplate reader (FlipR Tetra, Molecular Devices, San Jose, CA), which was used for the addition of the test compound, reference agonist or HBSS buffer (basal control), and for the measurements of changes in fluorescence intensity that varies proportionally to the free cytosolic Ca2+ ion concentration. For stimulated control measurements, serotonin at 0.25 pM was added in separate assay wells. The results were expressed as a percent of the control response to serotonin at 0.25 pM. The standard reference agonist was serotonin, which was tested in each experiment at several concentrations to generate a concentrationresponse curve from which its EC50 value was calculated.

[0285]

[0157] Western Blotting. Liver samples were prepared in a RIPA buffer (25 mM Tris-HCI pH 7.6, 150 M NaCI, 1% NP-40, 1% sodium deoxycholate, 0.1% SDS), the homogenates were prepared by using the BulletBlender® and zirconium oxide beads (Cat # ZROB10, Next Advanced, Inc., NY, USA). Protein concentrations were measured with the Pierce™ BCA Protein Assay Kit (Cat # 23225, Thermo Scientific, IL, USA). Samples were resolved by SDS-PAGE (4-15% acrylamide, 150V), and transferred to PVDF or nitrocellulose membranes using the Trans-Blot® Turbo™ Transfer System (Bio-Rad, CA). Membranes were then incubated for 1 h in 5% milk (in 1 x TBS-T) to block unspecific binding. Membranes were incubated overnight with cluster of differentiation 36 (CD36; Abeam, Cambridge, UK; Cat# ab252922), stearoyl-CoA desaturase 1 (SCD1 ; Cell Signalling Technology, Danvers, MA; Cat# 2794S), fatty acid synthase (FASN; Cell Signaling Technology, Danvers, MA, USA; Cat# 3180S), 5'- adenosine monophosphate (AMP)-activated protein kinase alpha (AMPKa; Cell Signaling Technology, Danvers, MA, USA; Cat# 2532S), phosphorylated-AMPKa (Cell Signaling Technology, Danvers, MA, USA; Cat# 2535S), acetyl-CoA carboxylase (ACC; Cell Signaling Technology, Danvers, MA, USA; Cat# 3662S), and phosphorylated-ACC (Cell Signaling Technology, Danvers, MA, USA; Cat# 3661 S) antibodies at 4 °C. Anti- rabbit / mouse horseradish peroxidase (HRP)-conjugated secondary antibodies were used for 1 h at room temperature, followed by chemiluminescence detection using Clarity™ Western ECL Blotting Substrate (Bio-Rad, CA). Densitometry was quantified using ImageJ software. Quantification was normalized to anti-p actin antibody (Abeam, Cambridge, UK; Cat# ab49900), or valosin-containing protein (VCP) (Abeam, Cambridge, UK; Cat# ab204290).

[0286]

[0158] Real-time PCR. mRNA from livers was extracted using a Bio-Tri RNA lysis buffer (Bio-Lab, Israel), followed by DNase I treatment (Thermo Scientific, IL, USA), and reverse transcribed using the qScript cDNA Synthesis kit (Quantabio, Beverly, MA, USA). Real-time PCR was performed using iTaq Universal SYBR Green Supermix (Bio-Rad, CA, USA) and the CFX connect ST system (Bio-Rad, CA, USA). A list of primers is provided in Table 3.

[0287] Table 3. Real-Time PCR Primer Sequences

[0288]

[0159] Statistics. The data are presented as mean ± SEM. Statistical analysis was conducted using GraphPad Prism 6.0 software (GraphPad Software, CA, USA). Differences between the two groups were determined using an unpaired two-tailed Student’s t-test. For comparisons involving multiple groups and time-dependent variables, ANCOVA was employed, followed by Tukey’s multiple comparisons test. Statistical significance was considered when p-values were less than 0.05. The EE ANCOVA analysis done for this work was provided by the NIDDK Mouse Metabolic Phenotyping Centers (MMPC; www.mmpc.org) using their Energy Expenditure Analysis page (http: / / www.mmpc.org / shared / regression.aspx) and supported by grants DK076169 and DK1 15255 (Table 4).

[0289]

[0160] Table 4. Energy Expenditure Adjusted for Lean Mass Using ANCOVA

[0290] RESULTS

[0291]

[0161] To assess the immediate effects of MEAI on food intake patterns and respirometric parameters, a single dose of 40, 60, or 100 mg / kg was administered two hours prior to the onset of the dark phase, as depicted in FIG. 1 A. The results indicated that the drug was well-tolerated, with no observable changes in behavior at the 40 and 60 mg / kg dosages. However, two subjects in the 100 mg / kg group died within a few hours of the drug administration, suggesting reduced tolerance at this dose in combination with the stress caused by metabolic testing, and thus they were excluded from the analysis. Minor changes in feeding patterns were observed during the active (dark) and inactive (light) phases following MEAI administration, but these changes did not reach statistical significance (FIGs. 1 B and 1 C). Moreover, there were no notable changes in water consumption (FIGs. 1 D and 1 E). In contrast to food intake, acute MEAI administration resulted in significant changes in metabolic parameters. Doses of 60 and 100 mg / kg markedly increased the respiratory exchange ratio (RER) during the light phase (FIG. 1 F), indicating a shift towards carbohydrate utilization. This finding was aligned with increased rates of oxygen consumption (VO2) and carbon dioxide emission (VCO2) (as demonstrated in FIGs. 1G and 1H). Across the 24-hour period examined, significant dose-dependent increases in hourly average energy expenditure levels (TEE / hr) were observed, culminating in significant elevation in total daily TEE, particularly at the 60 mg / kg dose (FIGs. 11 and 1 J). Acute MEAI administration did not lead to immediate changes in energy balance (FIG. 1 K). Furthermore, elevations in fat oxidation (FO) and carbohydrate oxidation (CHO) rates (FIGs. 1 L and 1M) were evident, suggesting a shift in the body's fuel preference towards both carbohydrates and fats at higher doses. Overall, these findings demonstrate that MEAI has the potential to acutely increase energy expenditure and promote changes in substrate utilization in mice.

[0292]

[0162] Next, the acute impact of MEAI on patterns on activity was investigated. Overall, there were no significant changes in the total number of beam breaks recorded, which represents the combination of ambulatory and fine movements (FIG. 2A). Notably, MEAI produced a significant and dose-dependent increase in directed voluntary activity and speed, such as moving around the cage for feeding, drinking, and grooming, at doses of 40 mg / kg and above (FIGs. 2B and 2C). This targeted activity, encompassing movements associated with feeding, drinking, and grooming, showed a clear rise at doses of 40 mg / kg and above. Notably, the 60 mg / kg dose produced a significant increase in pedestrian speed (FIG. 2C). Furthermore, the average and total distance traveled within the cage displayed a significant elevation across all doses (FIG. 2D), suggesting an overall increase in movement. Interestingly, MEAI did not significantly affect the sum of voluntary wheel running activity at any dose tested (FIG. 2E). Finally, a modest insignificant rise in activity-specific energy expenditure was observed following MEAI administration (FIG. 2F). These findings further support the potential of MEAI to impact energy balance.

[0293]

[0163] To assess the impact of MEAI on sweet taste preference, a sucrose preference test (SET), a commonly used reward-based test to detect anhedonia, was employed. Following a single injection, MEAI at a dosage of 40 mg / kg significantly reduced the acute preference of mice for sucrose solution, without any accompanying decrease in water intake levels. This effect was most evident during the initial 24-hour period, with a slight reduction noted during the subsequent 24-hour period (FIG. 3). These results indicate that MEAI has the potential to impede reward-stimuli, leading to decreased hedonic effects that are typically associated with palatable food.

[0294]

[0164] The impact of MEAI on food addiction behavior and the metabolic efficacy of MEAI in regulating appetite, treating obesity, and related abnormalities was assessed in a DIO mouse model (FIG. 4A). To evaluate the effects of chronic exposure and to ensure a balance between efficacy and minimizing potential side effects, a sub-optimal dose of 40 mg / kg / day of MEAI was tested in this model. At baseline prior to drug treatment, the mice fed with a HFD exhibited significantly greater weight compared to the control group fed with STD. Over the 28 days treatment period, MEAI treatment significantly reduced the body weight of HFD-fed mice (FIG. 4B), resulting in an approximate 15% decrease in total body weight compared to the obese vehicle-treated group (FIGs. 4C and 4D). Therefore, the overweight of mice on HFD was significantly reduced by MEAL Additionally, MEAI treatment reduced adiposity associated with obesity in the DIO model, preserved the lean body mass, the lean body mass ratio, and net lean mass (FIGs. 4E and 4F), while simultaneously reducing the overall fat mass (FIGs. 4G and 4H). Next, the effect of MEAI treatment on key metabolic hormones was evaluated. Notably, MEAI administration effectively countered the HFD-induced elevation in circulating leptin levels (FIG. 41). This suggests that MEAI may mitigate hyperleptinemia-induced leptin resistance, promoting feelings of fullness. In contrast, MEAI treatment did not significantly alter serum serotonin levels (FIG. 4J), both the HFD-vehicle and MEAI-treated groups displayed lower serotonin levels compared to lean mice on a STD, while a trend toward elevation in serotonin levels were observed in the MEAI-treated group.

[0295]

[0165] Mice consuming the HFD displayed altered feeding patterns, regardless of MEAI treatment. They exhibited a significant reduction in meal size, as evidenced by a decrease in food intake per meal (FIG. 5A). This suggests a potential dampening of appetite in response to the HFD. However, this reduced meal size was counterbalanced by the inherently higher caloric density of the HFD, resulting in similar total food intake over a 24-hour period across all groups (FIG. 5B). Notably, the thermic effect of food, which reflects the energy expended during digestion and absorption, also remained unchanged between groups (FIG. 5C). Consistent with the previous observations in lean animals under acute conditions (FIG. 1 D), MEAI administration did not exert any significant influence on water consumption in DIO mice (FIG. 5D).

[0296]

[0166] Metabollicaly, the RER was slightly decreased in both the HFD vehicle and MEAI-treated groups in comparison to the STD vehicle group (FIG. 5E). MEAI administration slightly increased the oxygen consumption and carbon dioxide production compared to the HFD vehicle-treated group (FIGs. 5F and 5G). Notably, the MEAI- treated group showed a significant increase in the average energy expenditure compared to both the HFD and STD vehicle-treated groups, with a clear elevation observed during both light and dark phases (FIG. 5H), culminating in increases in cumulative TEE, suggesting a sustained effect on metabolism (FIG. 5H). Importantly, ANCOVA analysis using lean mass as a covariant revealed that these significant differences in TEE were treatment-dependent (p=0.0097 vs. HFD-vehicle) that would otherwise not be apparent when using total mass as a covariate (FIG. 51, Table 3). While no significant changes in overall energy balance were detected across the groups (FIG. 5J), MEAI treatment did influence substrate utilization, demonstrating a significant increase in energy flux compared to vehicle groups (FIG. 5K), suggesting heightened metabolic activity. In addition, MEAI significantly boosted basal energy expenditure (FIG. 5L), potentially promoting calorie burning even at rest. Furthermore, MEAI treatment led to an increase in the overall rate of FO compared to both the HFD- and STD-vehicle-treated groups (FIG. 5M). This aligns with the observed decrease in RER and suggests MEAI may promote the use of fat for energy. However, CHO was markedly reduced in both the vehicle and MEAI-treated groups, with no effect of the drug itself (FIG. 5N).

[0297]

[0167] Analysis of locomotive activity indicated that MEAI treatment significantly increased voluntary ambulatory behaviors such as pedestrian activity and grooming. This effect was more prominent during the dark phase of the day, consistent with mice’s nocturnal nature (FIG. 6A). Interestingly, while MEAI treatment increased pedestrian locomotive activity, speed, and total distance travelled compared to the HFD-vehicle treated group, MEAI did not surpass the levels of the STD-vehicle treated group. This suggests that MEAI enhances activity without inducing an over-stimulatory effect (FIGs. 6B to 6D). A similar behavior pattern was observed in the wheel running parameter, which was a purely voluntary activity. MEAI-treated animals displayed an increased capability to run on the voluntary wheel, and their speed was similar to that of the STD- vehicle treated group (FIGs. 6E and 6F). Furthermore, an analysis of the time spent by mice engaging in various activities within the cage indicates that MEAI-treated mice exhibit a preference for voluntary activities such as wheel running, pedestrian locomotion, and extended interaction times with food and water dispensers (FIG. 6G). This suggests that MEAI treatment not only enhances physical activity but also promotes a more active engagement with the surrounding environment.

[0298]

[0168] MEAI Improves Glycemic Control in DIO Mice. Obesity is a well-known contributor to insulin resistance and hyperglycemia, which can ultimately lead to the onset of diabetes. In the DIO model, a substantial impairment in glucose tolerance and an increase in hyperinsulinemia was observed, as demonstrated by the results of glucose and insulin tolerance tests. However, following treatment with MEAI, a significant improvement in glucose metabolism was observed (FIGs. 7A to 7D), with fasting blood glucose and insulin levels also being reduced (FIGs. 7E and 7F). These beneficial effects of MEAI were reflected in HOMA-IR and ISI (FIGs. 7G and 7H), recognized markers of insulin insensitivity, suggesting that MEAI has a positive impact on glucose homeostasis, potentially by improving the body’s capacity to utilize insulin and maintain healthy blood sugar levels. Circulating levels of adiponectin, an adipokine- related hormone known for its insulin-sensitizing properties, remained unchanged across all groups (FIG. 71). Additionally, MEAI normalized insulin sensitivity (FIGs. 7C and 7D), indicating positive effects on glucose metabolism.

[0299]

[0169] Treatment with MEAI ameliorates HFD-induced dyslipidemia. To investigate whether MEAI can alleviate the dyslipidemia commonly associated with obesity, the blood lipid profile was analyzed. The results showed that MEAI treatment significantly reduced the levels of low-density lipoprotein cholesterol (LDL) compared to the HFD vehicle group, without notable changes in high-density lipoprotein cholesterol (HDL) levels. HDL is often referred to as “good cholesterol” and may play a crucial role in removing cholesterol from the bloodstream, whereas LDL is recognized as a major risk factor for cardiovascular disease. This reduction in LDL levels was accompanied by an increased HDL-to-LDL ratio, a recognized marker of overall lipid health and indicating a positive effect on lipid metabolism (FIGs. 8A to 8C). This finding suggests that MEAI treatment may exert beneficial effects on lipid metabolism, potentially contributing to improved cardiovascular health. Furthermore, there was a tendency towards decreased cholesterol levels in the MEAI-treated group (FIG. 8D), although this change was not statistically significant. Similarly, no significant alterations in circulating triglyceride levels were observed in any of the study groups (FIG. 8E). However, a trend towards reduced free fatty acids, another potential contributor to cardiovascular disease, was observed in the MEAI group (FIG. 8F). Collectively, these findings suggest that MEAI may have a potential therapeutic effect on improving dyslipidemia associated with obesity.

[0300]

[0170] Initial testing to check the effect of MEAI on renal function shows that kidney-to-body weight ratio is normalized following MEAI administration, accompanied by slight improvements of blood urea nitrogen (BUN) levels (FIGs. 9A to 9C).

[0301]

[0171] MEAI Reversed Obesity-Induced Hepatic Dysfunction and Steatosis. Obesity is a well-established risk factor for the development of liver disease, such as alcoholic fatty liver disease or metabolic dysfunction-associated steatotic liver disease (MASLD), characterized by hepatic steatosis resulting from an imbalance between hepatic fatty acid uptake, synthesis, oxidation, and export. Given the promising effects of MEAI on body weight, fat oxidation, and circulating lipid levels, MEAI’s impact on liver steatosis was investigated. The findings demonstrate that MEAI treatment reduced liver weight (FIG. 10A) and normalized its ratio to body weight (FIG. 10B) in HFD-fed mice. Although MEAI administration did not significantly alter ALT or AST levels compared to the HFD-vehicle group, it significantly reduced ALP levels, which may suggest reduced liver injury (FIGs. 10C to 10E). Moreover, treatment with MEAI had a positive effect on hepatic lipid accumulation, as evidenced by the significant reductions in liver triglycerides compared to the HFD vehicle control and a trend toward a reduction in hepatic cholesterol levels (FIGs. 10F and 10G). These findings were further supported by a decrease in Oil Red O staining and reduced lipid vacuole numbers in MEAI-treated livers compared to HFD vehicle-treated group (FIGs. 10H and 101). Overall, these findings suggest that MEAI may have a beneficial effect on hepatic lipid accumulation and liver function in the context of obesity-associated liver disease (e.g., MASLD).

[0302]

[0172] The molecular mechanism of MEAI was investigated by evaluating biomarkers associated with liver disease. For example, protein levels and mRNA expression of key genes involved in hepatic lipid metabolism using quantitative reverse transcriptase PCR (qRT-PCR) in DIO mice with or without MEAI administration were investigated (FIG. 11 A). This analysis focused on genes regulating various aspects of fatty acid metabolism, including those responsible for fatty acid oxidation (FAO). Genes such as peroxisome proliferator-activated receptor a (Ppara), carnitine palmitoyl transferase 1 & 2 (Cpt1 & Cpt2), acyl-CoA oxidase 1 (Acoxl), PPARy coactivator 1 alpha Pgcla), and the fatty acid transporter Cd36 were investigated. MEAI treatment significantly downregulated the mRNA expression of Cd36 (p < 0.05), suggesting reduced fatty acid uptake by hepatocytes. This finding aligns with the observed decrease in fat accumulation and implies a potential mechanism by which MEAI exerts its beneficial effects. Interestingly, protein levels of Cd36 remained unchanged (FIG.

[0303] 11 B), indicating a possible post-transcriptional regulatory mechanism or a timedependent effect of MEAI on protein expression.

[0304]

[0173] Further, the expression of genes regulating fatty acid lipolysis was analyzed. MEAI treatment resulted in a significant decrease in the mRNA level of lipoprotein lipase (Lpl) (p < 0.05). However, no significant changes were observed in the mRNA expression of hormone-sensitive lipase Hsl). These findings suggest that MEAI may primarily target LPL-mediated lipolysis, potentially contributing to the observed reduction in fat accumulation. The most prominent effects of MEAI were observed in genes regulating fatty acid synthesis. MEAI significantly decreased the mRNA expression of key lipogenic enzymes, including stearoyl-CoA desaturase 1 (Scoff), acetyl-CoA carboxylase alpha (Acaca), fatty acid synthase (Fas / i), fatty acid-binding protein 1 Fabpl), and glucose-6-phosphate dehydrogenase (G6pdx). Conversely, MEAI did not affect the expression of PPAR gamma (Pparg), CREB-binding protein (Crebp), diacylglycerol acyltransferase 2 (Dgat2), or sterol regulatory element-binding protein 1 Srebpl). Evaluation of genes associated with cholesterol metabolism, including HMG-CoA reductase (Hmgcr), LDL receptor (Lldr), liver X receptor alpha Nr1h3), and 7-dehydrocholesterol reductase (Dhcr), revealed no significant changes upon MEAI treatment. This suggests that MEAI's hepatic effects are primarily focused on fatty acid metabolism. To corroborate the observed changes in mRNA expression, protein levels of key regulators involved in fatty acid metabolism were further assessed. Consistent with the mRNA data, MEAI treatment significantly reduced the protein levels of SCD1 (FIGs. 11 C and 11 D) and FASN (FIGs. 11 E and 11 F), further substantiating its inhibitory effect on lipogenesis. Additionally, MEAI displayed a trend towards increased phosphorylated AMPK (p-AMPK) (FIG. 11 G), a known activator of fatty acid oxidation. Conversely, MEAI did not significantly affect the levels of phosphorylated ACC (p-ACC) (FIG. 11H). The observed increase in p-AMPK, coupled with the unchanged p-ACC, suggests a potential activation of the AMPK signaling pathway by MEAI, which may contribute to the reduction in lipogenesis. Taken together, these results demonstrate that MEAI exerts its anti-steatotic effect by suppressing fatty acid uptake and lipogenesis, offering a promising therapeutic strategy for liver disease.

[0305] Example 2: 5-Methoxy-2-aminoindan (MEAI) Mechanism of Action

[0306]

[0174] To gain further insight into MEAI’s mechanism of action, MEAI was screened against 87 receptors, enzymes, and transporters at a concentration of 10 pm. An inhibitory action above 50% was observed with several serotonergic receptors (e.g., 5-HT1 A, 5-HT2A, and 5-HT2B), the dopamine D2 receptor, and conversely, with the MAO-A enzyme (FIG. 12A). Considering potential safety concerns linked to 5-HT2B activation, MEAI’s functionality as a calcium flux agonist on 5-HT2B receptor was evaluated. The results are shown in FIG. 12B, which indicates that MEAI does not act as an agonist at the 5-HT2B receptor, as evidenced by a maximum response of 18.644% compared to serotonin’s positive control response of 99.891%.

[0307]

[0175] Embodiments of the present disclosure demonstrate that MEAI has promising ability to preserve glucose homeostasis by enhancing glucose tolerance and attenuating insulin resistance, reducing dyslipidemia, and improving liver health through reduced hepatic lipid accumulation. Molecular mechanisms underlying beneficial effects of MEAI on liver disease and hepatic lipid metabolism are disclosed. The liver disease may be obesity-associated liver disease or alcoholic liver disease. MEAI treatment significantly reduces Cd36 mRNA expression, suggesting a reduction in fatty acid uptake by hepatocytes and providing mechanistic insight into the lipid-lowering effects of MEAL MEAI treatment also led to a significant reduction in mRNA expression of lipogenic enzymes, including Scd1, Acaca, Fasn, Fabpl, and G6pdx, which may highlight MEAI’s inhibitory effect on de novo hepatic lipogenesis. Furthermore, MEAI treatment increased p-AMPK levels, which may suggest MEAI’s impact on suppressing lipogenesis and treating formation of liver disease.

[0308] Example 3: Exemplary Embodiments

[0309]

[0176] Exemplary embodiments of the disclosure include:

[0310] 1 . A method for treating a metabolic condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof, wherein the treatment reduces one or more metabolic syndromes in the subject.

[0311] 2. The method according to embodiment 1 , wherein the 5-methoxy-2- aminoindan or pharmaceutically acceptable salt thereof is administered as a dose of about 20 to about 520 mg.

[0312] 3. The method according to embodiment 1 , wherein the 5-methoxy-2- aminoindan or pharmaceutically acceptable salt thereof is administered as a dose of about 0.5 to about 40 mg.

[0313] 4. The method according to embodiment 1 , wherein the 5-methoxy-2- aminoindan or pharmaceutically acceptable salt thereof is administered as a dose of about 20 to about 100 mg, about 25 to about 90 mg, about 30 to about 80 mg, about 40 to about 70 mg, or about 50 to about 60 mg.

[0314] 5. The method according to any one of embodiments 2 to 4, wherein the dose is administered in a single dose or as more than one divided dose.

[0315] 6. The method according to any one of embodiments 2 to 5, wherein the dose is administered daily in a single dose or as more than one divided dose.

[0316] 7. The method according to any one of embodiments 2 to 6, wherein the 5- methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof is administered twice a day.

[0317] 8. The method according to any one of embodiments 1 to 7, wherein the therapeutically effective amount comprises about 0.0084 to about 0.67 mg / kg body weight / day, about 0.33 to about 8.67 mg / kg body weight / day, about 0.33 to about 1 .67 mg / kg body weight / day, about 0.42 to about 1 .5 mg / kg body weight / day, about 0. to about 1 .33 mg / kg body weight / day, about 0.67 to about 1 .17 mg / kg body weight / day, or about 0.83 to about 1 .0 mg / kg body weight / day.

[0318] 9. The method according to any one of embodiments 1 to 8, wherein the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier and / or excipient.

[0319] 10. The method according to embodiment 9, wherein the pharmaceutical composition is a free-flowing powder, a tablet, a capsule, a lozenge, a liquid, a liquid concentrate, suspension, or a syrup.

[0320] 11 . The method according to embodiment 10, wherein the pharmaceutical composition is a unit dosage form composition.

[0321] 12. The method according to embodiment 11 , wherein an amount of 5- methoxy-2-aminoindan or pharmaceutically acceptable salt thereof in the unit dosage form is about 20 to about 520 mg, about 0.5 to about 40 mg, about 20 to about 100 mg, about 25 to about 90 mg, about 30 to about 80 mg, about 40 to about 70 mg, or about 50 to about 60 mg.

[0322] 13. The method according to embodiment 12, wherein the amount of 5- methoxy-2-aminoindan or pharmaceutically acceptable salt thereof is about 50 mg.

[0323] 14. The method according to any one of embodiments 1 to 13, wherein administration of the pharmaceutical composition is oral, sublingual, buccal, vaginal, rectal, parenteral, transdermal, or by inhalation.

[0324] 15. The method of embodiment 14, wherein the parenteral administration is intravenous, intramuscular, or subcutaneous.

[0325] 16. A method for treating a metabolic condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising an N- acylethanolamine or a pharmaceutically acceptable salt thereof, wherein the treatment reduces one or more metabolic syndromes in the subject.

[0326] 17. The method according to embodiment 16, wherein the 5-methoxy-2- aminoindan or pharmaceutically acceptable salt thereof is administered as a dose of about 20 to about 520 mg.

[0327] 18. The method according to embodiment 16, wherein the 5-methoxy-2- aminoindan or pharmaceutically acceptable salt thereof is administered as a dose of about 0.5 to about 40 mg. 19. The method according to embodiment 16, wherein the 5-methoxy-2- aminoindan or pharmaceutically acceptable salt thereof is administered as a dose of about 20 to about 100 mg, about 25 to about 90 mg, about 30 to about 80 mg, about 40 to about 70 mg, or about 50 to about 60 mg.

[0328] 20. The method according to any one of embodiments 17 to 19, wherein the dose is administered in a single dose or in more than one divided dose.

[0329] 21 . The method according to any one of embodiments 17 to 20, wherein the dose is administered daily in a single dose or in more than one divided dose.

[0330] 22. The method according to any one of embodiments 16 to 21 , wherein the 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof is administered twice a day.

[0331] 23. The method according to any one of embodiments 16 to 22, wherein the therapeutically effective amount of the 5-methoxy-2-aminoindan or pharmaceutically acceptable salt thereof comprises about 0.0084 to about 0.67 mg / kg body weight / day, about 0.33 to about 8.67 mg / kg body weight / day, about 0.33 to about 1 .67 mg / kg body weight / day, about 0.42 to about 1 .5 mg / kg body weight / day, about 0. to about 1 .33 mg / kg body weight / day, about 0.67 to about 1 .17 mg / kg body weight / day, or about 0.83 to about 1 .0 mg / kg body weight / day.

[0332] 24. The method according to any one of embodiments 16 to 23, wherein the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier and / or excipient.

[0333] 25. The method according to embodiment 24, wherein the pharmaceutical composition is a free-flowing powder, a tablet, a capsule, a lozenge, a liquid, a liquid concentrate, suspension, or a syrup.

[0334] 26. The method according to embodiment 25, wherein the pharmaceutical composition is a unit dosage form composition.

[0335] 27. The method according to embodiment 26, wherein an amount of 5- methoxy-2-aminoindan or pharmaceutically acceptable salt thereof in the unit dosage form is about 20 to about 520 mg, about 0.5 to about 40 mg, about 20 to about 100 mg, about 25 to about 90 mg, about 30 to about 80 mg, about 40 to about 70 mg, or about 50 to about 60 mg.

[0336] 28. The method according to embodiment 27, wherein the amount of 5- methoxy-2-aminoindan or pharmaceutically acceptable salt thereof is about 50 mg. 29. The method according to any one of embodiments 16 to 28, wherein administration of the pharmaceutical composition is oral, sublingual, buccal, vaginal, rectal, parenteral, transdermal, or by inhalation.

[0337] 30. The method of embodiment 29, wherein the parenteral administration is intravenous, intramuscular, or subcutaneous.

[0338] 31 . The method of any one of embodiments 16 to 30, wherein the N- acylethanolamine is selected from N-palmitoylethanolamine (PEA), Me- palmitoylethanolamide (Me-PEA), palmitoylcyclohexamide, palmitoylbutylamide, oleoylethanolamine (OEA), palmitoylisopropylamide (PI A), salts thereof and any combination thereof.

[0339] 32. The method according to embodiment 31 , wherein the N- acylethanolamine is palmitoylethanolamide or a pharmaceutically acceptable salt thereof.

[0340] 33. The method of any one of embodiments 16 to 32, wherein the N- acylethanolamine or pharmaceutically acceptable salt thereof is administered as a dose of about 200 to about 1800 mg, about 250 to about 1550 mg, about 300 to about 1200 mg, about 350 to about 950 mg, about 400 to about 700 mg, about 450 to about 600 mg, or about 500 to about 550 mg.

[0341] 34. The method according to embodiment 33, wherein the dose is administered in a single dose or in more than one divided dose.

[0342] 35. The method according to embodiment 33, wherein the dose is administered daily in a single dose or in more than one divided dose.

[0343] 36. The method according to embodiment 35, wherein the N- acylethanolamine or a pharmaceutically acceptable salt thereof is administered twice a day.

[0344] 37. The method according to any one of embodiments 16 to 36, wherein the therapeutically effective amount of the N-acylethanolamine or pharmaceutically acceptable salt thereof comprises about 2.5 to about 36.0 mg / kg body weight / day, about 3.12 to about 31 .0 mg / kg body weight / day, about 3.75 to about 24.0 mg / kg body weight / day, about 4.38 to about 19.0 mg / kg body weight / day, about 5.0 to about 14.0 mg / kg body weight / day, about 5.62 to about 12.0 mg / kg body weight / day, or about 6.25 to about 11 .0 mg / kg body weight / day.

[0345] 38. The method of any one of embodiments 16 to 37, wherein the N- acylethanolamine is administered simultaneously with the 5-methoxy-2-aminoindan. 39. The method of embodiment 38, wherein the N-acylethanolamine and the 5-methoxy-2-aminoindan are administered in a single pharmaceutical composition.

[0346] 40. The method of embodiments 1 or 16, wherein administration is oral, mucosal, nasal, sublingual, inhalational, topical, rectal, vaginal, or parenteral route.

[0347] 41 . The method of embodiment 40, wherein the parenteral administration is intravenous, intramuscular, or subcutaneous.

[0348] 42. The method of any one of embodiments 1 to 41 , wherein treating metabolic syndrome involves one or more of decreasing blood pressure, decreasing blood sugar, reducing body fat around the waist, normalizing abnormal cholesterol or triglyceride levels, reducing obesity, reducing overweight, reducing body weight, increasing lean mass, reducing fat mass, reducing adiposity, increasing energy expenditure, improving glycemic control, decreasing hepatic steatosis, decreasing sugar intake, decreasing food intake, maintaining glucose homeostasis, lowering dyslipidemia, or preserving liver function.

[0349] 43. The method of embodiment 42, wherein improving glycemic control involves one or more of improving glucose metabolism, reducing fasting blood glucose level, or reducing insulin level.

[0350] 44. The method of embodiment 42, wherein increasing energy expenditure involves one or more of increasing oxygen consumption and carbon dioxide emission, increasing fat oxidation, increasing carbohydrate oxidation, or increasing locomotive activity.

[0351] 45. The method of embodiment 42, wherein treating metabolic syndrome reduces obesity.

[0352] 46. The method of embodiment 45, wherein treating metabolic syndrome involves reducing overweight associated with obesity.

[0353] 47. The method of embodiment 45 or 46, wherein treating metabolic syndrome preserves lean mass of the subject.

[0354] 48. The method of embodiment 45 or 46, wherein treating metabolic syndrome decreases fat mass of the subject.

[0355] 49. The method of embodiment 45 or 46, wherein treating metabolic syndrome reduces adiposity of the subject.

[0356] 50. The method of embodiment 45 or embodiment 46, wherein treating metabolic syndrome increases energy expenditure.

[0357] 51 . The method of embodiment 50, wherein food consumption is unchanged.

[0358] 52. The method of embodiment 50, wherein fat utilization is increased. 53. The method of embodiment 50, wherein locomotive activity is normalized without over-stimulatory effects.

[0359] 54. The method of embodiment 45 or embodiment 46, wherein treating metabolic syndrome improves glycemic control.

[0360] 55. The method of embodiment 45 or embodiment 46, wherein treating metabolic syndrome reverses hyperglycemia, glucose intolerance, or hyperinsulinemia.

[0361] 56. The method of embodiment 45 or embodiment 46, wherein treating metabolic syndrome improves hepatic steatosis.

[0362] 57. The method of embodiment 56, wherein improving hepatic steatosis involves one or more of reducing hepatic lipid accumulation, hepatic triglyceride levels, or hepatic cholesterol levels.

[0363] 58. The method of embodiment 45 or embodiment 46, wherein treating metabolic syndrome preserves glucose homeostasis.

[0364] 59. The method of embodiment 58, wherein preserving glucose homeostasis involves one or more of enhancing glucose tolerance, attenuating insulin resistance, reducing dyslipidemia, or reducing hepatic lipid accumulation.

[0365] 60. Use of a pharmaceutical composition comprising 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof for treating a metabolic condition as in any one of embodiments 1 -59.

[0366] 61 . Use of a pharmaceutical composition comprising 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof, and an N-acylethanolamine (e.g., palmitoylethanolamide) or a pharmaceutically acceptable salt thereof, for treating a metabolic condition as in any one of embodiments 16-59.

[0367] 62. A method for increasing metabolic activity in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof.

[0368] 63. The method according to embodiment 62, wherein the 5-methoxy-2- aminoindan or pharmaceutically acceptable salt thereof is administered as a dose of about 20 to about 520 mg.

[0369] 64. The method according to embodiment 62, wherein the 5-methoxy-2- aminoindan or pharmaceutically acceptable salt thereof is administered as a dose of about 0.5 to about 40 mg.

[0370] 65. The method according to any one of embodiments 62 to 64, wherein the 5-methoxy-2-aminoindan or pharmaceutically acceptable salt thereof is administered as a dose of about 20 to about 100 mg, about 25 to about 90 mg, about 30 to about 80 mg, about 40 to about 70 mg, or about 50 to about 60 mg.

[0371] 66. The method according to any one of embodiments 63 to 65, wherein the dose is administered in a single dose or as more than one divided dose.

[0372] 67. The method according to any one of embodiments 63 to 66, wherein the dose is administered daily in a single dose or as more than one divided dose.

[0373] 68. The method according to any one of embodiments 63 to 67, wherein the 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof is administered twice a day.

[0374] 69. The method according to any one of embodiments 62 to 67, wherein the therapeutically effective amount comprises about 0.0084 to about 0.67 mg / kg body weight / day, about 0.33 to about 8.67 mg / kg body weight / day, about 0.33 to about 1 .67 mg / kg body weight / day, about 0.42 to about 1 .5 mg / kg body weight / day, about 0. to about 1 .33 mg / kg body weight / day, about 0.67 to about 1 .17 mg / kg body weight / day, or about 0.83 to about 1 .0 mg / kg body weight / day.

[0375] 70. The method according to any one of embodiments 62 to 69, wherein the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier and / or excipient.

[0376] 71 . The method according to embodiment 70, wherein the pharmaceutical composition is a free-flowing powder, a tablet, a capsule, a lozenge, a liquid, a liquid concentrate, suspension, or a syrup.

[0377] 72. The method according to embodiment 71 , wherein the pharmaceutical composition is a unit dosage form composition.

[0378] 73. The method according to embodiment 72, wherein an amount of 5- methoxy-2-aminoindan or pharmaceutically acceptable salt thereof in the unit dosage form is about 20 to about 520 mg, about 0.5 to about 40 mg, about 20 to about 100 mg, about 25 to about 90 mg, about 30 to about 80 mg, about 40 to about 70 mg, or about 50 to about 60 mg.

[0379] 74. The method according to embodiment 73, wherein the amount of 5- methoxy-2-aminoindan or pharmaceutically acceptable salt thereof is about 50 mg.

[0380] 75. The method according to any one of embodiments 62 to 74, wherein administration of the pharmaceutical composition is oral, sublingual, buccal, vaginal, rectal, parenteral, transdermal, or by inhalation.

[0381] 76. The method of embodiment 75, wherein the parenteral administration is intravenous, intramuscular, or subcutaneous. 77. A method for increasing metabolic activity in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising an N- acylethanolamine or a pharmaceutically acceptable salt thereof.

[0382] 78. The method according to embodiment 77, wherein the 5-methoxy-2- aminoindan or pharmaceutically acceptable salt thereof is administered as a dose of about 20 to about 520 mg.

[0383] 79. The method according to embodiment 77, wherein the 5-methoxy-2- aminoindan or pharmaceutically acceptable salt thereof is administered as a dose of about 0.5 to about 40 mg.

[0384] 80. The method according to embodiment 77, wherein the 5-methoxy-2- aminoindan or pharmaceutically acceptable salt thereof is administered as a dose of about 20 to about 100 mg, about 25 to about 90 mg, about 30 to about 80 mg, about 40 to about 70 mg, or about 50 to about 60 mg.

[0385] 81 . The method according to any one of embodiments 78 to 80, wherein the dose is administered in a single dose or in more than one divided dose.

[0386] 82. The method according to any one of embodiments 78 to 81 , wherein the dose is administered daily in a single dose or in more than one divided dose.

[0387] 83. The method according to any one of embodiments 80 to 82, wherein the 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof is administered twice a day.

[0388] 84. The method according to any one of embodiments 77 to 83, wherein the therapeutically effective amount of the 5-methoxy-2-aminoindan or pharmaceutically acceptable salt thereof comprises about 0.0084 to about 0.67 mg / kg body weight / day, about 0.33 to about 8.67 mg / kg body weight / day, about 0.33 to about 1 .67 mg / kg body weight / day, about 0.42 to about 1 .5 mg / kg body weight / day, about 0. to about 1 .33 mg / kg body weight / day, about 0.67 to about 1 .17 mg / kg body weight / day, or about 0.83 to about 1 .0 mg / kg body weight / day.

[0389] 85. The method according to any one of embodiments 77 to 84, wherein the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier and / or excipient.

[0390] 86. The method according to embodiment 85, wherein the pharmaceutical composition is a free-flowing powder, a tablet, a capsule, a lozenge, a liquid, a liquid concentrate, suspension, or a syrup. 87. The method according to embodiment 86, wherein the pharmaceutical composition is a unit dosage form composition.

[0391] 88. The method according to embodiment 87, wherein an amount of 5- methoxy-2-aminoindan or pharmaceutically acceptable salt thereof in the unit dosage form is about 20 to about 520 mg, about 0.5 to about 40 mg, about 20 to about 100 mg, about 25 to about 90 mg, about 30 to about 80 mg, about 40 to about 70 mg, or about 50 to about 60 mg.

[0392] 89. The method according to embodiment 88, wherein the amount of 5- methoxy-2-aminoindan or pharmaceutically acceptable salt thereof is about 50 mg.

[0393] 90. The method according to any one of embodiments 77 to 89, wherein administration of the pharmaceutical composition is oral, sublingual, buccal, vaginal, rectal, parenteral, transdermal, or by inhalation.

[0394] 91 . The method of embodiment 90, wherein the parenteral administration is intravenous, intramuscular, or subcutaneous.

[0395] 92. The method of any one of embodiments 77 to 91 , wherein the N- acylethanolamine is selected from N-palmitoylethanolamine (PEA), Me- palmitoylethanolamide (Me-PEA), palmitoylcyclohexamide, palmitoylbutylamide, oleoylethanolamine (OEA), palmitoylisopropylamide (PIA), salts thereof, and any combination thereof.

[0396] 93. The method according to embodiment 92, wherein the N- acylethanolamine is N-palmitoylethanolamine (PEA) or a pharmaceutically acceptable salt thereof.

[0397] 94. The method of any one of embodiments 77 to 93, wherein the N- acylethanolamine or pharmaceutically acceptable salt thereof is administered as a dose of about 200 to about 1800 mg, about 250 to about 1550 mg, about 300 to about 1200 mg, about 350 to about 950 mg, about 400 to about 700 mg, about 450 to about 600 mg, or about 500 to about 550 mg.

[0398] 95. The method according to embodiment 94, wherein the dose is administered in a single dose or in more than one divided dose.

[0399] 96. The method according to embodiment 94, wherein the dose is administered daily in a single dose or in more than one divided dose.

[0400] 97. The method according to embodiment 96, wherein the N- acylethanolamine or a pharmaceutically acceptable salt thereof is administered twice a day. 98. The method according to any one of embodiments 77 to 97, wherein the therapeutically effective amount of the N-acylethanolamine or pharmaceutically acceptable salt thereof comprises about 2.5 to about 36.0 mg / kg body weight / day, about 3.12 to about 31 .0 mg / kg body weight / day, about 3.75 to about 24.0 mg / kg body weight / day, about 4.38 to about 19.0 mg / kg body weight / day, about 5.0 to about 14.0 mg / kg body weight / day, about 5.62 to about 12.0 mg / kg body weight / day, or about 6.25 to about 11 .0 mg / kg body weight / day.

[0401] 99. The method of any one of embodiments 77 to 98, wherein the N- acylethanolamine is administered simultaneously with the 5-methoxy-2-aminoindan.

[0402] 100. The method of embodiment 99, wherein the N-acylethanolamine and the 5-methoxy-2-aminoindan are administered in a single pharmaceutical composition.

[0403] 101 . The method of embodiments 62 or 77, wherein administration is oral, mucosal, nasal, sublingual, inhalational, topical, rectal, vaginal, or parenteral route.

[0404] 102. The method of embodiment 101 , wherein the parenteral administration is intravenous, intramuscular, or subcutaneous.

[0405] 103. The method of any one of embodiments 62 to 102, wherein increasing metabolic activity involves one or more of reducing obesity, reducing overweight, reducing body weight, increasing lean mass, reducing fat mass, reducing adiposity, increasing energy expenditure, promoting the use of fat for energy, increasing a rate of fatty acid oxidation, suppressing fatty acid uptake and lipogenesis, promoting caloric burning at rest, improving glycemic control, decreasing low-density lipoprotein cholesterol (LDL), increasing high-density lipoprotein cholesterol (HDL) to LDL ratio, decreasing sugar intake, decreasing leptin level, mitigating hyperleptinemia-induced leptin resistance, or decreasing food intake.

[0406] 104. The method of embodiment 103, wherein the therapeutically effective amount of 5-methoxy-2-aminoindan and / or the therapeutically effective amount of 5- methoxy-2-aminoindan and N-acylethanolamine increases energy expenditure by at least about 20%.

[0407] 105. The method of embodiment 103, wherein improving glycemic control involves one or more of improving glucose metabolism, reducing fasting blood glucose level, or reducing insulin level.

[0408] 106. The method of embodiment 103, wherein increasing energy expenditure involves one or more of increasing oxygen consumption and carbon dioxide emission, increasing fat oxidation, increasing carbohydrate oxidation, or increasing locomotive activity. 107. The method of embodiment 103, wherein increasing metabolic activity reduces obesity.

[0409] 108. The method of embodiment 107, wherein increasing metabolic activity involves reducing overweight associated with obesity.

[0410] 109. The method of embodiment 107 or 108, wherein increasing metabolic activity preserves lean mass of the subject.

[0411] 110. The method of embodiment 107 or 108, wherein increasing metabolic activity decreases fat mass of the subject.

[0412] 111. The method of embodiment 107 or 108, wherein increasing metabolic activity increases a ratio of lean body mass to fat mass.

[0413] 112. The method of embodiment 107 or 108, wherein increasing metabolic activity decreases leptin level or mitigates hyperleptinemia-induced leptin resistance.

[0414] 113. The method of embodiment 107 or 108, wherein increasing metabolic activity reduces adiposity of the subject.

[0415] 114. The method of embodiment 107 or embodiment 108, wherein increasing metabolic activity increases energy expenditure.

[0416] 115. The method of embodiment 114, wherein food consumption is unchanged and / or a subject is not on a diet.

[0417] 116. The method of embodiment 114, wherein fat utilization is increased.

[0418] 117. The method of embodiment 116, wherein fat mass is reduced, and lean mass is retained.

[0419] 118. The method of embodiment 114, wherein locomotive activity is normalized without over-stimulatory effects.

[0420] 119. The method of embodiment 107 or 108, wherein increasing metabolic activity suppresses fatty acid uptake and lipogenesis.

[0421] 120. The method of embodiment 119, wherein fat accumulation in the subject is reduced.

[0422] 121 . The method of any one of embodiments 62-120, wherein a dose of 5- methoxy-2-aminoindan administered is 5 mg / kg and the subject in need thereof is human.

[0423] 122. The method of any one of embodiments 62-121 , wherein the therapeutically effective amount of 5-methoxy-2-aminoindan or pharmaceutically acceptable salt thereof, or the therapeutically effective amount of 5-methoxy-2- aminoindan or a pharmaceutically acceptable salt thereof and an N-acylethanolamine (e.g., palmitoylethanolamide) or a pharmaceutically acceptable salt thereof is sufficient to decrease a fat mass percentage in the subject in need thereof by at least 30%.

[0424] 123. The method of any one of embodiments 62-122, wherein the therapeutically effective amount of 5-methoxy-2-aminoindan or pharmaceutically acceptable salt thereof, or the therapeutically effective amount of 5-methoxy-2- aminoindan or a pharmaceutically acceptable salt thereof and an N-acylethanolamine (e.g., palmitoylethanolamide) or a pharmaceutically acceptable salt thereof is sufficient to decrease a fat mass in the subject in need thereof by at least 35%.

[0425] 124. The method of any one of embodiments 62-123, wherein the therapeutically effective amount of 5-methoxy-2-aminoindan or pharmaceutically acceptable salt thereof, or the therapeutically effective amount of 5-methoxy-2- aminoindan or a pharmaceutically acceptable salt thereof and an N-acylethanolamine (e.g., palmitoylethanolamide) or a pharmaceutically acceptable salt thereof is sufficient to increase a fat oxidation rate in the subject in need thereof by at least 10% prior to treatment.

[0426] 125. Use of a pharmaceutical composition comprising 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof for increasing metabolic activity in a subject in need thereof as in any one of embodiments 62-124.

[0427] 126. Use of a pharmaceutical composition comprising 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof, and an N-acylethanolamine (e.g., palmitoylethanolamide) or a pharmaceutically acceptable salt thereof, for treating a metabolic condition in a subject in need thereof as in any one of embodiments 77-124.

[0428] 127. A method for decreasing expression of a lipogenic enzyme, the method comprising administering to a subject in need thereof a therapeutically effective amount of 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof as in any one of embodiments 62-124, wherein the lipogenic enzyme comprises lipoprotein lipase (Lpl), stearoyl-CoA desaturase 1 (Scd1 ), acetyl-CoA carboxylase alpha (Acaca), fatty acid synthase (Fasn), fatty acid-binding protein 1 (Fabpl ), and / or glucose-6-phosphate dehydrogenase (G6pdx).

[0429] 128. A method for decreasing expression of a lipogenic enzyme, the method comprising administering to a subject in need thereof a therapeutically effective amount of 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof, and an N- acylethanolamine (e.g., palmitoylethanolamide) or a pharmaceutically acceptable salt thereof as in any one of embodiments 77-124, wherein the lipogenic enzyme comprises lipoprotein lipase (Lpl), stearoyl-CoA desaturase 1 (Scd1 ), acetyl-CoA carboxylase alpha (Acaca), fatty acid synthase (Fasn), fatty acid-binding protein 1 (Fabpl), and / or glucose-6-phosphate dehydrogenase (G6pdx).

[0430] 129. A method for inhibiting lipogenesis, the method comprising administering to a subject in need thereof a therapeutically effective amount of 5-methoxy-2- aminoindan or a pharmaceutically acceptable salt thereof as in any one of embodiments 62-124, wherein the therapeutically effective amount of 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof reduces protein levels of stearoyl-CoA desaturase 1 (Scd1) and / or fatty acid synthase (FASN).

[0431] 130. A method for inhibiting lipogenesis, the method comprising administering to a subject in need thereof a therapeutically effective amount of 5-methoxy-2- aminoindan or a pharmaceutically acceptable salt thereof, and an N-acylethanolamine (e.g., palmitoylethanolamide) or a pharmaceutically acceptable salt thereof as in any one of embodiments 77-124, wherein the therapeutically effective amount of 5-methoxy- 2-aminoindan or a pharmaceutically acceptable salt thereof and the N-acylethanolamine or a pharmaceutically acceptable salt thereof reduces protein levels of stearoyl-CoA desaturase 1 (Scd1) and / or fatty acid synthase (FASN).

[0432] 131. A method for increasing expression of phosphorylated AMPK (p-AMPK), the method comprising administering to a subject in need thereof a therapeutically effective amount of 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof as in any one of embodiments 62-124.

[0433] 132. A method for increasing expression of phosphorylated AMPK (p-AMPK), the method comprising administering to a subject in need thereof a therapeutically effective amount of 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof, and an N-acylethanolamine (e.g., palmitoylethanolamide) or a pharmaceutically acceptable salt thereof as in any one of embodiments 77-124.

[0434] 133. A method of increasing a lean-to-fat body mass ratio, comprising administering to a subject in need thereof a therapeutically effective amount of 5- methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof as in any one of embodiments 62-124, wherein the therapeutically effective amount of 5-methoxy-2- aminoindan or a pharmaceutically acceptable salt thereof

[0435] 134. A method of increasing a lean-to-fat body mass ratio, comprising administering to a subject in need thereof a therapeutically effective amount of 5- methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof, and an N- acylethanolamine (e.g., palmitoylethanolamide) or a pharmaceutically acceptable salt thereof as in any one of embodiments 77-124. 135. The method of embodiment 133 or 134, wherein the method reduces overall fat mass while retaining lean mass.

[0436]

[0177] The many features and advantages of the present disclosure are apparent from the detailed specification, and thus it is intended by the appended claims to cover all such features and advantages of the present disclosure that fall within the true spirit and scope of the present disclosure. Further, since numerous modifications and variations will readily occur to those skilled in the art, it is not desired to limit the present disclosure to the exact construction and operation illustrated and described and accordingly, all suitable modifications and equivalents may be resorted to, falling within the scope of the present disclosure.

[0437]

[0178] Moreover, those skilled in the art will appreciate that the conception upon which this disclosure is based may readily be used as a basis for designing other structures, methods, and systems for carrying out the several purposes of the present disclosure. Accordingly, the claims are not to be considered as limited by the foregoing description or examples.

Claims

WE CLAIM:1 . A method for losing weight, comprising administering to a subject in need thereof a therapeutically effective amount of 5-methoxy-2-aminoindan (MEAI) or a pharmaceutically acceptable salt thereof for a period of time sufficient to increase basal energy expenditure in the subject.

2. The method of claim 1 , wherein administering the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof increases caloric burning without increasing physical activity of the subject.

3. The method of claim 1 or 2, wherein administering the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof increases the basal energy expenditure compared to another subject that does not receive the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof over the same period of time.

4. The method of any one of claims 1 to 3, wherein the period of time is at least about 5 days, at least about 10 days, at least about 15 days, at least about 20 days, at least about 25 days, at least about 30 days, at least about 45 days, at least about 60 days, at least about 90 days, at least about 120 days, at least about 150 days, at least about 180 days, at least about 210 days, at least about 240 days, at least about 270 days, at least about 300 days, at least about 330 days, or at least about 360 days.

5. The method of any one of claims 1 to 4, wherein the basal energy expenditure is: increased by about 10% over a baseline; increased by about 15% over a baseline; increased by about 20% over a baseline; increased by about 25% over a baseline; increased by about 30% over a baseline; increased by about 35% over a baseline; increased by about 40% over a baseline; increased by about 45% over a baseline; or increased by about 50% over a baseline;wherein the baseline is a basal energy expenditure of the subject prior to administering the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof.

6. The method of any one of claims 1 to 4, wherein the basal energy expenditure is increased by about 10% to about 15% over a baseline, wherein the baseline is a basal energy expenditure of an obese subject prior to administering the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof.

7. The method of any one of claims 1 to 6, wherein administering MEAI or pharmaceutically acceptable salt thereof does not alter an amount of time that the subject is sedentary compared to a period of sedentary time prior to administering the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof.

8. The method of any one of claims 1 to 7, wherein the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof comprises from about 0.5 mg to about 520 mg.

9. The method of any one of claims 1 to 8, wherein the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof comprises: from about 10 mg to about 520 mg; from about 10 mg to about 250 mg; from about 20 mg to about 520 mg; from about 20 mg to about 250 mg; from about 20 mg to about 200 mg; from about 20 mg to about 175 mg; from about 20 mg to about 150 mg; from about 20 mg to about 125 mg; from about 20 mg to about 100 mg; or from about 20 mg to about 50 mg.

10. The method of any one of claims 1 to 9, wherein the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof comprises: from about 20 mg to about 250 mg; from about 20 mg to about 200 mg;from about 20 mg to about 175 mg; or from about 20 mg to about 150 mg.11 . The method of any one of claims 1 to 10, wherein the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof is administered in a single dose.

12. The method of any one of claims 1 to 11 , wherein the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof is administered as more than one divided dose.

13. The method of any one of claims 1 to 12, wherein the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof is administered daily.

14. The method of any one of claims 1 to 13, wherein the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof is administered once daily.

15. The method of any one of claims 1 to 14, wherein the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof comprises: from about 0.0083 mg / kg body weight per day to about 8.67 mg / kg body weight per day; from about 0.042 mg / kg body weight per day to about 8.67 mg / kg body weight per day; from about 0.167 mg / kg body weight per day to about 8.67 mg / kg body weight per day; from about 0.33 mg / kg body weight per day to about 8.67 mg / kg body weight per day; from about 0.33 mg / kg body weight per day to about 4.167 mg / kg body weight per day; from about 0.33 mg / kg body weight per day to about 3.33 mg / kg body weight per day; from about 0.33 mg / kg body weight per day to about 2.92 mg / kg body weight per day;from about 0.33 mg / kg body weight per day to about 2.5 mg / kg body weight per day; from about 0.33 mg / kg body weight per day to about 2.08 mg / kg body weight per day; from about 0.33 mg / kg body weight per day to about 1 .67 mg / kg body weight per day; or from about 0.33 mg / kg body weight per day to about 0.83 mg / kg body weight per day.

16. The method of any one of claims 1 to 15, further comprising administering a therapeutically effective amount of an N-acylethanolamine or a pharmaceutically acceptable salt thereof.

17. The method of claim 16, wherein the therapeutically effective amount of the N-acylethanolamine or pharmaceutically acceptable salt thereof comprises: from about 200 to about 1800 mg; from about 250 to about 1550 mg; from about 300 to about 1200 mg; from about 350 to about 950 mg; from about 400 to about 800 mg; from about 450 to about 700 mg; or from about 500 to about 600 mg.

18. The method of claim 16 or 17, wherein the therapeutically effective amount of the N-acylethanolamine or pharmaceutically acceptable salt thereof comprises about 400 mg or about 800 mg.

19. The method of any one of claims 16 to 18, wherein the therapeutically effective amount of the N-acylethanolamine or pharmaceutically acceptable salt thereof comprises: from about 3.33 mg / kg body weight per day to about 30.0 mg / kg body weight per day; from about 4.17 mg / kg body weight per day to about 25.8 mg / kg body weight per day;from about 5.0 mg / kg body weight per day to about 20.0 mg / kg body weight per day; from about 5.83 mg / kg body weight per day to about 15.8 mg / kg body weight per day; from about 6.67 mg / kg body weight per day to about 13.3 mg / kg body weight per day; from about 7.5 mg / kg body weight per day to about 1 1 .67 mg / kg body weight per day; or from about 8.33 mg / kg body weight per day to about 10.0 mg / kg body weight per day.

20. The method of any one of claims 16 to 19, wherein the therapeutically effective amount of the N-acylethanolamine or pharmaceutically acceptable salt thereof is administered simultaneously with the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof.21 . The method of claim 20, wherein the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof and the therapeutically effective of N- acylethanolamine of pharmaceutically acceptable salt thereof are formulated in a single pharmaceutical composition.

22. The method of any one of claims 16 to 20, wherein the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof and the therapeutically effective of N-acylethanolamine of pharmaceutically acceptable salt thereof are formulated in separate pharmaceutical compositions.

23. The method of any one of claims 16 to 19, wherein the therapeutically effective amount of the N-acylethanolamine or pharmaceutically acceptable salt thereof and the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof are administered sequentially.

24. The method of any one of claims 16 to 23, wherein the N- acylethanolamine comprises N-palmitoylethanolamine (PEA), Me- palmitoylethanolamide (Me-PEA), palmitoylcyclohexamide, palmitoylbutylamide,oleoylethanolamine (OEA), palmitoylisopropylamide (PIA), pharmaceutically acceptable salts thereof, or any combination thereof.

25. The method of any one of claims 16 to 24, wherein the N- acylethanolamine or pharmaceutically acceptable salt thereof comprises PEA or a pharmaceutically acceptable salt thereof.

26. The method of any one of claims 1 to 25, wherein the subject has a healthy body weight or healthy body mass index.

27. The method of any one of claims 1 to 25, wherein the subject has at least one metabolic disorder.

28. The method of claim 27, wherein the at least one metabolic disorder results from chronic consumption of a high-fat diet.

29. The method of claim 27 or 28, wherein the at least one metabolic disorder is selected from obesity, dyslipidemia, diabetes, hyperglycemia, hyperlipidemia, hypercholesterolemia, insulin-resistance, hyperinsulinemia, glucose intolerance, and hepatic steatosis.

30. The method of any one of claims 1 to 29, wherein the subject is sedentary, unable to exercise, or not on an exercise regimen.31 . The method of any one of claims 1 to 30, wherein the subject is on a weight loss regimen.

32. The method of claim 31 , wherein the weight loss regimen alone led to a plateau in weight loss, at least one adverse side effect, or a combination thereof.

33. The method of claim 31 or 32, wherein the weight loss regimen comprises a diet regimen, an exercise regimen, a medication, or a combination thereof.

34. The method of claim 33, wherein the medication comprises a GLP-1 receptor agonist.

35. The method of claim 34, wherein the GLP-1 receptor agonist and MEAI increase metabolism and decrease caloric intake.

36. The method of any one of claims 31 to 35, wherein combining the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof with the weight loss regimen further increases weight loss in the subject relative to weight loss prior to administering the therapeutically effect amount of MEAI or a pharmaceutically acceptable salt thereof.

37. The method of any one of claims 33 to 36, wherein combining the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof with the weight loss regimen prevents or alleviates at least one adverse side effect caused by the medication in weight loss regimen.

38. The method of any one of claims 33 to 37, wherein combining the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof with the weight loss regimen increases an amount of time spent on the weight loss regimen.

39. A method of treating fatty liver disease comprising administering a therapeutically effective amount of 5-methoxy-2-aminoindan (MEAI) or a pharmaceutically acceptable salt thereof to a subject.

40. The method of claim 39, wherein administering the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof alters a level of at least one biomarker associated with lipid metabolism.41 . The method of claim 39 or 40, wherein the at least one biomarker associated with lipid metabolism comprises a protein and / or an mRNA level of a gene associated with lipid metabolism.

42. The method of claim 41 , wherein the gene associated with lipid metabolism comprises peroxisome proliferator-activated receptor alpha (Ppara), clusterof differentiation 36 (Cd36), lipoprotein lipase Lpl), stearoyl-CoA desaturase 1 (Scd1), acetyl-CoA carboxylase alpha (Acaca), fatty acid synthase (Fasn), fatty acid-binding protein 1 (Fabpl), glucose-6-phosphate dehydrogenase (G6pdx), and / or phosphorylated AMP-activated protein kinase (p-AMPK).

43. The method of claim 42, wherein the gene associated with lipid metabolism comprises Cd36.

44. The method of claim 39 to 43, wherein the at least one biomarker is measured by collecting a liver cell sample from the subject from a serum sample and / or by a method comprising a liver biopsy.

45. The method of any one of claims 41 to 44, wherein administering the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof reduces a level of the at least one biomarker.

46. The method of claim 45, wherein administering the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof reduces a level of Ppara, Cd36, Lpl, Scd1, Acaca, Fasn, Fabpl, or G6pdx compared to a baseline, wherein the baseline is a level of Ppara, Cd36, Lpl, Scd1, Acaca, Fasn, Fabpl, or G6pdx prior to administering the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof.

47. The method of claim 46, further comprising administering an additional amount of the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof if a decrease in a level of Ppara, Cd36, Lpl, Scd1, Acaca, Fasn, Fabpl, or G6pdx compared to the baseline is observed.

48. The method of any one of claims 45 to 47, wherein administering the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof reduces a level of the at least one biomarker by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90%, compared to a baseline, wherein the baseline is a level of the at least one biomarker of the subjectprior to administering the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof.

49. The method of claim 48, wherein administering the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof reduces a level of the at least one biomarker by about 60% compared to the baseline.

50. The method of any one of claims 45 to 49, wherein administering the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof reduces a level of the at least one biomarker by: about 40% compared to a baseline; about 50% compared to a baseline; about 60% compared to a baseline; about 70% compared to a baseline; or about 80% compared to a baseline; wherein the baseline is a level of the at least one biomarker of the subject prior to administration of the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof.51 . The method of claim 42, wherein administering the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof increases a level of p-AMPK compared to a level of p-AMPK in the subject prior to administering the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof.

52. The method of claim 51 , further comprising administering a further dose of the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof if an increase in a level of p-AMPK is observed.

53. The method of claim 51 or 52, wherein administering the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof increases a level of p-AMPK by about 40% or about 50% compared to a level of p-AMPK in the subject prior to administering the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof.

54. The method of any one of claims 39 to 53, wherein administering the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof reduces a protein level of Fasn or Scd1 by about 40% to 60% compared to a baseline, wherein the baseline is a protein level of Fasn or Scd1 in the subject prior to administering the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof.

55. The method of any one of claims 39 to 54, wherein administering the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof decreases fatty acid oxidation, lipolysis, or fatty acid synthesis in the subject compared to a level prior to administering the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof.

56. The method of claim 55, wherein administering the therapeutically effect amount of MEAI or pharmaceutically acceptable salt thereof decreases fatty acid oxidation, lipolysis, or fatty acid synthesis by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90% relative to the level prior to administering the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof.

57. The method of any one of claims 39 to 56, wherein the subject has a genetic risk for developing fatty liver disease.

58. The method of any one of claims 39 to 57, wherein the subject has a genetic mutation that alters a level of the at least one biomarker associated with lipid metabolism.

59. The method of any one of claims 39 to 58, wherein the fatty liver disease is a metabolic dysfunction-associated steatotic liver disease (MASLD) or an alcoholic fatty liver disease.

60. The method of any one of claims 39 to 59, wherein the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof comprises from about 0.5 mg to about 520 mg.61 . The method of any one of claims 39 to 60, wherein the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof comprises from: about 10 mg to about 520 mg; about 10 mg to about 250 mg; about 20 mg to about 520 mg; about 20 mg to about 250 mg; about 20 mg to about 200 mg; about 20 mg to about 175 mg; about 20 mg to about 150 mg; about 20 mg to about 125 mg; about 20 mg to about 100 mg; or about 20 mg to about 50 mg.

62. The method of any one of claims 39 to 61 , wherein the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof comprises: from about 20 mg to about 250 mg; from about 20 mg to about 200 mg; from about 20 mg to about 175 mg; or from about 20 mg to about 150 mg.

63. The method of any one of claims 39 to 62, wherein the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof is administered in a single dose.

64. The method of any one of claims 39 to 62, wherein the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof is administered as more than one divided dose.

65. The method of any one of claims 39 to 64, wherein the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof is administered daily.

66. The method of any one of claims 39 to 65, wherein the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof is administered once daily.

67. The method of any one of claims 39 to 66, wherein the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof is administered for about 5 days, about 10 days, about 15 days, about 20 days, about 25 days, about 30 days, about 45 days, about 60 days, about 90 days, or about 120 days.

68. The method of any one of claims 39 to 67, wherein the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof comprises: from about 0.007 mg / kg body weight per day to about 7.43 mg / kg body weight per day; from about 0.036 mg / kg body weight per day to about 7.43 mg / kg body weight per day; from about 0.143 mg / kg body weight per day to about 7.43 mg / kg body weight per day; from about 0.26 mg / kg body weight per day to about 7.43 mg / kg body weight per day; from about 0.26 mg / kg body weight per day to about 3.57 mg / kg body weight per day; from about 0.26 mg / kg body weight per day to about 2.86 mg / kg body weight per day; from about 0.26 mg / kg body weight per day to about 2.5 mg / kg body weight per day; from about 0.26 mg / kg body weight per day to about 2.14 mg / kg body weight per day; from about 0.26 mg / kg body weight per day to about 1 .79 mg / kg body weight per day; from about 0.26 mg / kg body weight per day to about 1 .43 mg / kg body weight per day; or from about 0.26 mg / kg body weight per day to about 0.71 mg / kg body weight per day.

69. The method of any one of claims 39 to 68, further comprising administering a therapeutically effective amount of an N-acylethanolamine or a pharmaceutically acceptable salt thereof.

70. The method of claim 69, wherein the therapeutically effective amount of the N-acylethanolamine or pharmaceutically acceptable salt thereof comprises: from about 200 to about 1800 mg; from about 250 to about 1550 mg; from about 300 to about 1200 mg; from about 350 to about 950 mg; from about 400 to about 800 mg; from about 450 to about 700 mg; or from about 500 to about 600 mg.71 . The method of claim 69 or 70, wherein the therapeutically effective amount of the N-acylethanolamine or pharmaceutically acceptable salt thereof comprises about 400 mg or about 800 mg.

72. The method of any one of claims 69 to 71 , wherein the therapeutically effective amount of the N-acylethanolamine or pharmaceutically acceptable salt thereof comprises: from about 2.86 mg / kg body weight per day to about 25.71 mg / kg body weight per day; from about 3.57 mg / kg body weight per day to about 22.14 mg / kg body weight per day; from about 4.29 mg / kg body weight per day to about 17.14 mg / kg body weight per day; from about 5.0 mg / kg body weight per day to about 13.57 mg / kg body weight per day; from about 5.71 mg / kg body weight per day to about 11.42 mg / kg body weight per day; from about 6.43 mg / kg body weight per day to about 10.71 mg / kg body weight per day; or from about 7.14 mg / kg body weight per day to about 8.57 mg / kg body weight per day.

73. The method of any one of claims 69 to 72, wherein the therapeutically effective amount of the N-acylethanolamine or pharmaceutically acceptable salt thereofis administered simultaneously with the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof.

74. The method of claim 73, wherein the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof and the therapeutically effective of N- acylethanolamine of pharmaceutically acceptable salt thereof are formulated in a single pharmaceutical composition.

75. The method of any one of claims 69 to 73, wherein the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof and the therapeutically effective of N-acylethanolamine of pharmaceutically acceptable salt thereof are formulated in separate pharmaceutical compositions.

76. The method of any one of claims 69 to 72, wherein the therapeutically effective amount of the N-acylethanolamine or pharmaceutically acceptable salt thereof and the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof are administered sequentially.

77. The method of any one of claims 69 to 76, wherein the N- acylethanolamine comprises N-palmitoylethanolamine (PEA), Me- palmitoylethanolamide (Me-PEA), palmitoylcyclohexamide, palmitoylbutylamide, oleoylethanolamine (OEA), palmitoylisopropylamide (PIA), pharmaceutically salts thereof, or any combination thereof.

78. The method of any one of claims 69 to 77, wherein the N- acylethanolamine or pharmaceutically acceptable salt thereof comprises PEA or a pharmaceutically acceptable salt thereof.

79. The method of any one of claims 39 to 78, wherein the subject has a healthy body weight or healthy body mass index.

80. The method of any one of claims 39 to 79, wherein the subject has at least one metabolic disorder.81 . The method of claim 80, wherein the at least one metabolic disorder results from chronic consumption of a high-fat diet.

82. The method of claim 80 or 81 , wherein the at least one metabolic disorder is selected from obesity, dyslipidemia, diabetes, hyperglycemia, hyperlipidemia, hypercholesterolemia, insulin-resistance, hyperinsulinemia, glucose intolerance, and hepatic steatosis.

83. The method of any one of claims 39 to 82, wherein the subject is on a weight loss regimen.

84. The method of claim 83, wherein the weight loss regimen alone led to a plateau in weight loss, at least one adverse side effect, or a combination thereof.

85. The method of claim 83 or 84, wherein the weight loss regimen comprises a diet regimen, an exercise regimen, a medication, or a combination thereof.

86. The method of claim 85, wherein the medication comprises a GLP-1 receptor agonist.

87. The method of claim 85, wherein the medication comprises metformin.

88. The method of any one of claims 83 to 87, wherein combining the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof with the weight loss regimen further increases weight loss in the subject relative to weight loss prior to administration of MEAI.

89. A method for losing weight comprising administering to a subject in need of weight loss a therapeutically effective amount of 5-methoxy-2-aminoindan (MEAI) or a pharmaceutically acceptable salt thereof and a GLP-1 receptor agonist.

90. The method of claim 89, wherein the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof comprises from about 0.5 mg to about 520 mg.91 . The method of claim 89 or 90, wherein the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof comprises from: about 10 mg to about 520 mg; about 10 mg to about 250 mg; about 20 mg to about 520 mg; about 20 mg to about 250 mg; about 20 mg to about 200 mg; about 20 mg to about 175 mg; about 20 mg to about 150 mg; about 20 mg to about 125 mg; about 20 mg to about 100 mg; or about 20 mg to about 50 mg.

92. The method of any one of claims 89 to 91 , wherein the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof comprises: from about 20 mg to about 250 mg; from about 20 mg to about 200 mg; from about 20 mg to about 175 mg; or from about 20 mg to about 150 mg.

93. The method of any one of claims 89 to 92, further comprising administering a therapeutically effective amount of an N-acylethanolamine or a pharmaceutically acceptable salt thereof.

94. The method of claim 93, wherein the therapeutically effective amount of the N-acylethanolamine or pharmaceutically acceptable salt thereof comprises: from about 200 to about 1800 mg; from about 250 to about 1550 mg; from about 300 to about 1200 mg; from about 350 to about 950 mg; from about 400 to about 800 mg; from about 450 to about 700 mg; or from about 500 to about 600 mg.

95. The method of claim 93 or 94, wherein the therapeutically effective amount of the N-acylethanolamine or pharmaceutically acceptable salt thereof comprises about 400 mg or about 800 mg.

96. The method of any one of claims 93 to 95, wherein the N- acylethanolamine comprises N-palmitoylethanolamine (PEA), Me- palmitoylethanolamide (Me-PEA), palmitoylcyclohexamide, palmitoylbutylamide, oleoylethanolamine (OEA), palmitoylisopropylamide (PIA), pharmaceutically acceptable salts thereof, or any combination thereof.

97. The method of any one of claims 93 to 96 wherein the N-acylethanolamine or pharmaceutically acceptable salt thereof comprises PEA or a pharmaceutically acceptable salt thereof.

98. The method of any one of claims 89 to 97, wherein the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof is administered for at least about 5 days, at least about 10 days, at least about 15 days, at least about 20 days, at least about 25 days, at least about 30 days, at least about 45 days, at least about 60 days, at least about 90 days, at least about 120 days, at least about 150 days, at least about 180 days, at least about 210 days, at least about 240 days, at least about 270 days, at least about 300 days, at least about 330 days, or at least about 360 days.

99. The method of any one of claims 89 to 98, wherein the GLP-1 receptor agonist is administered once every 7 days.

100. The method of claim 99, wherein the GLP-1 receptor agonist is administered at an amount of from about 0.25 mg to about 2.5 mg.101 . The method of claim 99 or 100, wherein the GLP-1 receptor agonist comprises semaglutide.

102. The method of any one of claims 89 to 98, wherein the GLP-1 receptor agonist is administered once daily.

103. The method of claim 102, wherein the GLP-1 receptor agonist is administered at an amount of from about 0.5 mg to about 2 mg.

104. The method of claim 102 or 103, wherein the GLP-1 receptor agonist comprises liraglutide.

105. The method of any one of claims 16 to 25, wherein a molar ratio of the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof to the therapeutically effective amount of N-acylethanolamine or pharmaceutically acceptable salt thereof is from about 1 :0.2 to about 1 :2000.

106. The method of claim 105, wherein the molar ratio is: from about 1 :0.2 to about 1 :100; from about 1 :0.2 to about 1 :50; from about 1 :0.2 to about 1 :40; from about 1 :0.2 to about 1 :30; from about 1 :0.2 to about 1 :20; or from about 1 :0.2 to about 1 :10.

107. The method of any one of claims 69 to 78, wherein a molar ratio of the therapeutically effective amount of MEAI or pharmaceutically acceptable salt thereof to the therapeutically effective amount of N-acylethanolamine or pharmaceutically acceptable salt thereof is from about 1 :0.2 to about 1 :2000.

108. The method of claim 107, wherein the molar ratio is: from about 1 :0.2 to about 1 :100; from about 1 :0.2 to about 1 :50; from about 1 :0.2 to about 1 :40; from about 1 :0.2 to about 1 :30; from about 1 :0.2 to about 1 :20; or from about 1 :0.2 to about 1 :10.

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