Concomitant medications, functional foods, and supplements: An Obesity Medicine Association (OMA) Clinical Practice Statement (CPS) 2022

Abstract

Background

This Obesity Medicine Association (OMA) Clinical Practice Statement (CPS) is intended to provide clinicians an overview of the body weight effects of concomitant medications (i.e., pharmacotherapies not specifically for the treatment of obesity) and functional foods, as well as adverse side effects of supplements sometimes used by patients with pre-obesity/obesity.

Methods

The scientific information for this CPS is based upon published scientific citations, clinical perspectives of OMA authors, and peer review by the Obesity Medicine Association leadership.

Results

This CPS outlines clinically relevant aspects of concomitant medications, functional foods, and many of the more common supplements as they relate to pre-obesity and obesity. Topics include a discussion of medications that may be associated with weight gain or loss, functional foods as they relate to obesity, and side effects of supplements (i.e., with a focus on supplements taken for weight loss). Special attention is given to the warnings and lack of regulation surrounding weight loss supplements.

Conclusions

This Obesity Medicine Association (OMA) Clinical Practice Statement (CPS) on concomitant medications, functional foods, and supplements is one of a series of OMA CPSs designed to assist clinicians in the care of patients with the disease of pre-obesity/obesity. Implementation of appropriate practices in these areas may improve the health of patients, especially those with adverse fat mass and adiposopathic metabolic consequences.

1. Introduction

Beginning in 2013, the Obesity Medicine Association (OMA) created and maintained an online Adult “Obesity Algorithm” (i.e., educational slides and eBook) that underwent yearly updates by OMA authors and was reviewed and approved annually by the OMA Board of Trustees [1]. This was followed by a similar Pediatric “Obesity Algorithm” with updates approximately every two years by OMA authors. This OMA Clinical Practice Statement (CPS) on concomitant medications, functional foods, and supplements was derived from this OMA Adult Obesity Algorithm and is one of a series of OMA CPSs designed to assist clinicians in the care of patients with pre-obesity/obesity.

2. Concomitant medications

Beyond anti-obesity medications, patients with pre-obesity/obesity are prescribed medications that may affect body weight. Table 1 lists 10 takeaway messages regarding obesity and concomitant medications.

Table 1.

Top 10 Takeaway Messages: Obesity and Concomitant Medications. Patients with obesity are often treated with multiple medications. Many drugs are associated with decreased, increased, or variable effects on body weight [2].

Anti-hypertensive medications most associated with body weight gain include some beta-blockers (propranolol, atenolol, and metoprolol) and some calcium channel blockers (weight gain mainly through edema, such as nifedipine and amlodipine).

Anti-diabetes medications that most promote body weight gain include most insulins, sulfonylureas, thiazolidinediones, and meglitinides

Hormone therapies that most promote body weight gain include glucocorticoids and injectable progestins.

Anti-seizure medications most associated with body weight gain include carbamazepine, gabapentin, valproate, and pregabalin.

Anti-depressants most associated with body weight gain include some tricyclic antidepressants (especially amitriptyline) some selective serotonin reuptake inhibitors (especially paroxetine), some selective serotonin and norepinephrine reuptake inhibitors (venlafaxine), some irreversible monoamine oxidase inhibitors (isocarboxazid, phenelzine), as well as other antidepressants such as mirtazapine.

Mood stabilizers most associated with body weight gain include gabapentin, divalproex, lithium, valproate, vigabatrin, cariprazine, and carbamazepine.

Migraine medications most associated with body weight gain include amitriptyline, gabapentin, paroxetine, valproic acid, and some beta blockers.

Antipsychotics most associated with body weight gain are clozapine, olanzapine, and zotepine.

Chemotherapeutic and anti-inflammatory agents most associated with body weight gain include tamoxifen, cyclophosphamide, methotrexate, 5-fluorouracil, aromatase inhibitors, and corticosteroids.

Other drugs associated with body weight gain include hypnotics such as zolpidem (i.e., sleep-related eating disorder) and diphenhydramine, some anti-seizure medications and antidepressants used for treatment of neuropathy, and some highly active antiretroviral therapies (HAART) protease inhibitors when not accompanied by lipodystrophy-associated weight loss.

2.1. Concomitant pharmacotherapy: Limitations in reported effects on body weight

Publications regarding the weight effects of concomitant non-anti-obesity medications should be interpreted with caution. With few exceptions, data from such publications are generally derived from observational studies not specifically designed to evaluate the effects of these medications on body weight. Comparisons of weight effects are often derived from the reported effects of medications from different studies, rather than derived from a direct head-to-head comparison within the same controlled clinical trial. Studies often report variable weight effects, depending on the condition being treated (e.g., psychiatric medications being used for multiple psychiatric conditions), dataset, and type of analysis (i.e., head-to-head, placebo-controlled, versus meta-analysis). Some therapeutics may especially have inconsistently reported weight effects (e.g., haloperidol, sertraline)] [[2], [3], [4], [5], [6], [7], [8], [9], [10]]. Finally, the reported weight effects of concomitant medications are most often expressed as mean values, with the potential for wide variances in individual weight responses to a particular drug.

2.2. Concomitant pharmacotherapy that might alter body weight

Many concomitant medications may potentially impact body weight. Table 2 shows cardiovascular medications and their potential effects on body weight. Table 3 shows diabetes mellitus medications and their potential impacts on body weight. Table 4 shows hormone treatments that may impact body weight. Table 5 shows anti-seizure medications that may impact body weight.

Table 2.

The Effect of Cardiovascular Medications on Body Weight. Shown are common cardiovascular medications and their potential effects on body weight.

Cardiovascular medication	Associated effect on body weight	References
Beta blockers
Propranolol, atenolol, metoprolol	May increase body weight	[11]
Carvediolol	May not increase body weight	[11]
Calcium channel blockers
Older and/or less lipophilic dihydropyridines (“dipine”), such as nifedipine and amlodipine	May increase body weight due to edema, possibly because these medications are more vasodilatory. The increased edema may exacerbate obesity-related edema (and sleep apnea related peripheral edema) and confound estimates of body fat when only measuring body weight.	[12,13]
Non-dihydropyridines (e.g., diltiazem and verapamil)	May not increase body weight (i.e., less edema)	[12,13]

Table 3.

The Effect of Diabetes Mellitus Medications on Body Weight. Shown are common diabetes mellitus medications and their potential effects on body weight.

Diabetes mellitus medication	Associated effect on body weight	References
Most insulins	May increase body weight	[12,14,15]
Sulfonylureas	May increase body weight	[12,14,15]
Thiazolidinediones (“-zones”)	May increase body weight	[12,14,15]
Meglitinides (e.g., nateglinide, repaglinide)	May increase body weight	[[12], [13], [14]]
Metformin	May decrease body weight	[[12], [13], [14], [15]]
Glucagon-like peptide-1 receptor agonists (e.g., “-tides”)	May decrease body weight	[[12], [13], [14], [15]]
Sodium glucose co-transporter 2 inhibitors (e.g., “-flozins”)	May decrease body weight	[12,15,16]
Alpha glucosidase inhibitors (e.g., acarbose, miglitol)	May decrease body weight	[12,13,15]
Amylin mimetic (pramlintide)	May decrease body weight	[[12], [13], [14], [15]]
Dipeptidyl peptidase-4 (DPP4) inhibitors (e.g., “-gliptins”)	Have a neutral effect on body weight	[12,14,15]

Table 4.

The Effect of Hormone Treatments on Body Weight. Shown are common hormone treatments and their potential effects on body weight^a.

Hormone	Associated effect on body weight	References
Glucocorticoids	May increase body weight, with a disproportionate increase in visceral fat	[13]
Progestin	Has a variable effect on body weight. Progestin contraceptives have effects that are dependent upon the individual; injectable or implantable progestins may have greatest risk for weight gain.	[15]
Estrogen	While individual variance may exist, combination oral hormonal contraceptives (i.e., estrogen and progestin) do not generally alter body weight. Postmenopausal estrogen replacement therapy may help mitigate menopausal-related increase in abdominal fat deposition.	[17,18]
Testosterone	Has a variable effect on body weight; may reduce percent body fat and increase lean body mass, especially if used to replace testosterone deficiency in men	[15]

^a“Bioidentical hormones” are compounded drugs that are marketed to be chemically and structurally identical to hormones produced by the human body. According to the FDA Office of Women's Health, the FDA does not have evidence that compounded “bioidentical hormones” are safer or more effective than FDA-approved hormone therapy. (https://www.fda.gov/media/130242/download) Among the most common reported side effects with bioidentical hormone replacement therapy is weight gain [19].

Table 5.

The Effect of Anti-Seizure Medications on Body Weight. Shown are common anti-seizure medications and their potential effects on body weight.

Anti-seizure medication	Associated effect on body weight	References
Carbamazepine	May increase body weight	[13,15]
Gabapentin	May increase body weight	[13,15]
Valproate	May increase body weight	[15]
Pregabalin	May increase body weight	[15,20]
Topiramate	May decrease body weight	[13,15,21]
Zonisamide	May decrease body weight	[13,15]

Reports on body weight are not always consistent regarding anti-depressants; common types of anti-depressants and their potential impact on body weight are shown in Table 6. Various mood stabilizers and their potential impacts on body weight are shown in Table 7. Table 8 shows migraine medications and their potential impacts on body weight. While reports are not uniform, Table 9 shows antipsychotic medications and their various reported effects on body weight. Table 10 shows hypnotics and their potential effects on body weight. Table 11 shows common neuropathy and pain treatments and their potential impacts on body weight. Table 12 shows human immunodeficiency virus (HIV) medications that may impact body weight. Table 13 shows chemotherapies and anti-inflammatory agents that may impact body weight. Table 14 shows antihistamines commonly used to treat allergy symptoms that may be associated with weight gain. Table 15 shows organ transplant medications and their potential impacts on body weight.

Table 6.

The Effect of Anti-Depressants on Body Weight. Shown are common anti-depressants and their potential effects on body weight.

Anti-depressant	Associated effect on body weight	References
Tricyclic antidepressants (tertiary amines) such as amitriptyline, doxepin, imipramine, and dosulepin	May increase body weight	[15,22,23]
Selective serotonin reuptake inhibitors such as paroxetine and citalopram	May increase body weight	[3,13,15,[22], [23], [24]]
Selective serotonin and norepinephrine re-uptake inhibitors such as venlafaxine	May increase body weight	[3,13,15]
Irreversible monoamine oxidase inhibitors such as isocarboxazid and phenelzine	May increase body weight	[15]
Trazodone, mirtazapine, and brexpiprazole	May increase body weight	[3,13,15,[23], [24], [25], [26]]
Bupropion	May decrease body weight	[13,15,[22], [23], [24]]
Tricyclic antidepressants (secondary amines) such as desipramine, nortriptyline, and protriptyline	Variable effects on body weight	[13,15,22]
Selective serotonin reuptake inhibitors, such as escitalopram and sertraline	Variable effects on body weight	[3,13,15,22]
Serotonin and norepinephrine re-uptake inhibitors, such as desvenlafaxine and duloxetine	Variable effects on body weight	[3,13,15,22]
Irreversible monoamine oxidase inhibitors such as tranylcypromine	Variable effects on body weight	[27]
Serotonergic agents such as vortioxetine	Variable effects on body weight	[28]

∗ As previously discussed, wide variance exists in individual weight responses to medications. Also, relatively few studies exist that directly compare individual drugs within the context of a prospective, randomized, controlled, dedicated body weight trial. Given the lack of available data and variance of data, it is challenging to objectively rank medications within a class, regarding their effects on body weight. However, certain antidepressant medications are described to be especially associated with weight gain, such as amitriptyline, paroxetine, and mirtazapine [29,30].

Table 7.

The Effect of Mood Stabilizing Medications on Body Weight. Shown are common mood stabilizing medications and their potential effects on body weight.

Mood stabilizing medication	Associated effect on body weight	References
Gabapentin	May increase body weight	[13,15]
Divalproex	May increase body weight	[13,15]
Lithium	May increase body weight	[13,23,31]
Valproate	May increase body weight	[15,23]
Vigabatrin	May increase body weight	[15]
Cariprazine	May increase body weight	[32,33]
Carbamazepine	May increase body weight	[13,15,23,33]
Lamotrigine	Variable or neutral effects on body weight; sometimes reported to decrease body weight	[13,15,23]
Oxcarbazepine	Variable or neutral effects on body weight	[23]

Table 8.

The Effect of Migraine Medications on Body Weight. Shown are common migraine medications and their potential effects on body weight.

Migraine medication	Associated effect on body weight	References
Non-steroidal anti-inflammatory drugs (NSAIDS)	Neutral effect on body weight. If weight gain occurs with some NSAIDS, then it may be due to edema from drug-induced kidney injury.	[34]
Amitriptyline	May increase body weight	[13,15,22]
Gabapentin	May increase body weight	[13,15]
Paroxetine	May increase body weight	[13,15,22,24]
Valproic acid and divalproex	May increase body weight	[15]
Some beta-blockers	May increase body weighta	[13]
Topiramate	May decrease body weight	[13,15]
Zonisamide	May decrease body weight	[13,15]
Dihydroergotamine [35]	Neutral effect on body weight	b
Triptans (e.g., sumatriptan, rizatriptan, zolmitriptan) [36,37]	Neutral effect on body weight	b
5-HT 1F receptor agonist (i.e., Lasmiditan) [36,37]	Neutral effect on body weight	b
Calcitonin gene-related peptide receptor (CGRP) receptor antagonists (e.g., ubrogepant, rimegepant, galcanezumab, atogepant) [37,38]	Neutral effect on body weight	b

^aSee Table 2.

^bLack of published data to support change in body weight.

Table 9.

The Effect of Antipsychotic Medications on Body Weight. Shown are common mood stabilizing medications and their potential effects on body weight^a.

Antipsychotic medication	Associated effect on body weight	References
Clozapine	May increase body weight	[2,2,13,15,23,24,39]
Olanzapine	May increase body weight	[2,13,15,23,27,39]
Zotepine (not available in U.S.)	May increase body weight	[2]
Chlorpromazine	May increase body weight	[39]
Brexpiprazole	May increase body weight	[2,25]
Iloperidone	May increase body weight	[2,24,39]
Lithium	May increase body weight	[13,23,31,39]
Quetiapine	May increase body weight	[2,13,15,24,39]
Risperidone	May increase body weight	[2,13,15,24,39]
Thioridazine	May increase body weight	[40]
Amisulpride	Neutral or variable effects on body weight	[2,15,23,39]
Aripiprazole	Neutral or variable effects on body weight	[2,13,15,23,24,39]
Asenapine	Neutral or variable effects on body weight	[2,24,39]
Cariprazine	Neutral or variable effects on body weight	[2,32,33]
Haloperidol	Neutral or variable effects on body weight	[2,13,39]
Loxapine	Neutral or variable effects on body weight	[41]
Lurasidone	Neutral or variable effects on body weight	[2,24,39]
Ziprasidone	Neutral or variable effects on body weight	[2,13,15,23,24,39]
Paliperidone	Neutral or variable effects on body weight	[2,24,39]
Perphenazine	Neutral or variable effects on body weight	[15,39]

^aAs previously discussed, wide variance exists in individual weight responses to medications. Also, relatively few studies exist that directly compare individual drugs within the context of a prospective, randomized, controlled, dedicated body weight trial. Given the lack of available data and variance of data, it is challenging to objectively rank medications within a class, regarding their effects on body weight. However, certain antipsychotic medications are described to be especially associated with weight gain, such as clozapine, olanzapine, and zotepine [42].

Table 10.

The Effect of Hypnotics on Body Weight. Shown are common mood stabilizing medications and their potential effects on body weight.

Hypnotic	Associated effect on body weight	References
Diphenhydramine	May increase body weight	[22,23]
Zolpidem	May increase risk of sleep-related eating disorder	[43]
Benzodiazepines	May have limited effects on body weight	[22,23]
Melatonergic hypnotics	May have limited effects on body weight	[22,23]
Trazodonea	May have limited effects on body weight	[22,23]

^aAs discussed, the reported effect of drugs on body weight can vary, depending on their intended use.

Table 11.

The Effect of Mood Stabilizing Medications on Body Weight. Shown are common mood stabilizing medications and their potential effects on body weight.

Neuropathy/pain treatment	Associated effect on body weight	References
Nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen	May not lead weight change (unless edema occurs due NSAID-induced kidney damage)	[15]
Gabapentin and pregabalin	May lead to weight gain	[15,20]
Antidepressants used for the treatment of neuropathy or pain (e.g., amitriptyline, doxepin, duloxetine, and venlafaxine)	Potential weight gain, especially with amitriptyline	[15,29,30]
Nortriptyline	Neutral effect on body weight	[15]
Topical treatments used for neuropathy and pain (capsaicin and lidocaine patches)	Neutral effect on body weight	[44]

Table 12.

The Effect of HIV Medications on Body Weight. Shown are common HIV medications and their potential effects on body weight HIV: Human Immunodeficiency Virus.

HIV medication	Associated effect on body weight	References
Highly active antiretroviral therapy (HAART) protease inhibitors without HIV-associated lipodystrophy	May increase body weight	[15,45]
Highly active antiretroviral therapies (HAART) protease inhibitors with HIV-associated lipodystrophy	May alter body composition with increase in abdominal and visceral fat	[45]
Dronabinol	Treatment may be associated with weight gain in patients with HIV or pretreatment anorexia nervosa	[[46], [47], [48]]

Table 13.

The Effect of Chemotherapies and Anti-inflammatory Agents on Body Weight. Shown are common chemotherapy and anti-inflammatory agents and their potential effects on body weight.

Chemotherapy/anti-inflammatory agent	Associated effect on body weight	References
Tamoxifen	May increase body weight	[49]
Cyclophosphamide	May increase body weight	[15,49]
Methotrexate	May increase body weight	[49]
5-fluorouracil	May increase body weight	[49]
Aromatase inhibitors	May increase body weight	[49]
Tumor necrosis factor alpha inhibitors	May increase body weight	[50]
Corticosteroids	May increase body weight	[15]
Apremilast	May decrease body weight	[51]
Dronabinol	May have no effect on weight in cancer patients and may decrease appetite in patients with somatic complaints	[[46], [47], [48]]

Table 14.

The Effect of Antihistamines on Body Weight.

Antihistamine	Associated effect on body weight	References
Diphenhydramine	May increase body weight	[[22], [23]]
Cyproheptadine	May increase body weight	[52]

Table 15.

The Effect of Organ Transplant Medications on Body Weight. Shown are common mood stabilizing medications and their potential effects on body weight.

Organ transplant medication	Associated effect on body weight	References
Corticosteroids (e.g., prednisone)	May increase body weight (as well as increase blood sugar, blood pressure, and blood lipids)	[53]
Calcineurin inhibitors (cyclosporin, tacrolimus)	May increase body weight as well as components of the metabolic syndrome	[54]
Mammalian target of rapamycin (mTOR) inhibitors (sirolimus, everolimus, temsirolimus)	May increase body weight as well as components of the metabolic syndrome	[54]

2.2.1. Metformin

Metformin is an oral medication used to treat high glucose levels in patients with type 2 diabetes mellitus. Metformin may:

• •Improve adiposopathic disorders, such as insulin resistance, polycystic ovary syndrome, and cardiovascular disease (especially when compared to sulfonylurea) [13,55,56].
• •Improve insulin sensitivity and reduce hunger via multifactorial effects such as enhancing the effects of gastrointestinal hormones applicable to weight loss (e.g., increased glucagon-like peptide-1 levels and receptors, increased peptide YY, decreased neuropeptide Y), all of which may facilitate long-term weight loss [[57], [58], [59]].
• •Help treat the complications of concurrent drug treatments, such as weight gain from antipsychotics and human immunodeficiency virus (HIV) protease inhibitors [55].
• •Metformin may help reduce the overall cancer rate and help improve the treatment of multiple cancers, including colon, ovary, lung, breast, and prostate [60,61].

2.2.2. Obesity and organ transplantations

The adiposopathic consequences of obesity promotes the most common metabolic disorders encountered in clinical practice (e.g., diabetes mellitus, hypertension, and dyslipidemia) [62], which are disorders that may contribute to organ failure (e.g., end-stage kidney disease, cardiomyopathy, non-alcoholic fatty liver disease) [63]. Additionally, obesity increases the difficulty, time, and rate of complications of surgical procedures, which may complicate the likelihood that patients with obesity will receive an organ transplant [64]. Once transplantation does occur, then a postoperative increase in body weight can be due to increased caloric intake, often related to a post-transplant improvement in health, symptoms, quality of life, and potential use of obesogenic drugs such as corticosteroids. However, corticosteroid avoidance alone does not mitigate increases in body weight after organ transplant [63].

Patients with obesity undergoing organ transplants (e.g., kidney transplant due to complications of obesity, diabetes mellitus, and hypertension, or liver transplant due to complications of obesity and non-alcoholic fatty liver disease) should optimally undergo pre-transplant medical nutrition therapy, physical activity recommendations, and possibly anti-obesity pharmacotherapy or bariatric surgery with continued weight management interventions post-operatively [64,65].

3. Functional foods

Functional foods are defined as nutrients with potentially favorable effects beyond basic macronutrient content (e.g., carbohydrates, fats, proteins) [66]. Ingested substances sometimes characterized as “functional foods” include fruits (e.g., berries, pomegranate, avocado), vegetables, nuts, seeds, legumes, whole grains, seafood, olive oil, fermented foods, herbs, and spices (e.g., ginger). Even beverages are sometimes described as functional foods (e.g., coffee, as well as green and black tea) [67]. Examples of bioactive compounds of functional foods include caffeine, catechins, gallic acid, anthocyanins, ascorbic acid, polyphenols, oleuropein, capsaicin, and quercetin [67].

Rarely, depending on the strength of the science, the FDA may grant functional foods health claims for marketing purposes, especially regarding prevention (as opposed to treatment) — such as a reduction in heart disease with soluble fiber. Specifically, foods made from oat bran (that contain beta-glucan and other healthful bioactive substances) can make claims regarding a reduction in heart disease, when combined with a low-fat diet. Table 16 lists common functional foods, their mechanisms of action, their efficacy, and adverse side effects.

Table 16.

Common Functional Foods. Shown are common functional foods, reported weight effects, and potential side effects. None of these functional foods are proven to induce and/or maintain clinically meaningful weight loss, none have been studied for safety with the level of rigor of FDA approved prescription medications, and none have undergone prospective, randomized, controlled clinical trials with clinical trial outcomes evidence of improvement in major outcomes health benefits (e.g., reduction in cardiovascular disease or reduction in mortality).

Intervention	Mechanism of Action	Effects	Side Effects
Dietary fiber [68,69]	May increase sense of fullness with meals, delay carbohydrate absorption, reduce fatty liver, and increase insulin sensitivity	While increased fiber may increase satiety and marginally decrease percent body fat, reported weight loss is inconsistent. Viscous fiber may promote mild weight loss.	Some patients may experience abdominal bloating or flatulence
Prebiotics [[70], [71], [72]]	While they may include non-carbohydrates, prebiotics usually contain indigestible oligosaccharides (e.g., fructo-oligosaccharides) that may stimulate intestinal bacteria growth (colonic lactobacilli and bifidobacteria), which may promote a microbiome conducive to weight loss	Some human studies support weight loss; weight loss most consistently reported in rodents	Bloating, flatulence
Probiotics [[70], [71], [72], [73], [74], [75]]	Bacteria such as lactobacilli (found in yogurt, dairy products, and sauerkraut) may provide protection against unfavorable yeast overgrowth and pathogenic bacteria	Some human studies support weight loss; weight loss most consistently reported in rodents	Generally safe, small risk of systemic infection in at-risk individuals [[76], [77], [78], [79]]
Caffeine with or without plant extracts [80,81]	May reduce hunger, increase fat oxidation, and improve alertness	Some studies suggest minor weight loss with caffeine containing foods and products [82]	High doses can cause anxiety, tremors, and cardiac dysrhythmias
Green tea (not extract) [[83], [84], [85]]	Contains caffeine, as well as epicatechin, epicatechin gallate, and epigallocatechin gallate (EGCG). While they may have antioxidant effects, it is unclear that the catechin component of green tea contributes to weight loss beyond the caffeine.	Meta-analyses suggest minor weight reduction.	Caffeine side effects include anxiety, tremors, and cardiac dysrhythmias; catechins may cause indigestion and constipation. Green tea extract is an important cause of liver injury.
Green coffee and extract [86]	Green coffee generally contains less caffeine than black coffee but also contains chlorogenic acid, which may have peroxisome proliferator activated receptor alpha activity.	Isolated studies suggest minor weight reduction with green coffee extract.	Caffeine side effects include anxiety, tremors, and cardiac dysrhythmias; catechins may cause indigestion and constipation.
Phytoestrogens [[87], [88], [89], [90]]	Plant-derived substances with potential estrogenic effects (isoflavones, flavones, and coumestans) often found in soy products	If soy-based foods are substituted for higher fat, higher calorie foods, then this may promote minor weight reduction. Animal studies suggest some phytoestrogens are associated with decreased lipogenesis.	Mild nausea, bloating, constipation. In women, phytoestrogens may disrupt endogenous hormone levels and ovulatory cycle. In men, typical doses are unlikely to cause feminization. Should be used with caution in women who are pregnant, nursing, or attempting to become pregnant.
Conjugated linoleic acid (CLA) [[91], [92], [93]]	Natural trans- or cis-fat (meats, milk, cheeses, butter, white mushrooms) may reduce lipogenesis and increase lipolysis, thermogenesis, and browning of white and brown adipose tissue.	May promote short-term, minimal weight reduction, with inconsistent data supporting sustained weight loss or clinically relevant long-term effects on body composition [94]	Supplements may cause nausea, indigestion, diarrhea, fatigue, fatty liver, insulin resistance, increased triglycerides, reduced high density lipoprotein cholesterol, and increase in inflammatory markers and white blood cell count [95].
Alpha Lipoic Acid (ALA) [96]	Antioxidant, short chain fatty acid found in yeast, liver, kidney, spinach, broccoli, and potatoes that may facilitate decreased food intake	A meta-analysis suggests alpha-lipoic acid may promote mild weight loss.	Rash, nausea, potentiation of hypoglycemic medications, potentially resulting in hypoglycemia
Medium Chain Triglycerides (MCT) [[97], [98], [99], [100]]	Fatty acid chains 6–12 carbons long (C6 = caproic acid; C8 = caprylic acid; C10 = capric acid; C12 = lauric acid) may increase anorexigenic hormones and ketone formation	Mild weight loss possibly due to increased release of anorexigenic leptin, peptide YY, increased satiety, effects on microbiome, and decreased hunger due to ketone facilitation	Nausea, vomiting, and diarrhea. May also increase orexigenic hormones associated with weight gain (ghrelin and neuropeptide Y), which may counteract and potentially mitigate other weight loss signaling
Vinegar (Apple Cider Vinegar) [[101], [102], [103], [104], [105]]	Fermenting yeast exposed to sugar (such as apple juice) generates alcohol. Vinegar may slow gastric emptying, increase satiety, and have effects upon the microbiome.	While small studies suggest vinegar may mildly reduce body weight, increase insulin sensitivity, and reduce postprandial glucose levels, a systemic review concluded that inadequate research of high quality exists to confirm health benefits from apple cider vinegar.	May promote erosion of tooth enamel; potentiate gastroparesis; cause esophagitis, bloating and indigestion; and potentially lower potassium blood levels
Resveratrol [106,107] [108]	Resveratrol was originally discovered in the roots of the white hellebore, but mostly recognized as the natural phenol and phytoalexin (i.e., natural anti-fungus agent) present in red wine.	A meta-analysis suggests that resveratrol intake may mildly reduce body weight, body fat, body mass index, and waist circumference.	The adverse effect profile of resveratrol is challenging due to contradictory data, and hormesis effects (i.e., biphasic low dose effects opposite of high dose effects).
Curcumin [109,110]	Curcumin is a polyphenol component of turmeric, which is a spice (curry powder).	Among patients with metabolic syndrome, a meta-analysis suggests curcumin may mildly reduce body weight and waist circumference.	Among the rare side effects reported include nausea, gastrointestinal/abdominal pain, and headache.
Ginger [67,111] [112]	Ginger is a member of the Zingiberaceae family, and a spice rich in volatile oils.	A meta-analysis suggests ginger intake may reduce body weight and waist to hip ratio.	Among the rare side effects include bad taste, heartburn, abdominal discomfort, weight gain, headache, dry mouth, and nausea.
Dairy products [113,114]	Dairy are milk-derived foods, containing sugars (lactose), fats, proteins, and calcium.	A meta-analysis suggests increased dairy consumption with an energy-restricted diet may result in lower body weight and fat mass.	Dairy products may cause nausea, bloating, and diarrhea, especially among patients with lactose intolerance, as well as potential worsening of acne.

4. Supplements

The Obesity Medicine Association has not endorsed the clinical use of any supplements. Supplements are defined as substances taken in addition to dietary intake, such as concentrated forms of a nutrient (e.g., vitamins), isolated formulations of a nutrient (e.g., herbs or botanicals), minerals, and amino acids [115]. Supplements do not go through an approval process by the FDA as occurs with pharmaceuticals; the FDA currently considers supplements more of a food than a drug. Supplements are not permitted to be marketed for the purpose of treating, diagnosing, preventing, or curing diseases, and supplement manufacturers are responsible for ensuring the supplement is safe and that claims of benefit are not false or misleading [116]. Table 17 shows the differences between supplements and functional foods. Table 18 lists the top 10 takeaways from the OMA regarding supplements as they relate to pre-obesity/obesity.

Table 17.

Supplements vs. Functional Foods. Supplements and functional foods have different definitions and marketing rules. Neither requires approval by the FDA.

	Supplements [115]	Functional Foods
Definition	Substances taken in addition to dietary intake, such as concentrated form of a nutrient (e.g., vitamins), isolated formulations of a nutrient (e.g., herbs or botanicals), minerals, and amino acids	Nutrients with potentially favorable effects beyond basic nutrition, such as oatmeal or foods high in substances that may have health benefits (e.g., many phytochemicals)
Approval process	Not applicable. The FDA considers supplements more of a food than drug.	Not applicable.
Marketing	Supplements are not permitted to be marketed for the purpose of treating, diagnosing, preventing, or curing diseases. Supplement manufacturers are responsible for ensuring the supplement is safe and that claims of benefit are not false or misleading [116].	The FDA may grant functional foods health claims, especially regarding prevention (as opposed to treatment), such as a reduction in heart disease with soluble fiber

Table 18.

Top 10 Takeaway Messages: Supplements and Pre-Obesity/Obesity. Shown are the top messages from the OMA regarding obesity and supplement use [117,118].

Supplements are substances taken in addition to dietary intake (e.g., vitamins, herbs, botanicals, minerals, and amino acids). No available supplement has prospective, randomized, controlled clinical trial evidence to support clinically meaningful and sustained weight loss with health outcomes benefits (i.e., reduction in cardiovascular disease or reduction in mortality).

The FDA does not approve supplements, as they are considered a food and not a drug.

Supplements are not permitted to be marketed for the purpose of treating, diagnosing, preventing, or curing diseases.

Some supplements have severe side effects, including death.

Herbal and dietary supplements are a common cause of hepatotoxicity (e.g., anabolic steroids and green tea extracts), especially multi-ingredient nutritional supplements.

The medical literature regarding supplements may be subject to publication bias.

Most dietary supplements have limited to no consistent data to support long-term weight loss efficacy and safety and have the potential for adverse supplement-to-drug interactions.

Some weight loss supplements continue to be marketed, even when banned by the FDA due to adverse effects.

Patients should be advised of the limited evidence supporting the efficacy and safety of many supplements and the lack of oversight by government agencies regarding the claims made about such supplements.

Human chorionic gonadotropin (HCG) is not effective for weight loss beyond hypocaloric intake. The FDA requires clinicians and facilities that market HCG for weight loss to post a disclaimer that “There is no substantial evidence that HCG increases weight loss beyond that resulting from caloric restriction, that it causes a more attractive or normal distribution of fat, or that it decreases the hunger and discomfort associated with calorie restrictive diets.”

4.1. 4.1 potential for publication bias

Clinicians should be cautious of the published literature regarding supplements or other therapies (including drugs), when the only available evidence is via infrequent and/or small studies. The disproportionate publication of positive or significant results compared to negative or non-significant results potentially compromises the objectivity of literature review and meta-analyses [119]. Negative or non-significant study results may be less likely to be submitted for publication, are often less likely to be accepted by journals for publication, and are potentially less likely to be cited by other journals and the media compared to studies with positive results [120].

4.2. Drugs are regulated differently than supplements

Supplements do not require an FDA negotiated clinical trial development program. Supplements are marketed without FDA approval, and are generally considered safe until proven unsafe. Drugs, on the other hand, require a development program acceptable to the FDA, cannot be marketed until they are FDA approved, and are not considered safe until they are proven safe. Once approved based upon clinical trial efficacy and safety, the FDA assigns an “indicated use” for pharmaceuticals. While they do not provide insight into health benefits or safety of supplements, independent organizations such as the United States Pharmacopeia Dietary Supplement Verification Program (USP verified logo) provide voluntary processes for supplement quality indicators (monographs), supporting that what is in the supplement matches what the label says is in the supplement [121]. Independent testing is also performed by companies such as ConsumerLab.com.

4.3. Supplements and hepatotoxicity

Increased herbal and dietary supplement (HDS) use is directly proportional to increased HDS-induced liver injury [118]. HDS-induced liver injury accounts for up to 20% of cases of hepatotoxicity in the U.S., and supplement-to-drug interactions may contribute to hepatotoxicity potential [122]. Major implicated agents include anabolic steroids and green tea extract. Most cases of HDS-induced liver injury are from multi-ingredient nutritional supplements [122].

4.4. Dietary supplement: definition according to the U.S. Food and drug administration

The Federal Food, Drug, and Cosmetic Act defines a dietary ingredient as a vitamin; mineral; herb or other botanical; amino acid; dietary substance for use by man to supplement the diet by increasing the total dietary intake; or a concentrate, metabolite, constituent, extract, or combination of the preceding substances. Unlike drugs, supplements are not intended to treat, diagnose, prevent, or cure diseases. That means supplements should not make claims, such as “reduces pain” or “treats heart disease.” Claims like these can only legitimately be made for drugs, not dietary supplements. Dietary supplements include such ingredients as vitamins, minerals, herbs, amino acids, and enzymes. Dietary supplements are marketed in forms such as tablets, capsules, softgels, gelcaps, powders, and liquids. Under existing law, including the Dietary Supplement Health and Education Act passed by Congress in 1994, the FDA can take action to remove products from the market, but the agency must first establish that such products are adulterated (e.g., that the product is unsafe) or misbranded (e.g., that the labeling is false or misleading).” [115].

4.5. Side effects of supplements with insufficient data

No supplement has sufficient human data to confirm consistent, clinically meaningful, long-term weight loss and improved health outcomes (i.e., reduction in cardiovascular disease or reduced mortality). Table 19 lists descriptions and potential side effects of these supplements.

Table 19.

Side Effects of Supplements with Insufficient Human Data to Confirm Consistent, Clinically Meaningful, Long-term Weight Loss.

Intervention	Side Effects	Description
Berberine [123]	Nausea, diarrhea, constipation, and abdominal pain	Alkaloid extract from plants such as berberis vulguris (barberry)
Chitosan [124,125]	Nausea, indigestion, bloating, flatulence, constipation, and possible allergic reactions	Derived from chitin, a component of crustacean/arthropod exoskeletons (starch like cellulose), has both insoluble and soluble properties
Forskolin [126]	Indigestion, hypotension with lightheadedness, syncope, blurred vision, nausea, pale skin, and fatigue	Extract from the mint family/Coleus forskohlii
Garcinia Cambogia [125,127,128]	Headache, nausea, mania, and possible rare cases of liver toxicity	Small green fruit extract containing hydroxycitric acid
Glucomannan [125,129,130]	Bloating, flatulence, and soft stools; tablets may cause esophageal obstruction	Hemicellulose polysaccharide soluble fiber from roots of the elephant yam
Glucosinolates [131]	High doses may cause goiter and hypothyroidism	Thioesters containing sulfur (mustard family)
Hoodia gordonii [125,132,133]	Increased blood pressure and pulse, headache, dizziness, nausea, vomiting	Succulent plant consumed by Bushmen in South Africa to reduce hunger
Irvingia gabonensis [125,134]	Flatulence, headache, sleep disturbances	Seeds from African mango/soluble fiber
Raspberry ketones [125]	Raspberry eructation (burps)	Extracted from raspberries
5-hydroxy-trypotophan [135]	Gastrointestinal symptoms and possible interactions with serotonergic drugs	Amino acid intermediate in the biosynthesis of serotonin, may be derived from seeds of the African Giffonia simplicifolia
Beta-glucans [125]	Flatulence	Soluble fiber polysaccharides found in wheat, oats, and barley
Caffeine added to other extracts [81,125]	Caffeine side effects include anxiety, tremors, and cardiac dysrhythmias.	Prior formulations included ephedra, resulting in hepatotoxicity, seizures, and adverse cardiovascular side effects.
Carnitine [125]	Nausea, vomiting, diarrhea, abdominal cramps, and fishy body odor. May increase trimethylamine N-oxide levels, which may increase the risk for cardiovascular disease.	Carnitine is a quaternary ammonium compound that transports long-chain fatty acids into mitochondria for oxidation and energy production.
Conjugated linoleic acid [125]	Abdominal discomfort, constipation, diarrhea, dyspepsia, and possible adverse effects on lipid and glucose metabolism	Fatty acids found in meat and dairy that may be either cis-fats or trans-fats.
Fucoxanthin [125]	Insufficient data to report side effects.	Marine xanthophyll carotenoid is found in seaweed and algae with limited vitamin functionality.
Guar gum [125]	Abdominal pain, flatulence, diarrhea, nausea	Galactomannan polysaccharide from guar beans
Pyruvate [125]	Diarrhea, gas, bloating, and possibly decreased HDL cholesterol levels	Alpha keto acid product of glycolysis. Can help generate amino acids, convert back to glucose, or help generate fatty acids.
Spinach extract [136]	May worsen hyperglycemia	Thylakoid derived from spinach
Yohimbine [125]	Headache, anxiety, agitation, hypertension, tachycardia, adverse cardiovascular events	Alkaloid found in African yohimbe tree bark that contains catecholamines

Abbreviations: HDL, high-density lipoprotein.

4.6. Weight loss supplements considered potentially unsafe by the FDA

Many weight loss supplements thought unsafe are available via the internet. Clinicians and patients should be aware of these products and their associated risks. Table 20 shows a selection of these supplements as well as their side effects and mechanisms of actions.

Table 20.

Weight Loss Supplements Considered Potentially Unsafe by the FDA. Clinicians and patients should be aware of potentially unsafe weight loss supplements that are available via the internet. Examples of such supplements along with their side effects and mechanisms of action are shown.

Intervention	Side Effects	Mechanism of Action
1,3-dimethylamylamine methylhexanamine- DMAA (geranium or pelargonium graveolens extract) [137]	Adverse adrenergic side effects (e.g., high blood pressure, myocardial infarction, psychiatric disorders, nervous system disorders, and sudden death)	Stimulant; often combined with caffeine
Ephedra (ma huang) [137]	Adverse adrenergic side effects (e.g., high blood pressure, palpitations, myocardial infarction, stroke, seizure, and sudden death)	Ephedrine and pseudoephedrine may reduce hunger
Bitter orange (citrus aurantium) is potentially unsafe when synephrine content is higher than recommended daily limits and when combined with caffeine or unsafe and undeclared synthetic ingredients [137]	Chest pain, anxiety, headache, musculoskeletal complaints, increased heart rate, increased blood pressure	Contains synephrine, which may reduce hunger
2,4 Dinitrophenol (2,4 DNP or DNP) [137]	Hyperthermia, tachycardia, diaphoresis, tachypnea, cardiac arrest, and death	Uncoupling of mitochondrial oxidative phosphorylation and increased fat metabolism
Phenylpropanolamine (PPA) [137]	Headache, tremor, insomnia, agitation, palpitations, high blood pressure, cerebral vasculitis, myocardial infarction, and hemorrhagic strokes	Synthetic sympathomimetic amine, functionally similar to amphetamine and ephedrine, with hunger suppressant effects
Sibutramine (some herbal “weight loss pills” are considered unsafe by the FDA due to sibutramine as an active component. The results of a clinical trial demonstrated prescription sibutramine increased myocardial infarction and stroke. Despite FDA warnings of the dangers of sibutramine, sibutramine can still be found as a “hidden ingredient” in weight loss supplements.) [137,138]	Headache, anxiety, dry mouth, insomnia, myocardial infarction, and stroke	Monoamine reuptake inhibitor, increasing norepinephrine, serotonin, and dopamine concentrations in the synaptic clefts and suppressing hunger. Sibutramine was removed from the market as an anti-obesity pharmaceutical in 2010.

4.7. Weight loss therapies with a mandated disclaimer by the FDA

Human chorionic gonadotropin (HCG) has a mandated disclaimer by the FDA. The 1976 FDA disclaimer for HCG states, “There is no substantial evidence that HCG increases weight loss beyond that resulting from caloric restriction, that it causes a more attractive or normal distribution of fat, or that it decreases the hunger and discomfort associated with calorie restrictive diets.” [139] The proposed mechanism of action, effects, and warnings for HCG are shown in Table 21.

Table 21.

Weight Loss Therapies with Mandated Disclaimer by the FDA. Human chorionic gonadotropin is marketed for weight loss, but evidence does not support clinically significant weight loss. The FDA has mandated a disclaimer for HCG, and the American Medical Association considers it inappropriate to use for weight loss [141].

Intervention	Proposed mechanism of action	Effects
Human chorionic gonadotropin (HCG) [81,137,140,141]	Marketed as reducing appetite and preserving muscle mass during administration of very low-calorie diets	Meta-analyses do not support clinically significant weight loss. Since 1976, the FDA has mandated a disclaimer for those who administer HCG.	In 2016, the American Medical Association passed policy that “The use of HCG for weight loss is inappropriate.”

5. Conclusions

This Obesity Medicine Association (OMA) Clinical Practice Statement (CPS) on concomitant medications, functional foods, and supplements is designed to assist clinicians in the care of patients with the disease of pre-obesity/obesity. Both clinicians and patients may benefit with knowledge of the pros, cons, and potential dangers of foods, medications, and supplements that may be used or marketed for weight loss. Avoiding the potential side effects and potential toxicities of supplements may improve the health of patients, especially those with pre-obesity/obesity and the adiposopathic metabolic consequences.

6. Transparency [142]

This manuscript was largely derived and edited from the 2021 Obesity Medicine Association (OMA) Obesity Algorithm. Beginning in 2013, OMA created and maintained an online Adult “Obesity Algorithm” (i.e., educational slides and eBook) that underwent yearly updates by OMA authors and was reviewed and approved annually by the OMA Board of Trustees. This was followed by a similar Pediatric “Obesity Algorithm,” with updates approximately every two years by OMA authors. Authors of prior years’ version of the Obesity Algorithm are included in Supplement #1.

7. Group composition

Over the years, the authors of the OMA Obesity Algorithm have represented a diverse range of clinicians, allied health professionals, clinical researchers, and academicians. (Supplement #1) The authors reflect a multidisciplinary and balanced group of experts in obesity science, patient evaluation, and clinical treatment.

Author contributions

JT and HEB reviewed, edited, and approved the document.

Managing Disclosures and Dualities of Interest

Potential dualities or conflicts of interest of the authors are listed in the Individual Disclosure section. Assistance of a medical writer paid by the Obesity Medicine Association is noted in the Acknowledgements section. Neither the prior OMA Obesity Algorithms, nor the publishing of this Clinical Practice Statement received outside funding. The authors of prior OMA Obesity Algorithms never received payment for their writing, editing, and publishing work. Authors of this Clinical Practice Statement likewise received no payment for their writing, editing, and publishing work. While listed journal Editors received payment for their roles as Editors, they did not receive payment for their participation as authors.

8. Individual Disclosures

JT and HEB have no potential conflicts of interest to disclose.

9. Evidence

The content of the OMA Obesity Algorithm and this manuscript is supported by citations, which are listed in the References section.

10. Ethics review

This OMA Clinical Practice Statement manuscript was peer-reviewed and approved by the OMA Board of Trustee members prior to publication. Edits were made in response to reviewer comments and the final revised manuscript was approved by all the authors prior to publication. This submission did not involve human test subjects or volunteers.

11. Conclusions and recommendations

This Clinical Practice Statement is intended to be an educational tool that incorporates the current medical science and the clinical experiences of obesity specialists. The intent is to better facilitate and improve the clinical care and management of patients with pre-obesity and obesity. This Clinical Practice Statement should not be interpreted as “rules” and/or directives regarding the medical care of an individual patient. The decision regarding the optimal care of the patient with pre-obesity and obesity is best reliant upon a patient-centered approach, managed by the clinician tasked with directing an individual treatment plan that is in the best interest of the individual patient.

12. Updating

It is anticipated that sections of this Clinical Practice Statement may require future updates. The timing of such an update will depend on decisions made by Obesity Pillars Editorial team, with input from the OMA members and OMA Board of Trustees.

13. Disclaimer and limitations

Both the OMA Obesity Algorithms and this Clinical Practice Statement were developed to assist health care professionals in providing care for patients with pre-obesity and obesity based upon the best available evidence. In areas regarding inconclusive or insufficient scientific evidence, the authors used their professional judgment. This Clinical Practice Statement is intended to represent the state of obesity medicine at the time of publication. Thus, this Clinical Practice Statement is not a substitute for maintaining awareness of emerging new science. Finally, decisions by practitioners to apply the principles in this Clinical Practice Statement are best made by considering local resources, individual patient circumstances, patient agreement, and knowledge of federal, state, and local laws and guidance.

Appendix A. Supplementary data

The following is the Supplementary data to this article: