CPE Monthly: Hazardous Supplements
By Alexandria Hardy, RDN, LDN
Today’s Dietitian
Vol. 26 No. 2 P. 32

Dietary Supplements and Their Interactions

Take this course and earn 2 CEUs on our Continuing Education Learning Library

Dietary supplements are a step in many people’s daily routines for a variety of health and wellness reasons. The Academy of Nutrition and Dietetics (the Academy) states that micronutrient supplementation can be important and necessary if an individual isn’t consuming adequate nutrition through the diet. This may be due to pregnancy, lactation, aging, chronic disease, or potential malabsorption because of medication use.1 An example of a dietary supplement bridging a dietary gap is vitamin D, which can aid in musculoskeletal health and is a nutrient of concern per the 2020–2025 Dietary Guidelines for Americans.2,3 However, the utilization of dietary supplements can be considered risky, as efficacious doses, risk vs reward ratios, and pharmacological interactions aren’t clinically proven for all existing supplements. The Academy doesn’t recommend routine use of micronutrient supplementation for the general population due to inadequate research and potentially unsubstantiated regulatory claims.1

What Makes a Supplement Hazardous?
Supplements often are viewed as natural alternatives to pharmacological therapy, but many individuals don’t consider the risks they may carry due to a lack of regulation and scientific-based evidence. The safety and efficacy of ingesting certain botanical ingredients aren’t well researched in humans, and the dosage and frequency of consumption, combined with other supplements or medications, may create a dangerous reaction.4 Researchers hypothesize this is because both the dietary supplement and the drug share a similar structure for their absorption, distribution, metabolism, and/or excretion. As the two substances challenge one another, their actions in and on the body are altered.5 Another less frequent cause is a pharmacodynamic interaction, where the action of the dietary supplement directly affects the role of the drug in the body.5 Dietary supplements have been associated with various toxicities, including cardiac, hepatic, renal, neural, reproductive, dermal, and endocrine.4,6 The most commonly compromised categories of supplements include those touting weight loss, sexual enhancement, glycemic control, or athletic support claims.7-9

This continuing education course will evaluate dietary supplements for their safety and efficacy, with a focus on supplements that claim to improve health. Identification of hazardous supplements and their origins, application, and potential interactions will be reviewed as well as regulatory gaps and adverse events (AEs).

What Is a Dietary Supplement?
In 1994, the Dietary Supplement Health and Education Act defined supplements as “a vitamin; a mineral; an herb or other botanical; an amino acid; a dietary substance for use by man to supplement the diet by increasing the total dietary intake; or a concentrate, metabolite, a constituent, extract, or combination of any ingredient mentioned above.”1,10 They can be consumed orally as a powder, pill, tablet, liquid, gummy, or capsule or used topically as a cream or ointment.1,11 A dietary supplement’s purpose can be as general as a daily multivitamin or as specific as a powder for joint health.

Herbal supplements fall under the category of dietary supplements, and also can be known as botanicals or herbal remedies.12 An herbal dietary supplement is defined as a supplement whose active ingredients are derived from herbs, plants, algae, fungi, or lichen with the purpose to maintain or improve health.12,13 An entire plant or its components can be used in the development of herbal dietary supplements, including the seeds, roots, berries, and leaves.14 These extracts are rich in antioxidants, polyphenols, carotenoids, alkaloids, flavonoids, glycosides, saponins, and lignans.14,15 Individuals interested in herbal supplements may be more likely to use functional or integrative medicine and may use them to combat aches, pains, and colds, and to support their mental or emotional health.4 Herbal supplements often are viewed as more natural than traditional supplements or medications, which may appeal to individuals interested in holistic health.4 These supplements may be at best harmless but at worst have toxic potential; consumers should always discuss their dietary supplement intake with their health care providers.16

Brief History of Supplement Usage
The National Health and Nutrition Examination Survey (NHANES) has been collecting information regarding dietary supplements since the 1970s.17 NHANES data primarily are provided through recalls and questionnaires, which allows for a high possibility of human error in recalling type, quantity, and frequency of consumption.17

NHANES I (1971–1974) cited that 32.9% of 25- to 74-year-olds used dietary supplements.17 That number rose in NHANES II to 34.9%, though the population surveyed expanded the definition of adult to include individuals aged 18 to 74.17 The trend of increased supplement use continued to increase, with 40% of 20- to 74-year-olds reporting the use of at least one supplement in the past month in NHANES III and up to 52% in NHANES 1999–2000.17 This number remained a relatively accurate indicator of supplement use into the early 2010s, though 45% of adults surveyed reported taking more than one daily supplement.17

Today, roughly one-half of the American adult population uses supplements, with a projected 40% to 60% of individuals with chronic disease reportedly taking some form of dietary supplement.5 About 20% to 25% of individuals who take prescription medication also use dietary supplements, which is particularly concerning as these supplements may or may not be disclosed to their health care team, which can lead to negative drug-supplement interactions.5

Children and adolescents are a much smaller piece of the dietary supplement puzzle, with NHANES 1999–2000 reporting a decrease in dietary supplement use in children aged 1 to 5 and a stable rate of consumption for youths aged 6 to 19.17 Though the interdisciplinary team is most likely to recommend supplementation to children under the age of 2, only 17% of that age group regularly consumes a dietary supplement per NHANES 2007–2010.1 That percentage jumps to 45% in children aged 2 to 5 and then drops off to 35% in those aged 6 to 11 and 23% in individuals aged 12 to 19.1

Characteristics of Routine Supplement Purchasers
Supplements are used more frequently by women, non-Hispanic whites, nonsmokers, exercisers, individuals with an advanced education, people with more expendable income, and those who are in generally good health.1,18 A study published in Nutrients examined a group of 2,545 collegiate students in Warsaw, Poland, evaluating their supplement usage in comparison with their lifestyle choices.18 The researchers found that dietary supplement users were more likely to adhere to a special diet (26.7%), reported having high nutrition acuity (51.8%), and consumed meals more frequently throughout the day (55.8%), per a five-day food record.18 Dietary supplement users also were more likely than nondietary supplement users to follow a Mediterranean-style eating pattern, which aligns with the self-reported higher intakes of fruits, vegetables, proteins, legumes, seeds, and nuts.18

Adults typically take dietary supplements with the goal of improving or maintaining health, preventing future health problems (including high cholesterol, low bone density, and cardiac events), or bridging gaps in the diet.1,9 Individuals also are more likely to use a dietary supplement if they take more than three prescriptive medications; their dietary supplements generally are regarded as a means to enhance their overall wellbeing.6 It’s estimated that only 25% of supplements are recommended by a physician, and the rest are self-selected.9

Specific Supplement Usage
Athletes are one of the most common groups of people who turn to dietary supplementation, typically to legally improve their performance and health.8,14 Research estimates that 40% to 70% of athletes use dietary supplements, and up to 15% of those supplements may contain hazardous ingredients or components.8 One of the most common hazards is when an active ingredient is included in the dietary supplement but not disclosed on the label; examples include formerly approved drugs, experimental drugs, and drugs not intended for human use or consumption.8

Regulatory Practices
Dietary supplements currently are regulated by the FDA Center for Food Safety and Applied Nutrition.1,10 The FDA isn’t required to approve dietary supplements and doesn’t track the creation, marketing, and selling of new supplements.11 There’s no master list of all the different dietary supplements available for purchase in the United States.4,11 This can be problematic when clinicians are asked to review or recommend herbal supplements, as they can contain harmful botanical ingredients.4,11 For example, a review using information from the National Library of Medicine journal database and SciFinder discovered that there are up to 47 toxic components in 55 species in 46 different plant families that can cause detrimental effects on the heart, liver, kidneys, and digestive system.4

Safety and Quality
It’s the responsibility of the producers (manufacturers and distributors) to verify that the dietary supplement is safe before marketing and selling.1,11 Dietary ingredients that aren’t recognized as food substances sold after the implementation of the Dietary Supplement Health and Education Act must be proved to the FDA that they’re generally recognized as safe.1,4 Research shows that up to 20% of supplements may contain a banned ingredient.9 For example, if an ingredient in a sports supplement meets two of the following standards, it’s considered a banned ingredient. 19 The standards are as follows: Does the ingredient improve performance, is it deemed harmful for the consumer, and does it negatively impact the character of the game?19 If the FDA deems that the product isn’t safe, they possess the authority to remove it from the market.1,11 Quality control for dietary supplements is provided by the companies that manufacture them, not the FDA.

Labeling
All ingredients included in the dietary supplement must be listed on either the Supplement Facts panel or on the “other ingredients” list.11 Supplement ingredients can be listed as a vitamin, mineral, or macronutrient, while other ingredients can include preservatives, stabilizers, or flavor/color additives.11 Information regarding serving size, amount per serving, percentage of DV, and domestic contact information also must be included for reporting AEs.11 Manufacturers can submit their products to an impartial third party who can vet and certify the supplement by assessing their label claims, formulation, and potential contaminants. This is an optional process and not all DS should be viewed as safe as a result of this vetting.

Adverse Events
The FDA recommends that individuals consult with health care professionals before consuming dietary supplements to ensure supplement use is warranted.11 If an individual has a negative response or reaction after using a supplement, they’re to report this to their primary care physician, who can evaluate them and determine if an AE report should be filed.11 An AE is considered serious if it ends in death or a life-endangering experience, hospitalization, a disability, an anomaly, or a birth defect, or requires surgical or medical intercession.1

AEs can be reported by consumers, members of the interdisciplinary team, or manufacturers.1 These reports go through medWatch, which is the FDA Safety Information and Adverse Event Reporting Program.1 These AE reports must be presented to the FDA within 15 business days and are kept on file for six years.1 An AE doesn’t necessarily indicate that the supplement caused the incident, as there could be underlying health issues, medications, etc, that were responsible for the reaction.1 All reporters and subjects of AEs are classified.11

Weight loss supplements are the most likely type of dietary supplement to cause a serious AE, with more than 13,000 AEs and 2,000 hospitalizations reported annually.9 The primary complaints in these charges are cardiac complications, which are similar to the main symptoms of AEs in sports and sexual enhancement supplements.9 Supplements that claim to aid in glycemic control are the second type of dietary supplement most likely to cause a serious AE, and these typically affect the heart, nervous system, and gastrointestinal (GI) tract.7

Label Claims
A dietary supplement must be clearly marked as such on the label.10 Per FDA regulations, they also may carry a label claim, similar to a food or food product.20 These can be health claims, nutrient content claims, or structure/function claims. Health claims exist to explain the risk reduction between a supplement and a disease or health-related condition.20

Nutrient content claims use legal, descriptive language (eg, lite, free, reduced) to relate information about the supplement; “healthy” would be an example of a nutrient content claim.20 Structure/function claims can appear on foods, drugs, and dietary supplements.20 Their purpose is to describe how an ingredient may impact bodily structure or function.20 Dietary supplements also must include a disclaimer that states that the FDA hasn’t evaluated this statement and that the aim of the product isn’t to heal or alleviate disease; only drugs are legally allowed to carry this claim.11,20 These types of claims may reflect both nutritive and nonnutritive properties.20

Commonly Consumed Hazardous Supplements
Herbal medicine and herbal dietary supplement use is well documented throughout various cultures and regions worldwide.14 Per an article in Planta Medica, four billion people who live in developing countries use some form of herbal medicine as their initial form of medical management.4 The Herbal Supplements and Remedies marketplace in the United States was reportedly worth $12.2 billion in 2020, with projections reaching to $111.6 billion by 2026.13,21 Below is a discussion of 10 commonly consumed hazardous supplements and their potential risks, benefits, and efficacy. This continuing education course doesn’t recommend or endorse consumption of the following dietary supplements, particularly without oversight from members of the interdisciplinary team.

Aconitum
Aconitum is a category of herbal medicine that belongs to the family Ranunculaceae. 14,22 There are more than 400 species of these perennial plants worldwide, all recognized for their usage in traditional Chinese medicine.14,22-24 Historically, aconitum was used to relieve pain in inflammatory, digestive, and respiratory disease; it also was used to ease abdominal pains related to irregular menstruation.22

The active components of aconitum are alkaloids, and one of the most toxic is aconitine.22 A toxic dose of aconitine is one-tenth of 2 mg, with 2 mg considered a lethal dose.22 Toxicity occurs when aconite binds to and changes sodium channels, which can lead to a perpetually open channel that increases intracellular sodium and calcium while depolarizing the membrane.24 An AE can occur as early as 15 to 30 minutes postconsumption of the leaves or root and typically presents as cardiac in nature; the effects of toxicity are proportional to the dose ingested.24

Bitter Orange
Bitter orange also is known as Citrus aurantium or the Seville orange and is a fruit native to parts of Eastern Africa, Southeast Asia, the Arabian Peninsula, and Syria.25,26 Bitter orange is used topically to treat infections, pain, and bruising and is incorporated into weight loss products as an appetite suppressant.25,27-29 The main active ingredient in bitter orange is p-synephrine, which bears a chemical resemblance to ephedrine.25,28 Ephedrine is a banned substance per the FDA and the National Collegiate Athlete Association for its cardiac complications, and p-synephrine usually replaces it in supplements.25

When used in weight loss supplements, it’s frequently added to products that also contain stimulants, which can cause an increase in cardiac activity.27 Though bitter orange is generally recognized as safe, pregnant women and nursing mothers should abstain from use.27 This is partially because of a lack of research regarding its use in this population but also based on available data on animals, which suggest that adrenergic agents can decrease milk production.27

Chaparral
Chaparral is the name of the botanical extract from the leaves of the desert creosote bush, also known as Larrea tridentata.30 Chaparral historically has been used by Indigenous people to treat a variety of inflammatory and respiratory illnesses, primarily as a tea.30 Today, a more concentrated version of tea is still consumed, and chaparral also is used topically as a salve and ingested as a pill.30 Its active ingredient is nordihydroguaiaretic acid, which is present in the twigs and leaves of the plant. It can cause hepatotoxicity that’s dose and time dependent. Liver injury traditionally occurs within one to three months of beginning the supplement, but a toxic dose threshold is unknown.30,31

Chamomile
There are two aromatic plants that are both known as chamomile: the German chamomile (Matricaria recutita) and the Roman chamomile (Chamaemelum nobile).32,33 These plants can be used topically as an oil to treat skin abrasions or lacerations (German chamomile), ingested to ease GI symptoms, and used as a sleep and anxiety aid (Roman chamomile).32-35 There’s no clear understanding of chamomile’s active ingredients or medicinal effects.33,35 Hazardous uses of chamomile occur when tea leaves are incorrectly prepared and stored, which can lead to botulism.32 Drinking tea made from Roman chamomile leaves also can worsen skin rashes and, in some women, incite contact dermatitis or anaphylaxis.32 When consumed with asters (including echinacea, feverfew, and milk thistle, all of which can be found in herbal tea blends), cross-reactivity or sensitivity can occur.32

Colloidal Silver
Colloidal silver usually is taken as part of a homeopathic remedy for internal cleansing, cancer, diabetes, and arthritis.36 Ingestion of colloidal silver can cause leukocytoclastic vasculitis when ingested orally as a liquid; this is a particular risk if consumed multiple times per day.36 Historically, silver has been used to treat wounds due to its antimicrobial nature.37-39 The US Environmental Protection Agency set a reference dose of 5 μg/kg bw/day for chronic oral silver exposure; this is roughly the level where argyria (blue-gray skin discoloration) is seen.36,37 Many colloidal silver supplements exceed this limit, as they contain 10 to 30 mg/L of silver per serving; checking the label and serving size is important to avoid ingesting too much.37

Comfrey
Comfrey or Symphytum officinale is a type of flowering plant that can be consumed as a tea or capsule, or used topically.40-42 The pyrrolizidine alkaloids (a type of plant toxin) found in comfrey have been associated with liver damage, particularly acute sinusoidal obstruction syndrome and death.41 It’s currently considered a banned ingredient in the United States, per the FDA, in its oral form.42 As a topical cream, the extract is applied to treat minor scrapes, muscle pain, and blunt traumas.40 It’s sometimes used for pain relief on inflamed breasts by breastfeeding women but isn’t recommended because it may cause liver damage to the nursing infant if consumed.42

Greater Celandine
Greater celandine, also known as Chelidonium majus L, is a member of the poppy family.43,45 The entire plant contains a yellow-orange milky sap often used topically as an antimicrobial healer for warts, with the roots and immature fruit containing the most concentrated sources of active ingredients (alkaloids and phenolic acids).43-45

Side effects of greater celandine include cytotoxicity, hepatotoxicity, and phytotoxicity, which typically follows oral ingestion.44,45 Research suggests that liver damage may be reversible if supplementation desists, and that liver damage may be negatively impacted by drug interactions, particularly NSAIDS.44 Consumption should not exceed 6 g per day, or a total 2.5 mg of alkaloids, as these are believed to be toxic thresholds.43 Greater celandine shouldn’t be used in individuals with obstructed bile ducts or acute cholecystitis and hasn’t been studied in pregnant, lactating, or pediatric populations.43,45

St. John’s Wort
St. John’s wort, also known as Hypericum perforatum, is a flowering shrub found in temperate and tropical regions in Europe and Asia.46 It’s primarily used as an herbal agent to treat postpartum and mild-to-moderate clinical depression, often in conjunction with an antidepressant drug.46,47 Its active ingredient is unknown, but research suggests that its quercetin, hypericin, or hyperforin concentrates may mimic the actions of a serotonin reuptake inhibitor.46-49 St. John’s wort can be prepared as a tablet, liquid, tea, or capsule by grinding the flowers and leaves.46,47 St. John’s wort can react negatively when combined with other supplements or drugs (including but not limited to oral contraceptives, warfarin, simvastatin, indinavir, and digoxin) and can cause phytotoxicity, agitation, GI distress, hallucinations, hypertension, and tachycardia; it’s not recommended for individuals using these therapies.5,46,47,49-51 A suggested dosage is 300 mg with a 0.3% hypericin content three times daily, and only short-term; supervised use is recommended due to its propensity for side effects.46,47,51

Vitamin B17
Vitamin B17 also is known as amygdalin, laetrile (a drug created from amygdalin), or apricot seed, and is a biomolecule found in the pit of an apricot.52,53 It’s a bitter compound that can make hydrogen cyanide, which may be able to kill breast, cervical, bladder, and hepatic cancer cells but also can harm at-risk individuals.15,52,53

There are no controlled clinical trials available to draw data from, but both case and anecdotal reports haven’t proven its efficacy.53 The FDA hasn’t approved laetrile as a treatment for any medical condition.53 Side effects of laetrile treatments can include but aren’t limited to GI distress, headache, nerve damage, hypoxemia, coma, very low blood pressure, and death.53 These effects can worsen when taken orally and while also consuming excessive vitamin C, crushed fruit pits, raw almonds, and specific kinds of produce like celery, bean sprouts, peaches, and carrots, which also contain amygdalin.53

Yohimbine
Yohimbine, or Pausinystalia yohimbe, is found in the bark of an evergreen tree on the tropical African west coast.54 It traditionally has been used as a sexual enhancement supplement to boost low libido and prevent erectile dysfunction, though it also has been combined with lipolytic components in an effort to promote weight loss via lipolysis.55,56 The recommended dosage of yohimbine is 5 to 10 mg three times daily, though it may take time to build to that level.56

Its mechanism of action is unknown, but after being consumed in a powder or tablet form, yohimbine can pass through the blood-brain barrier and alter mood and behavior by affecting the central and peripheral nervous systems.54 It’s an alpha-2 adrenergic receptor antagonist, which means it can boost the quantity of epinephrine and norepinephrine in the blood stream.55,56 While seldom lethal, moderate to severe adverse effects are associated with ingestion, most of which are cardiac in nature.54,56

Areas of Future Research, Study Limitations
Many studies rely on self-reported data, which allow for a margin of error. There are few safe pharmacological profiles of the supplements discussed in this course, which leads to difficulty in making efficacious recommendations. Much of the published research regarding herbal dietary supplement use doesn’t contain an upper limit or threshold regarding dosage, or information on how the supplement in question reacts with other supplements or ingredients. Studying those questions in a variety of populations is an important step to fully understand the scope of their help or harm.33

Supplement production and storage also can affect safety and efficacy of the final product, and these variables often aren’t accounted for in clinical trials.44 Using the data in the NHANES database could be helpful to study overall dietary supplement use, consumer motivation, trends in usage, and how supplement use impacts overall health status.17 These data also could advise policymakers and help them better understand dietary deficiencies and potential changes to mass food fortification.17

Putting It Into Practice
All members of the interdisciplinary team should possess an elemental understanding of common poisonous plants, particularly those that are frequently used in herbal supplements.57 Primary care physicians can and should inquire about regular or incidental supplement use, and nurses or other clinical staff may request that the patient bring supplement bottles/packages to appointments.5 Patients may be hesitant to initiate this conversation, with some reports estimating that only 5% of people who take supplements discuss this in an outpatient setting with a primary care physician.6 Training clinicians to be aware of proven dietary supplement/drug interactions can be a critical step in ensuring patients receive safe, quality care.5

Pharmacists, pharmacologists, and dietitians are well suited to assess potential drug interactions and dietary gaps and can provide safety information and explain labeling claims as needed.1,5 For example, individuals who smoke or who have been exposed to asbestos shouldn’t take a supplement containing beta-carotene due to the association between lung cancer risk and beta-carotene supplementation.58 Reviewing label claims and ingredient lists with clients and decoding marketing claims and active/inactive ingredients is an important way to provide clients with knowledge they need to confidently and independently assess their supplements.8 Pointing out third-party confirmation of product ingredients also can be a helpful way to discern manufacturers who willingly have submitted their supplements for unbiased review, which hopefully indicates another degree of safety.8

Supplementation can be a helpful way to fill nutrient gaps in the diet and aid in normative growth and functions. However, taking unsupervised herbal dietary supplements can be unnecessary and even dangerous due to regulatory gaps, inappropriate claims, and a lack of scientific evidence.9,12 It’s the responsibility of each health care professional to be knowledgeable regarding banned substances (particularly for pregnant/lactating women and athletes), to clearly communicate the potential risks that accompany supplement use, and reiterate the difference in regulations and label claims.5,8

— Alexandria Hardy, RDN, LDN, is owner of Pennsylvania Nutrition Services, an insurance-based private practice in Pennsylvania.

 

Learning Objectives
After completing this continuing education course, nutrition professionals should be better able to:
1. Define the term “dietary supplement” per the FDA, and explain the potential effects of regular usage.
2. Distinguish five hazardous supplements and identify why they’re considered hazardous.
3. Analyze current government oversight of dietary supplements in the United States.

 

Examination
1. Who’s responsible for verifying the safety of a supplement?
a. The FDA
b. Producers
c. Marketers
d. Consumers

2. What type of supplement is responsible for the most adverse events and serious adverse events annually?
a. Supplements for weight loss
b. Supplements for glycemic control
c. Supplements for athletic support
d. Supplements for sexual enhancement

3. What percentage of American adults take a daily supplement?
a. 0% to 20%
b. 20% to 40%
c. 40% to 60%
d. 60% to 80%

4. What’s the most hazardous way to consume vitamin B17?
a. Intravenously
b. Topically
c. Orally
d. Intramuscularly

5. What percentage of supplements are recommended by a physician?
a. 10%
b. 15%
c. 20%
d. 25%

6. What’s considered a toxic dose of aconitine?
a. One-tenth of 1 mg
b. One-tenth of 2 mg
c. One-tenth of 3 mg
d. One-tenth of 4 mg

7. What can occur if bitter orange is added to a weight loss supplement?
a. Elevated cholesterol
b. Increase in blood sugar
c. Increase in cardiac activity
d. Renal failure

8. Which of the 10 supplements discussed in the course is most likely to have a hazardous absorption, distribution, metabolism, and/or excretion issue with a pharmacological agent?
a. Colloidal silver
b. Greater celandine
c. Chamomile
d. St. John’s wort

9. Which supplement can pass through the blood-brain barrier and affects the central and nervous systems?
a. Yohimbine
b. Vitamin B17
c. Comfrey
d. Chaparral

10. Comfrey contains pyrrolizidine alkaloids, which can cause damage to which organ?
a. Heart
b. Liver
c. Brain
d. Kidneys

 

References
1. Marra MV, Bailey RL. Position of the Academy of Nutrition and Dietetics: micronutrient supplementation. J Acad Nutr Diet. 2018;118(11):2162-2173.

2. Pludowski P, Takacs T, Boyanov M, et al. Clinical practice in the prevention, diagnosis and treatment of vitamin D deficiency: a Central and Eastern European expert consensus statement. Nutrients. 2022;14(7):1483.

3. US Department of Agriculture; Health and Human Services. Dietary Guidelines for Americans, 2020–2025. 9th Edition. https://www.dietaryguidelines.gov/sites/default/files/2020-12/Dietary_Guidelines_for_Americans_2020-2025.pdf. Published December 2020.

4. Hudson A, Lopez E, Almalki AJ, Roe AL, Calderón AI. A review of the toxicity of compounds found in herbal dietary supplements. Planta Med. 2018;84(9-10):613-626.

5. Asher GN, Corbett AH, Hawke RL. Common herbal dietary supplement–drug interactions. Am Fam Physician. 2017;96(2):101-107.

6. Mehta N, Germain MS, Quiel L. Dietary supplements: when too much of a good thing becomes harmful. Clin Case Rep. 2021;9(9):10.1002.

7. Schmitz SM, Lopez HL, Mackay D, Nguyen H, Miller PE. Serious adverse events reported with dietary supplement use in the United States: a 2.5 year experience. J Diet Supp. 2020;17(2):227-248.

8. Cadwallader AB. Seven points for athletes to consider before using a dietary supplement. AMA Journal of Ethics. 2022;24(5):E443-451.

9. Wierzejska RE. Dietary supplements—for whom? The current state of knowledge about the health effects of selected supplement use. Int J Environ Res Public Health. 2021;18:8897.

10. Dietary Supplement Health and Education Act of 1994. Public Law 103-417. 103rd Congress. National Institutes of Health Office of Dietary Supplements website. https://ods.od.nih.gov/About/DSHEA_Wording.aspx. Updated October 25, 1994. Accessed October 12, 2022.

11. Questions and answers on dietary supplements. FDA website. https://www.fda.gov/food/information-consumers-using-dietary-supplements/questions-and-answers-dietary-supplements. Updated May 6, 2022. Accessed October 13, 2022.

12. Williams CT. Herbal supplements: precautions and safe use. Nurs Clin North Am. 2021;56(1):1-21.

13. New analysis from global industry analysts reveals steady growth for herbal supplements and remedies, with the market to reach $111.6 billion worldwide by 2026. PR Newswire website. https://www.prnewswire.com/news-releases/new-analysis-from-global-industry-analysts-reveals-steady-growth-for-herbal-supplements-and-remedies-with-the-market-to-reach-111-6-billion-worldwide-by-2026--301486219.html. Updated February 22, 2022. Accessed October 18, 2022.

14. Kozhuharov VR, Ivanov K, Ivanova S. Higenamine in plants as a source of unintentional doping. Plants (Basel). 2022;11(3):354.

15. Felemban SG, Aldubayan, Alhowail AH, Almami IS. Vitamin B17 ameliorates methotrexate-induced reproductive toxicity, oxidative stress, and testicular injury in male rats. Oxid Med Cell Longev. 2020;4372719.

16. Charen E, Barbord N. Toxicity of herbs, vitamins, and supplements. Adv Chronic Kidney Dis. 2020;27(1):67-71.

17. Gahche JJ, Bailey RL, Potischman N, et al. Federal monitoring of dietary supplement use in the resident, civilian, noninstitutionalized US population: national health and nutrition examination survey. Nutr J. 2018;1436S-1444S.

18. Sicinska E, Madej D, Szmidt MK, Januszko O, Kałuża J. Dietary supplement use in relation to socio-demographic and lifestyle factors, including adherence to Mediterranean-style diet in university students. Nutrients. 2022;14(13):2745.

19. Mathews NM. Prohibited contaminants in dietary supplements. Sports Health. 2018;10(1):19-30.

20. Label claims for conventional foods and dietary supplements. FDA website. https://www.fda.gov/food/food-labeling-nutrition/label-claims-conventional-foods-and-dietary-supplements. Updated March 7, 2022. Accessed October 12, 2022.

21. Herbal supplements and remedies world market report. Global Industry Analysts website. https://www.strategyr.com/market-report-herbal-supplements-and-remedies-forecasts-global-industry-analysts-inc.asp. Updated February 2022. Accessed October 18, 2022.

22. Chan YT, Wang N, Feng Y. The toxicology and detoxification of Aconitum: traditional and modern views. Chin Med. 2021;16(1):61.

23. Yang X, Dai J, Guo D, et al. Changes in the properties of Radix Aconiti Lateralis Preparata (Fuzi, processed aconite roots) starch during processing. J Food Sci Technol. 2019;56(1):24-29.

24. Wood C, Coulson J, Thompson J, Bonner S. An intentional aconite overdose: a case report. J Crit Care Med. 2020;6(2):124-129.

25. Bitter orange. National Center for Complementary and Integrative Health website. https://www.nccih.nih.gov/health/bitter-orange. Updated May 2020. Accessed November 2, 2022.

26. Suntar I, Khan H, Patel S, Celano R, Rastrelli L. An overview on Citrus aurantium L.: its functions as food ingredient and therapeutic agent. Oxid Med Cell Longev. 2018;7864269.

27. Bitter orange. Drugs and Lactation Database National Library of Medicine website. https://www.ncbi.nlm.nih.gov/books/NBK501892/. Updated June 21, 2021. Accessed November 1, 2022.

28. Stohs SJ. Safety, efficacy, and mechanistic studies regarding Citrus aurantium (bitter orange) extract and p-synephrine. Phytother Res. 2017;31(10):1463-1474.

29. Dososky NS, Setzer WN. Biological activities and safety of Citrus spp. essential oils. Int J Mol Sci. 2018;19(7):1966.

30. Chaparral. LiverTox: clinical and research information on drug-induced liver injury. National Library of Medicine website. https://www.ncbi.nlm.nih.gov/books/NBK548355/. Updated May 25, 2022. Accessed November 2, 2022.

31. Manda G, Rojo AI, Martínez-Klimova E, Pedraza-Chaverri j, Cuadrado A. Nordihydroguaiaretic acid: from herbal medicine to clinical development for cancer and chronic diseases. Front Pharmacol. 2020;11:151.

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