Clinical Implications of Herbal Supplements in Conventional Medical Practice: A US Perspective

Herbal supplements are common complementary and alternative medicine (CAM) approaches with an ever-increasing use trend in the last two decades among the US population. Self-medication with herbal supplements which are promoted for general well-being, weight loss, immunity, and memory boost, and mental and physical health claims are very prevalent. There is a misperception that herbal supplements are harmless as they are prepared from natural sources. Unlike conventional drugs, the US Food and Drug Administration (FDA) does not regulate herbal supplements for premarketing purity and potency. Hence, there is a growing concern for health risks due to misbranded toxic ingredients, contaminants, adulterants, and herb-drug interactions (HDI) with co-administered drugs. The spectrum of pharmacological and toxicological effects of herbal supplements includes deranged lab results, allergic reactions, genotoxicity, carcinogenicity, teratogenicity, organ damage, and even fatality contributing to sizable emergency visits and hospitalizations in the US. The use of herbal supplements should be carefully monitored in high-risk groups such as pediatric and geriatric populations, pregnant women, breastfeeding mothers, immunocompromised patients, and surgical candidates. The deleterious health effects of herbal supplements are loosely addressed in conventional medical practice in part due to the limited knowledge of practitioners. This comprehensive narrative review aims to explore the clinical implications of herbal supplements in order to fill the knowledge gaps by summarizing scientific publications. It also highlights the pivotal roles physicians can play in minimizing the health risks of herbal supplements by encouraging patients to disclose usage through a non-judgmental approach, employing HDI screening tools, and reporting adverse reactions to FDA. Formal training of physicians, a standardized pharmacovigilance system, stricter regulation of the herbal industry, and more scientific studies are keys to establishing herbal safety and efficacy in clinical practice.


Predictors
In a recent systematic review on the potential factors that influence the use of CAM including herbal supplements amongst cancer patients and patients with other chronic illnesses, the most commonly reported reasons include benefits, safety, dissatisfaction with CM, influence by their social network, internal health locus of control, affordability, willingness to try/use, practitioners' recommendation, easy access, Based on the 2015 National Consumer Survey on a total of 26,157 eligible respondents, Rashrash et al. in their study on the prevalence of herbal medicine use among the US adults found that 35% (around onethird) reported current use of at least one herbal medicine and the average number of herbal supplements used was 2.6 [20].
The American Botanical Council (ABC), also known as the Herbal Medicine Institute, is a nonprofit research and education organization that reports on the herbal market in its quarterly journal (HerbalGram) [40]. According to ABC, the sale of herbal products exceeded US$5.3 billion in the United States in 2011 showing a 4% increase over 2010 [20,40].
In 2020, the herbal market hit a record high with double-digit growth of 17.3% of the previous year for the first time due to market demand fueled by COVID-19-driven herbal use for claimed immune health and stress relief. The annual sales of herbal supplements over the last two decades continued to increase and reached a record-breaking $11.261 billion spending in 2020, $1.659 billion more than in 2019 [11].

List of herbs consumed in the US
Fact sheets by NCCIH's Herbs at a Glance webpage, recently also launched as HerbList (App), published about the safety and effectiveness of 50+ popular herbal products marketed for health purposes to help consumers, patients, healthcare providers, and other users in quick access of research-based information ( Table 1) [18]. Recently (in 2021), a natural product market research firm (SPINS) based in Chicago, Illinois, a natural products industry publication named Nutrition Business Journal (NBJ) based in Boulder, Colorado, and the ABC based in Austin, Texas jointly provided data on the US retail sales of herbal supplements. SPINS specifically reported on the 40 top-selling herbal supplements available in the US market which are published by HerbalGram, a quarterly journal of ABC ( Table 1) [11]. Most of the herbs are promoted for claimed health benefits such as immune, cardiovascular, respiratory, digestive, prostate, and mental health ( Table 2) [11,18,[41][42][43][44]. The Colorado State University also published a fact sheet with a list of toxic herbs posing life-threatening side effects which are flagged by the FDA warning ( Table 3) [15].     [45]. The two federal agencies are mainly involved in the regulatory aspects of DS; the FDA regulates the quality, safety, and labeling, and the Federal Trade Commission (FTC) monitors the advertisements and marketing [25].

Source List of Herbs
According to the DSHEA, FDA received jurisdiction to regulate herbal products but its scope of regulation is limited mostly to post-marketing surveillance carrying the burden of proof in demonstrating that these products pose significant health risks before removal from the market [25,46]. Unlike conventional drugs, manufacturers are not expected to prove the safety of herbs before marketing unless they are introducing new ingredients identified after 1994. Enforcing the notification of new ingredients by the FDA is also very challenging. Despite a dramatic jump in the total sale of DS from 4000 in 1994 to 90,000 in 2014, FDA was notified of new ingredients only in 170 DS cases in two decades (1994-2012) [25].
Without undergoing evaluation as conventional drugs by FDA, manufacturers of herbal supplements are prohibited from making health claims about their products' ability to diagnose, mitigate, treat, cure, or prevent a specific disease or class of diseases [13,45,47]. By law, manufacturers and distributors of herbal supplements and ingredients are prohibited from marketing adulterated or misbranded products [48]. The FDA requires manufacturers to include the following information on labels: name of the product or supplement, name and the address of the manufacturer or distributor, complete list of ingredients, and amount of product or supplement in the container or package. The statement "Not evaluated by the FDA. Not intended to diagnose, treat, cure, or prevent any disease" should also be incorporated on the labels [47,49]. Permissible health claims characterizing how the dietary supplement (herb) maintains the normal structure or function in humans can be incorporated into the labels [25,47]. Supplement companies must uphold that claims on the labels of their products must be truthful and not misleading [50]. FDA also requires manufacturers to inform any adverse events reported directly to them [47][48][49][50].
In 2007, the FDA established non-binding current good manufacturing practice (cGMP) guidelines to ensure consistency in product quality in terms of identity, purity, strength, and composition of dietary supplements. According to cGMP, manufacturers are required to test the quality of products, confirm products are free from some contaminants, verify the accuracy of product labeling, adhere to the minimum manufacturing and packing standards, closely monitor reports of adverse events (AE), and avail all records for FDA inspection [25,[50][51][52]. However, cGMP guidelines still lack to ensure the safety of the supplements as manufacturers are not uniformly adopting them [52,53].
The FDA can remove herbal supplements from the market if they are found to be unsafe, adulterated, or misbranded with false or misleading labels [49,54]. FDA states that it will evaluate the marketplace and take action on unsafe herbal supplements to protect the public if consumers, healthcare professionals, manufacturers, packers, distributors, and researchers submit adverse reactions through the Safety Reporting Portal (SRP) [55,56]. Consumers can also contact the local FDA Consumer Complaint Coordinator assigned for the state using the provided numbers to report serious reactions or illnesses which arise from using herbal supplements [57]. In addition to the Center for Food Safety and Applied Nutrition (CFSAN) dedicated to the FDA mission, and a flagship alert system, MedWatch, the FDA issues warning letters, recalls, seizures and injunctions, press announcements, public notifications, and safety alerts for health fraud scams involving products with unproven claims [58]. FDA randomly and periodically inspects manufacturing facilities or supplements [59].

Quality Assurance
ConsumerLab.com, NSF International, and U.S. Pharmacopeia are some of the independent organizations in the US which offer quality testing and allow manufacturers to display a seal of quality assurance if their herbal products pass the tests [59]. Electron microscopy, thin layer chromatography (TLC), highperformance liquid chromatography (HPLC), liquid chromatography-mass spectrometry, and DNA barcoding are newer techniques applied in biological testing used to evaluate the quality of herbal products [60][61][62]. Since imported herbal supplements pose questionable regulations, it is advised to purchase qualitytested products that are made in the US and available in established outlets [63].

Ephedra: The First Banned Supplement
Ephedra (ma huang) which contains ephedrine alkaloids became the first supplement banned by the FDA in February 2004 for posing unreasonable risks of illness or injury to the public [64]. According to the 68-page final rule, FDA stated the action of prohibiting the sale of ephedra was based on the "well-known pharmacology of ephedrine alkaloids, the peer-reviewed scientific literature on the effects of ephedrine alkaloids, and the adverse events reported to have occurred in individuals following consumption of dietary supplements containing ephedrine alkaloids" [65]. Marketed as a weight-loss and energy-enhancement agent in the US during the 1990s and early 2000s, Ephedra caused fatal cardiovascular and neurologic effects including myocardial infarction, stroke, and seizure through its direct adrenergic stimulation and indirect endogenous catecholamine release. A 13-year post-ban follow-up showed a dramatic decline in ephedrarelated total deaths and poisoning reports [66].

The Federal Trade Commission
The Federal Trade Commission (FTC) protects consumers and competition from deceptive, and unfair business practices through law enforcement, advocacy, and education [67]. Each year, the FTC enforces laws against hundreds of individuals and businesses involved in fraud, scams, identity theft, false advertising, privacy invasion, anti-competitive behavior, and more [68]. Along with FDA, FTC also makes consumers aware of tainted products, recalls, alerts, and advisories [69]. It is common to see problematic advertising of herbal products promoted with false claims which mislead consumers and pose safety issues. Recently, FTC sent warning letters to more than 120 marketers to stop making unsubstantiated claims that their products and therapies can treat or prevent COVID-19 [70].
Following is the summary of herbal regulation and quality control in the US ( Table 4) [71].

Sources of adulterants and contaminants in herbal supplements
There is a growing concern among the public and medical community about health risks of contaminants such as heavy metals, microbial pathogens, pesticide residues, and misidentified plants as well as adulterants such as prescription medications, toxic plant extracts, and inappropriate additives introduced during agricultural processing, product preparation and packaging (  contained undeclared pharmaceuticals such as ephedrine, chlorpheniramine, methyltestosterone, and phenacetin purposefully and illegally added to achieve the desired effect. Significant amounts of heavy metals were also identified including lead, arsenic, and mercury in 24 (9%), 36 (14%), and 35 (14%) products respectively. Moreover, 23 (9%) had more than one adulterants [17,73]. The toxicities introduced by heavy metals, prescription drugs, or unapproved ingredients pose serious health hazards to unsuspecting consumers [74][75][76][77].
To protect consumers, US retailers such as CVS launched a third-party independent evaluation for contaminants such as heavy metals, yeast, mold, pesticides, biological pathogens, and industrial compounds like polychlorinated biphenyls on DS supplied by makers and distributors before they are available in their stores or online [78].

Undesirable Health Outcomes
According to the national estimates of using natural product supplements for wellness purposes among U.S. adults in 2012, general wellness or disease prevention (83.3%), improve immune function (42.0%), improve energy (31.0%), focuses on the whole person (mind, body, and spirit) (26.5%) and improve memory or concentration (22.2%) were among the top reasons mentioned [79]. Though perceived as safe due to their natural source, herbal supplements constitute different side effects and adverse health outcomes originating from biologically active herbal constituents, contaminants, and herb-drug interactions (HDI) [17].
A study on 105 morbid case series of Chinese-herb nephropathy seen as an outbreak in Belgium among users of weight-reducing pills inadvertently manufactured with nephrotoxic and carcinogenic Aristolochia fangchi showed end-stage renal failure (43 cases of which 39 had prophylactic kidney removal) and urothelial carcinoma due to DNA adducts (18 cases) [17,81].
Using herbal remedies as galactagogues and as therapies for postpartum conditions such as constipation, postpartum depression, and upper respiratory tract infection by breastfeeding women may constitute health risks to the infant due to herbal chemical constituents, contaminants, and heavy metals which enter human milk [82]. It is also common to see the use of herbal supplements during pregnancy to improve the wellbeing of the mother and/or baby, reduce nausea and vomiting episodes, treat infections, relieve gastrointestinal problems, facilitate labor or ease labor pains. Pregnant women with pre-existing conditions like epilepsy and asthma are at increased risk of potential herb-drug interactions. Besides, theoretical concerns exist about some herbs' teratogenic or embryotoxic effects [83,84].
Drug-induced liver injury (DILI) is the most difficult form of liver disease diagnosed by exclusion. The challenges of DILI are mainly due to its occurrence without warning, the absence of specific distinguishing features or markers, and its mimicry of multiple liver diseases [85]. An Icelandic study revealed that 16% of DILI was attributed to the use of herbals and dietary supplements (HDS) whereas the US DILI Network (DILIN) study on the hepatotoxicity caused by conventional medications and HDS showed an increase in liver injury caused by HDS from 7% to 20% during 2004-2013 study period resulting in hospitalization, liver transplantation and even death [85,86].
A US survey of 500 ambulatory surgical patients revealed that 42.7% of them took alternative medicines in the two weeks period before their surgical procedure which had significant implications for both anesthesia and surgical care. Further analysis of the survey showed these CAMs inhibit coagulation (19.8%), affect blood pressure (14.4%), and result in both cardiac (7.4%) and sedative (8%) effects [87]. Harmful interactions of herbal supplements with conventional medicines through the cytochrome P450 pathway systems may also have potentially deleterious effects during the perioperative period and wound healing [88].
The effects of herbal supplements on laboratory test results are many folds. Abnormal liver function tests (LFT), renal function tests (RFT), and thyroid function tests (TFT) are related to significant organ damage. Kava-Kava, chaparral, germander, and mistletoe for example can cause abnormal LFT secondary to liver damage. An abnormal level of therapeutic drug reflected during routine monitoring may reveal unexpected HDI. Lead poisoning can occur after consuming DS contaminated with heavy metals. A patient may show a falsely abnormal digoxin level when digoxin and certain Chinese medicine such as Chan Su or Lu-Shen-wan are taken together due to direct interference of a component of Chinese medicine with the antibody used in an immunoassay [89].

Herbal Supplements to Avoid During Surgery, Pregnancy, and Breastfeeding
The following table (

Herbal Adverse Reactions
The traditional classification of adverse drug reactions (ADRs) intended for conventional/synthetic medicine can be applied to further describe the adverse effects of herbal supplements (Table 7) [72,[93][94][95]. Adverse drug event (ADE) is sometimes used as an umbrella term that includes ADRs and medication errors (MEs) [96]. According to the World Health Organization (WHO) definition, ADR is implied to any noxious, unintended, and unwanted response to a drug used for treatment, prophylaxis, or diagnosis at normal doses [96]. A policy publication by Walji et al. also stated the 1995 definition of ADRs by WHO as 'unintended consequences suspected to be related to the use of medicinal products, including herbal medicines' [97].   [98]. Similarly, due to the upsurge of herbal supplements which are used alone or co-administered with conventional drugs, adverse reactions and drug interactions attributed to herbal supplements are becoming a significant safety concern [35,99].

Type of Reaction
Due to poor regulation of herbal products, impurities like allergens, pollen, and spores and batch-to-batch variability could contribute to some of the reported herb-related adverse effects and drug interactions [100]. Information about potential herb-related adverse reactions is very limited [101]. Estimates of adverse events related to dietary supplements (including herbs) suggest that only 1% of cases are reported to the FDA [102]. A manual review of case reports from PubMed identified approximately 21, seven, and seven herbs as being risks for liver, kidney, and heart toxicity, respectively [101]. Currently, advancement in modern technology is continually improving how ADRs are predicted, prevented, detected, and managed [95].

Herb-Drug Interaction (HDI)
Concurrent consumption of herbal supplements and conventional drugs results in HDI which has important clinical significance in medical practice [103]. Drugs with a narrow therapeutic index (such as warfarin and digoxin) and drugs prescribed for the long-term treatment of chronic or life-threatening illnesses raise serious safety concerns when coadministered with herbal supplements [35]. As evident in multiple case reports, case series, and pharmacokinetic trials, herbal supplements and prescribed drugs may interact in the intestine, liver, kidneys, and targets of action of which up or down-regulation of cytochrome P450s and/or P-glycoprotein are most prominent [104].
Pharmacokinetic HDI mechanisms affecting drug absorption, induction and inhibition of metabolic enzymes and transport proteins, and changes in renal excretion of drugs alter the level of drugs and their metabolites which can be countered by safe adjustment of the drug. Moreover, less common pharmacodynamic HDI mechanisms due to intrinsic pharmacologic properties of herbal supplements acting on drug sites/receptors can result in synergistic, additive, and/or antagonistic effects of the concomitant drug without alteration of its level and are also unlikely countered by a change in drug dosage (Table 8) [35,103,105]. It is worth noting that patient factors such as age, gender, and pathological status; drug factors such as dose, dosing regimen, and route of administration; and herb factors such as herb pretreatment, herb-herb interactions, and chemical and physical modification of herb ingredients are among the potential influencers in the pharmacokinetics of herbal supplements [106].

HDI Screening Tools/Checkers
Despite an ever-increasing use of dietary supplements including herbal products, only 12-14% of users in Canada and the United States are reporting adverse effects [107,108]. With the advent of the internet, there are several online screening tools designed to check HDI to minimize or intervene in adverse events. These tools are available as web pages with unique Uniform Resource Locators (URLs) and or as mobile applications either for free or subscription-based access which can be consulted by herbal consumers, clinicians and researchers in order to determine HDI (

Patient Safety and Potential HDI of Common Herbal Supplements
The following table (

Case Reports Showcasing the Health Hazards of Herbs
Since randomized controlled trials (RCTs) could not reliably identify an ever-increasing incidence of rare adverse events emerging with the use of herbal supplements, case reports, case series, and post-marketing surveillance studies fill the evidence gap. Case reports coupled with pharmacokinetic trials provide the highest level of evidence. The pitfalls of case reports include the inability to establish causal relationships and the limited number of cases showing severe clinical reactions [104].

The roles of physicians in minimizing health risks of herbal supplements
With an ever-increasing use of herbal supplements along with prescription and over-the-counter medications, a prudent clinical practice should embrace identifying susceptible groups and safer treatment plans which should monitor and mitigate any possible adverse effects [95,136]. Physicians should be cognizant of purported adverse effects and deleterious drug interactions associated with herbal supplements and should ask all patients about the use of these products as part of their medication history [100]. An anonymous survey to determine the physicians' knowledge regarding the toxic effects and drug interactions of herbal remedies revealed that they are provided with little training in herbal toxicities and drug interactions and hence are poorly familiar with these topics [137].
The 2012 National Health Interview Survey (NHIS) based on 34,525 adult respondents revealed that around 30% used CAM at least once in the past year and 66% had Primary Care Physician (PCP). Then, further analysis based on 7493 respondents who both use CAM and had PCP showed around 42% did not disclose their most used CAM modality including herbal supplements (in 25%) attributing the non-disclosure mainly to physicians not asking about CAM (57%), not believing that physicians should know about their CAM use (46%) and due to past (2%) or potential (3%) discouragement by physicians [138].
According to a review by Rowe and Baker, around 40%-70% of US patients did not report their CAM use to their doctors whereas 91% of patients who seek care from naturopathic doctors discussed their use of prescription medication. The same review also mentioned some of the most common reasons for nondisclosure of using herbal supplements such as apprehension of disapproval, misunderstanding, disinterest, or lack of knowledge by their physicians in addition to patients' assumption that the supplements have no connection to their current care [88,[139][140][141][142][143].
Physicians are expected to educate themselves and their patients about the effectiveness and harmful interactions of herbal preparations. Belief in herbal products' efficacy based on advertising, advice from friends, personal experience, dissatisfaction with the conventional health care system, and a desire to be in control of own life and health are among the most common reasons mentioned by patients for using herbal supplements. Since the subject of herbal medicine is complex, physicians often need to discuss the merits and drawbacks of herbs as part of normal history taking through good communication and open discussion by withholding judgment to reach decision making and "relationship-centered" care [144,145]. Patients have very limited and reliable resources regarding the use of herbal medicine, and their most common sources of advice are friends and relatives [146]. Some overseas studies have also identified that medical students and resident physicians are not in a better position than patients because they lack the relevant knowledge and therefore cannot provide expert advice to patients [147][148][149]. Hence, many patients and providers are not aware of herb-related complications, adverse reactions, and HDI [87]. Patients should be free to choose what healthcare they want but should be informed about the safety and efficacy of their choice [150]. Interprofessional communication (IPC) between health care practitioners (HCP), services, and patients is also critical in providing safe and effective patient-centered care [151].
Physicians can play pivotal roles in promoting patient safety and mitigating the health risks of herbal supplements. Encouraging patients to discuss their use of herbal supplements, addressing any adverse effects including HDI during medication history taking, and providing reliable information about the authenticity, safety, and effectiveness of a disclosed herbal product are very helpful during each encounter with physicians ( Figure 3) [95,100,105,152]. Physicians should keep themselves informed by reviewing scientific evidence available in literature databases like PubMed, publications by professional associations like American Medical Associations (AMA), and government websites like NCCIM and FDA [153][154][155][156][157]. Physicians can also help notify herbal adverse reactions to FDA by filling out a safety report and submitting the complaint through the Safety Reporting Portal [56].  There is a growing tendency to integrate CAM with CM in centers and clinics which are both reimbursed with insurance coverage and have close ties to medical schools and teaching hospitals [158]. Physicians can contribute to the development and delivery of courses integrated with continuing medical education (CME) as well as the curricula of medical schools and graduate medical education (GME) training addressing the clinical implications of herbal supplements including the management of HDI [138,154,159,[160][161][162]. Due to the paucity of evidence concerning the safety and efficacy of herbal supplements in medical practice, physicians can fill the gap by involving themselves in clinical research through collaboration with grant providers like NIH [163,164].
Physicians fostering collaboration with both mainstream and internet media is critical in educating safety of herbal supplements to boost consumers' awareness [165]. There is a 20-time increase in the number of dietary supplements including herbal products over the last three decades since 1994 of DSHEA which enabled manufacturers to exploit the regulatory loophole. Physicians should be vocal to advocate for stricter regulation of the herbal manufacturing industry. It is also time now for physicians in the US to push for the passing of the Dietary Supplement Listing Act of 2022 which mandates manufacturers to uphold a comprehensive listing of product ingredients along with warnings, precautions, and allergen information [166,167].
Finally, it is worth introducing an exemplary physician who is spearheading the fight to stop herbal products from endangering the lives of unsuspecting consumers, Dr. Stephen Barrett. He is a retired psychiatrist from North Carolina who is an award-winning health educator, author, editor, peer-reviewer, and consumer advocate. His renowned contributions are reflected through the multiple websites he is operating including quackwatch.com. Currently, he is co-editing 'consumer health digest' which is a free weekly newsletter summarizing scientific reports, legislative developments, enforcement actions, news reports, website evaluations, recommended and non-recommended books, and other information relevant to consumer protection and consumer decision-making [168].
The following table (Table 12) summarizes key roles and major activities physicians can contribute to the overall effort to minimize the health risks of herbal supplements in clinical practice.

Patient Care
Discuss the use of HS HerbLlist App, Monographs, PEM (Appendix/ Figure 4) Review medication history HDI Checker tools (

Conclusions
Herbal supplement usage is complex and interwoven into anecdotes, cultural traditions, social influence, health misinformation, affordability, accessibility, profitable industry, sophisticated marketing, and consumer autonomy. Herbal medicine is practiced everywhere irrespective of geographic and demographic variations. Still little is known about the safety and efficacy of most herbal products. DSHEA of 1994 severely limited the regulatory ability of the FDA. Patients tend to not disclose or underreport the use of herbal supplements to their physicians. Since more patients are dissatisfied with the herb-related knowledge of conventional medical practitioners, it is advised to be a well-informed physician who stayed abreast with the current trends in order to address herb-related questions. It is not advisable to generalize about the efficacy and safety of herbal supplements. Government websites, NIH's HerbList App, and HDI checkers are reliable and neutral sources of information. Physicians can enormously contribute to the overall safety of herbal supplements by collaborating with educational and research organizations, media outlets, and lawmakers. Further clinical trials, formal training, regulatory amendment, and global collaboration are crucial in curbing the health care burden of herbal supplements in the US clinical practice.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.