The need for clearer boundaries has been amplified by rapid product innovation. Kratom, derived from the tree Mitragyna speciosa, has long been consumed in Southeast Asia as fresh or dried leaves, including through chewing, brewing and aqueous preparations. Its contemporary US market is more diverse, extending to powders, capsules, tablets, gummies, tea bags, liquid shots and other formulations. The abstract cites an estimated 10 to 16 million US consumers. Surveys describe use for pain, mental health conditions, withdrawal symptoms and general wellness, but these reports are observational and often cannot identify the exact product involved. As a result, they cannot reliably establish which product composition is associated with any particular adverse outcome.

Native kratom leaf is chemically complex, containing alkaloids alongside flavonoids, polyphenolic compounds, triterpenoids, saponins, monoterpenes and secoiridoids. The proposed definition focuses on four principal alkaloids: mitragynine, paynantheine, speciogynine and speciociliatine. Mitragynine is generally the most abundant, representing a reported 51% to 82% of the alkaloid fraction, although it usually remains below 2.5% of total leaf weight. The framework sets an expected mitragynine range of 0.5% to 2.5% by dried leaf weight, with each of the other three major alkaloids at 0.1% to 1.0%. It also proposes a total alkaloid content below 3.0%.

A particularly consequential distinction concerns 7-hydroxymitragynine, or 7-HMG. It was initially considered a naturally occurring leaf constituent but is now recognized as an oxidative metabolite of mitragynine, detectable at trace levels in some post-harvest materials. The authors state that it should not exceed 0.01% by weight under their definition of unaltered leaf. This matters because its pharmacology differs sharply from that of mitragynine. A cited experimental study reported respiratory depression from 7-HMG comparable to morphine that was reversed by naloxone, whereas mitragynine increased respiratory frequency and was unaffected by naloxone. These are experimental findings about the compounds, not evidence that every kratom product produces those effects in users.

Category 1 covers traditional botanical preparations, including teas, decoctions and aqueous or aqueous-ethanol fluidized extracts containing less than 10% alkaloids. Category 2 covers more concentrated material, divided into semi-purified extracts with 10% to 40% alkaloids and purified extracts with 40% to 60%. Category 3 applies to isolates containing more than 60% alkaloids. Category 3a may qualify as a dietary ingredient when an isolate preserves the natural alkaloid ratios and no chemical alteration has occurred. Category 3b comprises isolated fractions or compounds that do not reflect the plant’s natural composition and that the authors recommend treating as novel drugs.

Category 4 covers substances that are not properly described as kratom: synthetic duplicates of natural alkaloids, chemically altered compounds and other novel drug molecules. Examples include semi-synthetic 7-HMG and mitragynine pseudoindoxyl, as well as synthetic alkaloids derived from 7-HMG or other kratom compounds. The authors argue that purity alone does not make an isolate natural. A product can be derived from the plant yet no longer preserve its chemical composition, which places it outside the scope of the traditional botanical. Their distinction also reflects a difference in evidentiary history: isolated pure kratom alkaloids do not have the same history of use in concentrated form as components commonly present in food, such as caffeine or vanilla.

The policy assessment places the proposal within a fragmented legal environment. The US Food and Drug Administration changed its treatment of kratom from an unapproved drug in 2012 to a dietary ingredient and new dietary ingredient in 2013. The Drug Enforcement Administration proposed scheduling mitragynine and 7-HMG in 2016 but later rescinded that action. In July 2025, the FDA recommended restricting 7-HMG products and proposed that the DEA schedule 7-HMG, while leaving kratom leaf products outside that recommendation; the perspective says no federal scheduling action had been taken by publication. State policies vary widely, encompassing bans, age restrictions, alkaloid limits, serving-size rules, labeling requirements and consumer-protection laws.

The authors reject what they describe as two equally inadequate extremes: blanket inaction and an unsupported ban on all kratom. They argue that inaction would leave concentrated, semi-synthetic and synthetic products exposed to consumers without the safety evidence or regulatory controls expected for conventional products. Conversely, they say available preclinical evidence, observational studies, Southeast Asian history of use and human clinical trials do not justify treating properly labeled leaf and traditional preparations as equivalent to Schedule I compounds. They also cite the World Health Organization’s conclusion that evidence was insufficient to recommend international scheduling. This is a policy assessment based on existing evidence, not a new demonstration that kratom is broadly safe or effective for any particular condition.

Manufacturing recommendations draw on the US dietary-supplement framework, including current good manufacturing practice requirements. Manufacturers would need written specifications for identity, purity, strength, composition and contaminants, supported by scientifically valid testing or examination. Required documentation would include test methods, evidence that those methods are suitable and valid, master manufacturing records, batch records and adverse-event collection. For leaf, Category 1 and Category 2 products, the authors also recommend visible serving measurements, limiting the number of servings in solid packages and providing a measured device for liquids. These measures are intended to reduce confusion and exposure from poorly controlled portions, rather than to imply that a standard serving eliminates risk.

Labeling proposals call for a supplement-facts panel showing the amount of each ingredient per serving and the percent daily value, with “no daily value established” displayed where appropriate for kratom. Labels should list ingredients in descending order of predominance and identify “kratom” in the ingredient list. Additional requested information includes serving size, daily serving recommendations, use instructions and duration, expiration date, a complete ingredient list, mitragynine percentage by weight and lot number. Products should also disclose 7-HMG content per serving or the method’s limit of detection. Suggested warnings cover pregnancy, breastfeeding, medical conditions, medication use, oral-only use, combining the product with alcohol or other drugs, possible physical dependence and discontinuation if adverse effects occur.

For properly prepared leaf and traditional Category 1 products, the perspective derives a recommended maximum of 40 mg mitragynine per serving and no more than two servings, or 80 mg, in 24 hours. The authors say this limit has reasonable assurance of safety when the products are prepared traditionally and used as directed, while stressing that it cannot automatically be applied to concentrated or altered products. For Category 2 extracts, they recommend that manufacturers demonstrate no chemical alteration during processing, obtain ingredient safety data and file the required new-dietary-ingredient notification. Absent such evidence, the same 40 mg limit may be considered only when mitragynine exceeds 40% of total alkaloids and 7-HMG remains below 0.01% on a dry-weight basis. No scientifically supported serving limits are proposed for Category 3b or Category 4 products, which the paper says should be regulated as unapproved drugs.

Subject of Research: Evidence-based product classification and regulation for kratom, extracts and synthetic alkaloid products in the United States

Article Title: Defining kratom: evidence-based policy guidelines for a rapidly evolving market

Article References: Berthold, E., Brown, P. N., Chan, M., Grundmann, O., McCurdy, C. R., Sharma, A., & Singh, D. (2026). Defining kratom: evidence-based policy guidelines for a rapidly evolving market. Frontiers in Pharmacology, 17, 1925809. https://doi.org/10.3389/fphar.2026.1925809

Image Credits: AI Generated

DOI: 10.3389/fphar.2026.1925809

Keywords: kratom, Mitragyna speciosa, mitragynine, 7-hydroxymitragynine, product regulation, dietary supplements, novel drugs, public health, adulteration, United States, Defining, evidence-based

The distinction begins with chemistry. Ashwagandha’s bioactivity is dominated by steroidal lactones called withanolides, but the withanolide profile differs sharply between organs. Comparative HPLC and UHPLC–MS/MS analyses show that leaves accumulate high levels of withaferin A and related epoxide-bearing withanolides, compounds with potent cytotoxic and anti-inflammatory properties. Roots, by contrast, are relatively enriched in withanolide A, withanolide D, and glycowithanolides, the marker compounds used in pharmacopoeial monographs and standardized commercial root extracts. In chemotype studies such as the variety Poshita, withaferin A peaks in field-grown leaves while withanolide A predominates in roots across multiple chemotypes, establishing a consistent gradient between the more cytotoxic leaf chemistry and the so-called tonic-type root chemistry.

That gradient maps onto a long history of differentiated use. Classical Ayurvedic texts describe ashwagandha primarily as a root-based Rasayana, a rejuvenating tonic prescribed as a powder with milk or ghee for stress, debility, insomnia, and neuromuscular disorders. The leaf appears only sparsely in the classical compendia but features prominently in regional and tribal ethnomedicine across India, where it is applied as pastes, poultices, and decoctions for painful swellings, wounds, boils, scorpion stings, and dental pain, and occasionally ingested for fever and metabolic complaints. In other words, tradition itself drew a line between the root as a systemic tonic and the leaf as a more localized, indication-specific remedy, a historical differentiation of expected benefit–risk profiles that modern science is now rediscovering.

Preclinical pharmacology reflects both shared and distinct activities. Root extracts show robust anti-stress, anxiolytic, anti-inflammatory, cardioprotective, and neuroprotective effects in rodent models, mechanisms linked to modulation of the hypothalamic–pituitary–adrenal axis, GABAergic and serotonergic signaling, and the NF-κB and Nrf2 pathways. Leaf extracts, richer in withaferin A and other electrophilic withanolides, display striking anticancer, immunomodulatory, and neuroprotective activity in vitro and in selected animal models, including selective killing of tumor cells and inhibition of NF-κB and STAT3 signaling. In some comparative experiments leaf preparations match or exceed root extracts on antioxidant and antitumor endpoints, but these studies typically employ higher withaferin A exposures over short durations, leaving the translational safety margins for chronic oral use in humans undefined.

The human evidence base is even more lopsided. Nearly all controlled clinical data derive from root extracts, typically at doses of 240 to 600 milligrams per day, and randomized double-blind placebo-controlled trials in adults with stress, anxiety, or poor sleep consistently report improvements in perceived stress, anxiety scales, sleep quality, and cortisol, with favorable tolerability over 6 to 12 weeks. A 12-month open-label study of a standardized root extract at 600 milligrams per day found no serious adverse drug reactions and no signal for cumulative hepatic, renal, thyroid, or hematologic toxicity, and a systematic review covering 30 clinical trials of root preparations reported no serious adverse events across indications ranging from chronic stress to rheumatoid arthritis and male infertility.

Leaf-specific human data are minimal but revealing. A Phase I open-label trial of a pharmaceutical-grade leaf extract known as RH324 in patients with advanced non-small cell lung cancer reported tolerability and preliminary disease stabilization over 28 days, while a separate Phase I study of a leaf-derived preparation in osteosarcoma patients recorded dose-dependent liver enzyme elevations in five of eleven participants. A small number of randomized trials have tested combined root-and-leaf aqueous extracts for chronic stress and resistance training, but these remain limited. The review’s authors stress that this sparse record does not prove the leaf is inherently unsafe; rather, the leaf evidence is insufficient for chronic systemic use, a critical distinction that much of the current regulatory debate has blurred.

Complicating the picture further is adulteration. The US Botanical Adulterants Prevention Program has documented frequent detection of leaf material in commercial products labeled as root or root-only extract, driven by economics: leaves are cheaper, renewable, and richer in withaferin A. Crucially, the program warns that assays based solely on total withanolides cannot distinguish root from leaf, since withanolides occur throughout the plant. Reliable authentication requires orthogonal methods combining HPTLC or HPLC fingerprinting, targeted quantification of withaferin A and quercetin-related metabolites, and DNA-based tools. This matters because some of the toxicological signal in European risk evaluations derives from studies on leaf or whole-plant preparations rather than authenticated root.

The regulatory consequences have been dramatic. In 2020, a literature-based risk assessment by the Technical University of Denmark concluded that a safe intake level for ashwagandha in supplements could not be established, citing potential thyroid and sex hormone effects and possible abortifacient properties, prompting Denmark to ban ashwagandha-containing supplements from 2023. Independent critiques argue the assessment over-weighted limited animal and case-report data, relied on low-quality sources, and conflated root with leaf and whole-plant preparations while overlooking the broader clinical safety dataset on standardized root extracts. Subsequent evaluations by the Dutch RIVM, Germany’s BfR, France’s ANSES, and the UK Food Standards Agency have flagged hepatotoxicity, thyroid, and reproductive concerns, even while acknowledging that much of the adverse-event literature involves products of uncertain composition and plant part.

Pharmacovigilance adds another layer of ambiguity. Published case reports of liver injury in ashwagandha users describe products that were never analytically characterized for plant part, and causality assessments using the RUCAM method reached only possible or probable scores, never definite. One research group has hypothesized that undeclared leaf adulteration, with its substantially higher withanone and withaferin A content, could contribute to hepatotoxicity, providing a plausible mechanistic basis for the case clusters. If some European hepatotoxicity reports in fact reflect exposure to unlabeled leaf or whole-plant material sold as root, then the central regulatory problem is quality and authenticity rather than plant identity alone, and plant-part-agnostic risk assessments risk punishing the wrong ingredient.

The review’s prescriptions are concrete. Monographs and guidance should define ashwagandha for internal use as root or root extract unless leaf or aerial parts are explicitly declared, with separate dossiers and safety data required for leaf products. Regulators should mandate validated orthogonal authentication methods in manufacturing release and market surveillance, treat undeclared aerial-part content as adulteration, and consider a dose-based framework for leaf anchored to withaferin A limitation, analogous to thresholds set for pyrrolizidine alkaloids, once adequate human pharmacokinetic and dose-escalation data exist to derive a safe exposure level. Priority research needs include comparative randomized trials of authenticated root, leaf, and whole-plant extracts with matched chemotyping, comprehensive hepatic, thyroid, and reproductive safety studies for leaf preparations, and a plant-part-stratified meta-analysis of adverse events across all published trials. Until such data arrive, the authors conclude, authenticated root remains the best-characterized material for systemic use, and the case for treating ashwagandha as a plant-part-specific medicine, not a generic herb, is now firmly on the scientific and regulatory agenda.

Subject of Research: Comparative safety, efficacy, and regulation of ashwagandha root versus leaf preparations

Article Title: Plant Part–Specific Differences in Ashwagandha (Withania somnifera): A Comparative Evaluation of Root and Leaf Evidence for Safety and Regulation

Article References: Dutta, A., & Gupta, J. B. (2026). Plant Part–Specific Differences in Ashwagandha ( Withania somnifera ): A Comparative Evaluation of Root and Leaf Evidence for Safety and Regulation. Food Science & Nutrition, 14(10), Article e72364. https://doi.org/10.1002/fsn3.72364

Image Credits: AI Generated

DOI: 10.1002/fsn3.72364

Keywords: ashwagandha, Withania somnifera, withanolides, withaferin A, herbal supplements, hepatotoxicity, adulteration, phytochemistry, regulation, Ayurveda, food safety, clinical trials