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Elemental impurities (heavy metals) in kratom products: an assessment of published individual product analyses
Clinical Toxicology
Abstract
Introduction:
Kratom is commonly used by consumers, and the elemental impurity exposure that consumers would have at different kratom ingestion doses has been determined.
Methods:
This assessment used original data from independent third-party laboratory testing of kratom products to identify the percentage of products that exceeded permissible daily exposure limits for lead (5 µg/day), nickel (200 µg/day), arsenic (15 µg/day), and cadmium (5 µg/day), the interim reference level for lead in adults (12.5 µg/day), and the tolerable upper intake level for manganese (11 mg/day) and nickel (1 mg/day). We assessed all products regardless of type and then evaluated non-extract products, extract products, and a soda preparation separately for elemental impurities.
Results:
Three assessments of elemental impurities in kratom products have been published, totaling 68 products. Assessing all products and assuming a 3 g daily dose of kratom, 7.4% would exceed the permissible daily exposure limits for lead, 0% for nickel, 3.1% for arsenic, and 0% for cadmium. At a kratom dose of 25 g daily, 70.6% would exceed the permissible daily exposure limits for lead, 20.6% for nickel, 9.4% for arsenic, and 0% for cadmium. The interim reference level for lead would be exceeded by 1.5% of products at a kratom daily dose of 3 g and 33.8% of products at 25 g. The tolerable upper intake level for manganese would be exceeded by 12.5% of products at a kratom daily dose of 3 g and 41.7% of products at 25 g. Non-extract products generally contain greater concentrations of elemental impurities than extract products or the soda preparation.
Discussion:
Apart from their concentrations in a gram of product, assessing the amount of exposure to elemental impurities at different kratom ingestion doses is also important. Elemental impurities exceeding regulatory permissible concentrations for many products, especially with greater daily kratom ingestion doses, may impact human health.
Conclusions:
Some kratom products contain excessive concentrations of elemental impurities of toxicological concern, such as lead and arsenic. Non-extract products (powders, capsules, tablets) generally contain greater concentrations of elemental impurities than extract products or the soda preparation. Daily use of these products can result in exposures exceeding regulatory thresholds and adverse health effects.
... 4 The predominant demographic of users has recently shifted from middle-aged males to younger people and females. 5 Consumers can purchase these products in smoke shops, convenience stores, gas stations, and over the Internet without a prescription. 4 In the United States (U.S.), kratom is available in several dosage forms (capsules, concentrated extracts, powder, raw leaves, and tablets) and doses (depends on the dosage form). ...
... However, some kratom products have been found to exceed these regulatory thresholds; non-extract products (capsules, powders, and tablets) often have higher concentrations compared to extracts. 5 A potential cause of lead and nickel contamination is the country of origin of the kratom trees (Indonesia and Thailand, for example, naturally have greater lead concentrations in their soil and water). 10,11 Local water is used to wash the picked leaves which may leave an elemental impurity residue and the trees themselves can pick up the heavy metal from the soil. ...
Kratom (Mitragyna speciosa) is a tropical tree that is indigenous to Southeast Asia. Kratom leaf products have been used in traditional folk medicine for their unique combination of stimulant and opioid-like effects. Kratom is being increasingly used in the West for its reputed benefits in the treatment of pain, depression, and opioid use disorder (OUD). Recent studies from the United States Food and Drug Administration (FDA, Silver Spring, MD, USA) and our laboratory have shown that many kratom products being sold in the United States are contaminated with potentially hazardous levels of lead (Pb). In this commentary, we discuss the public health implications of the presence of Pb in kratom products, particularly as they relate to the predicted levels of Pb exposure among kratom users. We also considered the specific toxic effects of Pb and how they might relate to the known physiologic and toxicologic effects of kratom. Finally, we consider the possible sources of Pb in kratom products and suggest several areas for research on this issue.
There is limited understanding regarding kratom use among US adults. Although motivations for use are increasingly understood, typical kratom doses, threshold of (low and high) doses for perceived effectiveness, and effects produced during cessation are not well documented. We aimed to extend prior survey work by recruiting adults with current and past kratom exposure. Our goal was to better understand kratom dosing, changes in routines, and perception of effects, including time to onset, duration, and variability of beneficial and adverse outcomes from use and cessation. Among respondents who reported experiencing acute kratom effects, we also sought to determine if effects were perceived as helpful or unhelpful in meeting daily obligations. Finally, we attempted to detect any signal of a relationship between the amount of kratom consumed weekly and weeks of regular use with ratings of beneficial effects from use and ratings of adverse effects from cessation. We conducted an online survey between April-May 2021 by re-recruiting participants from a separate study who reported lifetime kratom use. A total of 129 evaluable surveys were collected. Most (59.7%) had used kratom >100 times and reported currently or having previously used kratom >4 times per week (62 weeks on average). Under half (41.9%) reported that they considered themselves to be a current “regular kratom user.” A majority (79.8%) reported experiencing acute effects from their typical kratom dose and that onset of effects began in minutes but dissipated within hours. Over a quarter reported that they had increased their kratom dose since use initiation, whereas 18.6% had decreased. Greater severity of unwanted effects from ≥1 day of kratom cessation was predicted by more weeks of regular kratom use (β = 6.74, p = 0.02). Acute kratom effects were largely reported as compatible with, and sometimes helpful in, meeting daily obligations. In the absence of human laboratory studies, survey methods must be refined to more precisely assess dose-effect relationships. These can help inform the development of controlled observational and experimental studies needed to advance the public health understanding of kratom product use.
Kratom (Mitragyna speciosa, Korth) is a tree-like plant that is indigenous to Southeast Asia. Kratom leaf products have been used in traditional folk medicine for their unique combination of stimulant and opioid-like effects. Kratom is being increasingly used in the West for its reputed benefits in the treatment of pain, depression and opioid use disorder. Recently, the United States Food and Drug Administration and Centers for Disease Control have raised concerns regarding the contamination of some kratom products with toxic metals (Pb and Ni) and microbes such as Salmonella. To further explore this issue, eight different kratom products were legally purchased from various “head”/”smoke” shops in the Western Suburbs of Chicago and then tested for microbial burden, a panel of metals (Ni, Pb, Cr, As, Hg, Cd), and levels of the main psychoactive alkaloid mitragynine. All of the samples contained significant, but variable, levels of mitragynine (3.9–62.1 mg/g), indicating that the products were, in fact, derived from kratom. All but two of the samples tested positive for the presence of various microbes including bacteria and fungi. However, none of the samples tested positive for Salmonella. Seven products showed significant levels of Ni (0.73–7.4 µg/g), Pb (0.16–1.6 µg/g) and Cr (0.21–5.7 µg/g) while the other product was negative for metals. These data indicate that many kratom products contain variable levels of mitragynine and can contain significant levels of toxic metals and microbes. These findings highlight the need for more stringent standards for the production and sale of kratom products.
Nickel is a transition element extensively distributed in the environment, air, water, and soil. It may derive from natural sources and anthropogenic activity. Although nickel is ubiquitous in the environment, its functional role as a trace element for animals and human beings has not been yet recognized. Environmental pollution from nickel may be due to industry, the use of liquid and solid fuels, as well as municipal and industrial waste. Nickel contact can cause a variety of side effects on human health, such as allergy, cardiovascular and kidney diseases, lung fibrosis, lung and nasal cancer. Although the molecular mechanisms of nickel-induced toxicity are not yet clear, mitochondrial dysfunctions and oxidative stress are thought to have a primary and crucial role in the toxicity of this metal. Recently, researchers, trying to characterize the capability of nickel to induce cancer, have found out that epigenetic alterations induced by nickel exposure can perturb the genome. The purpose of this review is to describe the chemical features of nickel in human beings and the mechanisms of its toxicity. Furthermore, the attention is focused on strategies to remove nickel from the environment, such as phytoremediation and phytomining.
FDA developed the interim reference level (IRL) for lead of 3 μg/day in children and 12.5 μg/day in women of childbearing age (WOCBA) to better protect the fetus from lead toxicity. These IRLs correspond to a blood lead level (BLL) of 0.5 μg/dL in both populations. The current investigation was performed to determine if the IRL for WOCBA should apply to the general population of adults. A literature review of epidemiological studies was conducted to determine whether a BLL of 0.5 μg/dL is associated with adverse effects in adults. Some studies reported adverse effects over a wide range of BLLs that included 0.5 μg/dL adding uncertainty to conclusions about effects at 0.5 μg/dL; however, no studies clearly identified this BLL as an adverse effect level. Results also showed that the 75 μg/day lead PTTDI for adults may not be health protective, supporting use of a lower reference value for lead toxicity in this population group. Use of the 12.5 μg/day IRL as a benchmark for dietary lead intake is one way FDA will ensure that dietary lead intake in adults is reduced.
Introduction:
Kratom (Mitragyna speciosa) has generated substantial clinical and scientific interest as a complex natural product. Its predominant alkaloid mitragynine and several stereoisomers have been studied for activity in opioid, adrenergic, and serotonin receptors. While awaiting clinical trial results, the pre-clinical evidence suggests a range of potential therapeutic applications for kratom with careful consideration of potential adverse effects.
Areas covered:
The focus of this review is on the pharmacology, pharmacokinetics, and potential drug-drug interactions of kratom and its individual alkaloids. A discussion on the clinical pharmacology and toxicology of kratom is followed by a summary of user surveys and the evolving concepts of tolerance, dependence, and withdrawal associated with kratom use disorder.
Expert opinion:
With the increasing use of kratom in clinical practice, clinicians should be aware of the potential benefits and adverse effects associated with kratom. While many patients may benefit from kratom use with few or no reported adverse effects, escalating dose and increased use frequency raise the risk for toxic events in the setting of polysubstance use or development of a use disorder.
The Centers for Disease Control and Prevention (CDC) utilizes a blood lead reference value (BLRV) to identify children with elevated blood lead levels (BLLs). At or above the BLRV, the CDC recommends actions be taken to reduce children's BLLs. In 2021, the CDC updated its BLRV to 3.5 μg/dL. To align with the CDC's updated BLRV, the FDA is updating its interim reference levels (IRLs) for lead from food to 2.2 μg/day for children and 8.8 μg/day for females of childbearing age. The updated FDA IRLs for lead will serve as a benchmark to evaluate whether lead exposure from food is a potential concern. The children's BLL associated with the updated IRL is less than those predicted by other agencies to result in 1 intelligence quotient point loss. Dietary lead exposure estimates for children in the U.S. suggest exposures greater than the mean may exceed the updated FDA IRL for children, indicating a need for additional efforts to reduce lead in foods consumed by young children. The US FDA is addressing this need by implementing its Closer to Zero action plan to reduce babies' and children's dietary exposure to toxic elements (e.g., lead, cadmium, arsenic, mercury) over time.
Objective
Assess the current daily interim reference level of lead and the amount contained in current mineral and multivitamin-multimineral (MVM) products.
Data Sources
PubMed search from 1980 to May 15, 2021, limited to the English language, via the search strategy ((mineral OR multivitamin OR calcium OR iron OR magnesium OR copper OR zinc OR chromium OR selenium) AND (heavy metals OR Pb OR lead)).
Study Selection and Data Extraction
Narrative review of studies assessing lead content in mineral or MVM products.
Data Synthesis
Products containing different calcium forms (dolomite, bone meal, natural carbonate) have historically had higher lead levels than others (refined carbonate, lactate, gluconate, acetate, sevelamer), but the gap has closed considerably since the year 2000. Although only limited assessments of magnesium and zinc supplements have been conducted, no alarming average lead amounts were found. MVM products assessed since 2007 had low median or mean lead concentrations. However, large interproduct differences exist, with many products having very little lead and some products having concerning amounts.
Relevance to Patient Care and Clinical Practice
It is difficult for pharmacists and consumers to know the amount of lead in an actual product unless it is tested in an independent third-party lab. The United States Pharmacopeia and NSF International will provide a seal on the products stating that the products have a low level of lead, but even so, children could receive more lead than the Food and Drug Administration’s Interim Reference Level.
Conclusions
The threat from lead exposure in mineral and MVM products have diminsihed considerably over time but some products can still have excessive amounts. Without third-party testing, it is difficult for clinicians and consumers to know which outlier products to avoid.
Introduction. Kratom is a plant with partial opioid agonist effects, and its use has become popular to ameliorate symptoms of opioid withdrawal. Use, however, has been linked to thousands of poisonings, although most have involved use of other drugs. Little is known regarding prevalence and correlates of use in the general US population.
Methods. Data were examined from the 2019 National Survey on Drug Use and Health, a nationally representative probability sample of noninstitutionalized individuals age >12 in the US (N=56,136). Prevalence and correlates of past-year kratom use were estimated. Data were analyzed in 2020.
Results. An estimated 0.7% (95% CI: 0.6-0.8) of individuals in the US have used kratom in the past year. Past-year proxy-diagnosis of prescription opioid use disorder was associated with increased odds for kratom use (aOR= 3.20, 95% CI: 1.38-7.41), with 10.4% (95% CI: 6.7-15.9) of those with use disorder reporting use. Opioid misuse not accompanied with use disorder was not associated with kratom use. Those reporting past-year cannabis use both with (aOR=4.33, 95% CI: 2.60-7.19) and without (aOR=4.57, 95% CI: 3.29-6.35) use disorder, and those reporting past-year cocaine use (aOR=1.69, 95% CI: 1.06-2.69) and prescription stimulant misuse (aOR=2.10, 95% CI: 1.44-3.05) not accompanied with use disorder, were at higher odds for kratom use.
Conclusions. Kratom use is particularly prevalent among those with prescription opioid use disorder, but it is also prevalent among people who use other drugs. Research is needed to determine reasons for use and potential dangers associated with adding kratom to drug repertoires.
The Dietary Supplement Health and Education Act led to a flood of poor-quality dietary supplements. The Food and Drug Administration’s (FDA’s) jurisdiction is limited to removing products proven unsafe, rather than prospectively assessing them for quality manufacturing. With so many products available, there is very little FDA oversight until reports of patient harm occur. Microbial and heavy metal contamination, adulteration with synthetic drugs (including drugs banned from the United States), substituting herbs, and fraudulently specifying ingredients on the label have all occurred. Clinicians should collectively advocate for legislative change, only recommend products tested by outside laboratories for quality, and educate consumers about the risks of using unverified products.
Purpose
This article presents updated information on kratom (Mitragyna speciosa), a natural opioid with stimulant properties that is currently sold in the United States without a prescription.
Summary
Kratom exerts opioid and alpha-2 agonistic effects, as well as anti-inflammatory and mild stimulant effects. Respiratory depression has not been commonly reported, but kratom does cause a host of adverse effects. While kratom may have a role in patients who are in chronic pain or dependent on opioid painkillers or heroin, this needs to be established in clinical trials. Kratom may have drug interactions as both a cytochrome P-450 system substrate and inhibitor. Kratom does not appear in normal drug screens and, especially when ingested with other substances of abuse, may not be recognized as an agent of harm. There are numerous cases of death in kratom users, but many involved polypharmaceutical ingestions. There are assessments where people have been unable to stop using kratom therapy and withdrawal signs/symptoms occurred in patients or their newborn babies after kratom cessation. Both banning and failure to ban kratom places people at risk; a middle-ground alternative, placing it behind the pharmacy counter, might be useful.
Conclusion
Kratom has a unique pharmacologic profile that might offer advantages over other opioids, but its high abuse liability, potential for drug interactions and adverse events, and inadequate research into the balance of benefits to harm are concerning. There is mounting information on the adverse events associated with kratom use and potential treatments that can be useful to clinicians.
Kratom is a plant material exhibiting both analgesic and stimulant effects and is also forensically relevant since it is abused as a “legal high.” It is regulated in several countries but not scheduled in the United States at the federal level. This study used inductively coupled plasma–mass spectrometry (ICP–MS) to measure the concentrations of 13 elements in 19 kratom samples obtained from an online distributor selling kratom, from Borneo, Malaysia, Indonesia, Thailand, and Vietnam, for the purpose of using the elements to discriminate among purported country of origin, “suborigin,” and strain. Analysis of variance revealed statistical differences in concentrations of elements from each group, while discriminant function analysis (using leave‐one‐out classification) successfully classified kratom samples by their purported country of origin (100%), “suborigin,” (100%), and strain (86%). Our method illustrates the possibility of utilizing ICP–MS for determination of commercially available kratom samples by purported origin, “subororign,” or by product line.
Background:
Kratom preparations have raised concerns of public health and safety in the US. Investigation into the demographics, perceived beneficial and detrimental effects of Kratom as well as common doses and purposes of its use are important to properly evaluate its potential health impact.
Methods:
An anonymous cross-sectional online survey was conducted in October 2016 of 10,000 current Kratom users through available social media and online resources from the American Kratom Association. A total of 8049 respondents completed the survey.
Results:
Kratom is primarily used by a middle-aged (31-50 years), middle-income ($35,000 and above) population for purposes of self-treating pain (68%) and emotional or mental conditions (66%). Kratom preparations present with a dose-dependent effect with negative effects, which were primarily gastrointestinal related including nausea and constipation, mainly presenting at high (5g or more/dose) and more frequent (22 or more doses/week) dosing.
Conclusions:
Kratom shows a dose-dependent opioid-like effect providing self-reported perceived beneficial effects in alleviating pain and relieving mood disorders. Kratom was primarily used for self-treatment of pain, mood disorders, and withdrawal symptoms associated with prescription opioid use.
Laboratory analysis of kratom products for heavy metals
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