Essay: Is Kratom toxicity intrinsic or idiosyncratic?

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Is Kratom toxicity intrinsic or idiosyncratic?

Written by Helen Magnani, MSc. 2022.

It can be difficult to find the point at which the benefits of an herb outweigh the risks, especially when the difference lies in the nuance of how the public uses it. A quick look at Mitragyna speciosa, commonly known as Kratom, immediately brings up the question of regulating herbs and potentially reclassifying those once considered safe. Kratom has a long traditional use in Asia among the farm populations of improving work productivity with historically little question of its safety or reports of adverse reactions despite its widespread availability. Studies confirm that Kratom’s chemical constituents have beneficial pharmacological actions, but as its popularity increases in the West, there have also been increasing numbers of reports of negative effects and even deaths. Kratom consumed in small doses can be beneficial for a wide variety of ailments, but in large doses, it produces narcotic effects that can be dangerously toxic, especially when mixed with other substances. There seems to be no mechanistic explanation for how or when this toxicity occurs, and studies have failed to reproduce these toxic occurrences in animal models, further driving concerns as to what we can expect from this herb as more and more people consume it. Despite its potential abuse, it provides many benefits to the natives for whom it is culturally woven into daily life. Kratom should be standardized so that safe doses can be regulated and used properly since its toxicity is idiosyncratic, dose dependent and not fully preventable. We may lose some of the cultural use of the plant, but standardizing it ensures the public can continue to safely benefit from its use.

Mitragyna speciosa comes from a tropical tree-like plant native to Thailand, Malaysia, Indonesia and neighboring countries in the Southeast Asia region (Prozialeck et al., 2019). It is known as Kratom, Ketum, or Biak-biak and is a psychotropic plant from the Rubiaceae coffee family (Sharma & McCurdy, 2020). The name Kratom refers to both the plant and the botanical derivatives of its leaves, which is the main part used. Similar to coffee, Kratom has historically been brewed as a tea made from the freshly harvested leaves; its leaves can be chewed or smoked as is often done by the natives, or it can be taken as a powder as well (Sharma & McCurdy, 2020). It is described as being stimulating when chewed and as a relaxing analgesic when brewed into a tea (Veltri & Grundmann, 2019). Traditionally, Kratom is used to treat pain, combat the fatigue and strain of physical labor, boost mood, improve work productivity, increase alertness, optimize endurance, stop diarrhea, manage diabetes, help mitigate the symptoms of opiate withdrawal, and is notably an inexpensive alternative to alcohol and opiates themselves (Cinosi et al., 2015; Eastlack et al., 2020; Meireles et al., 2009; Sharma & McCurdy, 2020). Its widespread use is in part attributed to its local availability, but also to the large Muslim population in Southeast Asia for whom alcohol is forbidden, and for whom drinking Kratom leaf tea fills this void by providing a relatively similar effect (Sharma & McCurdy, 2020). Used in this way, one can argue that Kratom may be less toxic than alcohol since alcohol can cause organ damage, weaken the immune system, and interfere with the brain’s communication pathways when ingested for long periods of time (NIH, 2021). Nonetheless, Kratom’s use is culturally woven into the lives of South East Asians. It forms a part of socioreligious ceremonies as well as medicinal treatment protocols for various household conditions and health maladies such as those previously mentioned, and professionally for hypertension, cough, fever, fatigue, pain, and for managing opioid dependance (Cinosi et al., 2015; Prozialeck et al., 2019). When the plant’s leaves are brewed into low-dose teas, extracts or decoctions, Kratom’s stimulating, pain relieving, warding off of fatigue and feelings of euphoria make it an attractive and easy to use recreational substance (Eastlack et al., 2020). In higher doses, it behaves like a drug, eliciting a sedative psychoactive effect similar to opioids; the unregulated, difficult to discern higher doses are what seem to be the problem.

Kratom is considered safe in its native setting having been consumed this way for centuries. Multiple problems are now being associated with its use in developed countries with the disparity directly correlated to the difference between the traditional use and modern manufactured commercial products (Sharma & McCurdy, 2020). Questions about its safety have risen after cases of dependency, adverse effects and even deaths have occurred. It has grown in popularity in the West alongside its reputation for being a legal, “safe high,” increasingly used by people in Europe and the United States, with the American Kratom Association estimating 3-5 million active and regular users in the US alone (Alsarraf et al., 2019; Eastlack et al., 2020) Kratom products show up as powdered dried leaves or as concentrated extracts formulated into tablets, gelatin capsules, mixed powders, liquid shots and energy drinks in the US, commercially available in gas stations, local specialty shops, and on e-commerce websites (Sharma & McCurdy, 2020). Often times, it can be found as a mixture of preparations sold as herbal drugs that can actually be plant material spiked with synthetic active components, known as adulterations or contaminants (Kronstrand et al., 2011). Kratom can easily be found on the internet, so the source of its origin may be unknown, and regularly comes mixed with another μ-opioid receptor agonists added (Kronstrand et al., 2011). A common such preparation, called Krypton, consists of powdered Kratom leaves mixed with O-desmethyltramadol, the active metabolite of the analgesic tramadol which-as a drug on its own -has been linked to abuse potential and unintentional fatalities (Kronstrand et al., 2011). Kratom is dose-dependent and therefore potent by itself, but more so when adding μ-opioid receptor agonists or unknown adulterants which can make it even more powerful; consumers never really know what they are taking nor the strength of their dose when ingesting these types of preparations.

While Kratom is not scheduled as a controlled substance nationwide quite yet, according to Coonan & Tatum, the United States Food and Drug Administration has issued a public health advisory warning about Kratom’s potential for abuse, addiction, and serious health consequences, including focal and generalized seizures as well as epilepsy (Coonan & Tatum, 2021). An attempt to categorize Kratom as a Schedule 1 drug by the US Drug Enforcement Administration was made in August of 2016 with little tread way among policymakers, which has kept it unrecognizable as a controlled substance and therefore not subject to regulation by the US Controlled Substances Act (Eastlack et al., 2020). Unfortunately, this means little restriction or control of its sale, which further fuels the current opioid epidemic as prescribers are forced to cut back on supplying medications and patients look for alternatives to support their opioid habit (Eastlack et al., 2020). According to Meireles et al, “since it is available on the internet for purchase, its use is now widely a drug of abuse, namely as a new psychoactive substance, being a cheaper alternative to opioids that does not require medical prescription in most countries” (Meireles et al., 2009). Currently it is not illegal in most European countries either despite attempts to regulate it. However, in Denmark, Latvia, Lithuania, Poland, Romania, and Sweden, Mitragyna speciosa and/or its active constituents mitragynine and 7-HMG are considered controlled drugs due to their high misuse potential (Meireles et al., 2009). In New Zealand, Australia, Malaysia, Myanmar, and Thailand it is controlled by the the narcotics laws; in Thailand in particular, Kratom was banned and considered an illicit drug until recently when it was legalized for medicinal use (Meireles et al., 2009; Eastlack et al., 2020).

Mitragyna speciosa contains various phytochemicals that contribute to its pharmacological uniqueness and toxicological ambiguity (Cinosi et al., 2015). It has over 40 identified alkaloids, mitragynine being the most significant component, acting as a partial, biased agonist at μ-opioid receptors, and a competitive antagonist at both κ- and δ-opioid receptors (Hughes et al., 2022; Cinosi et al., 2015). The alkaloids mitragynine, which gives Kratom its psychoactive property, and 7-hydroxymitragynine are central nervous system targets only found in Mitragyna speciosa, appearing to be mediated through several pathways including opioid, adrenergic, dopaminergic and serotonergic receptors in the brain and int he body (Cinosi et al., 2015; Hughes et al., 2022; Sharma & McCurdy, 2020). Cytochrome P450 (CYP450) enzymes are responsible for about 95% of the oxidation and reduction of chemicals and form the main pathway involved in the metabolism of drugs, steroids, fat-soluble vitamins, chemical carcinogens, industrial chemicals and other entities (Guengerich, 2020) It is important to note that Mitragynine is also primarily metabolized by CYP450 enzymes, with minor contributions from cytochromes 2D5 and 2C9 (Sharma & McCurdy, 2020). Many drugs, pharmaceutical and illicit, along with herbs and dietary supplements share these CYP isoenzyme modulating pathways, which may in part explain why Kratom has been implicated in clinically significant unanticipated toxicities and/or deaths, if any of these happened to be dosed together. Additionally, mitragynine demonstrates blood brain barrier permeability and inhibits the P-glycoprotein system, which rids the brain of substances, ultimately increasing the bioavailability of susceptible drugs (Coonan & Tatum, 2021). This is worth noting when it comes to mitagrynine ingestion and concurrent pharmacoactive substances. Kratom use is often times combined with daily consumed that are contraindicated, such as caffeine, alcohol, sedatives, benzodiazepines, prescribed medications or illicit drugs (Sethi et al., 2021). It is unknown what other silent constituents may play role in Kratom’s psychoactive effects as well, or if they may interact with commonly consumed substances, if at all.

Natural products mixed with other substances add a significant amount of pharmacological complexity, of which we already have limited scientific research information on, much less on the toxicology of these interactions (Cinosi et al., 2015). This complexity is further exasperated with the possibility of adding in layers of adulterations or contaminants. If the risk wasn’t already high enough, taking psychoactives that are adulterated pushes the dangers of ill health or life threatening consequences even further (Cinosi et al., 2015). The fact that Kratom’s phytochemicals have been found to only appear in Kratom add to the difficulty of understanding its idiosyncrasies, since researchers don’t have another plant with these specific constituents to compare it to.

Commercially available powdered Kratom products in the US have recommended doses of 2–6 g depending on the strain and the intended use (Grundmann, 2017). In most cases, users will titrate themselves up from lower doses until they reach the desired effect (Grundmann, 2017). A cross-sectional survey of 293 regular Kratom users conducted in the community across three northern states of Malaysia found that more than 50% of regular users, defined as 6 months or more, developed severe Kratom dependency problems, while 45% showed moderate dependence (Singh et al., 2014). The average amount of mitragynine in a single dose of a Kratom drink was 79 mg, suggesting an average daily intake of 276.5 mg for participants; those who consumed more than 3 glasses a day had higher odds of developing a severe dependence, with a reported inability to control Kratom cravings (Singh et al., 2014). As they weaned off, the physical withdrawal symptoms commonly experienced included restlessness, tension, anger, sadness, nervousness, muscle spasms, pain, difficulty sleeping, watery eyes and nose, hot flashes, fever, decreased appetite, and diarrhea (Singh et al., 2014). “Kratom preparations present with a dose-dependent effect with negative effects” at high doses of 5g or more a day and frequent doses of 22 or more per week (Grundmann, 2017).

Some case reports of Kratom users state seizures, intrahepatic cholestasis, arrhythmia, impaired memory function, coma, and in the worst cases, death (Fluyau & Revadigar, 2017) Acute overdose or toxic symptoms include tremors, anorexia, frequent urination, weight loss, seizures, delusions, hallucinations, liver damage and death (Generes, 2022). The psychological manifestations described from its use besides euphoria and feeling relaxed include such severe symptoms as aggression, hostility, and psychosis (Fluyau & Revadigar, 2017). The American Botanical Council report adds lethargy, irritability, yawning, runny nose, muscle pain, cramps, joint pain, restlessness, tension, aggression, sadness, delusion, hallucination, intense cravings, anxiety, depression, moodiness, annoyance and sleeplessness to the list of withdrawal symptoms (Singh et al., 2016). Nausea, chills, diarrhea, excessive drooling, vomiting, irritability, hypothermia, excessive sweating and nervousness also make the list (Generes, 2022). While Kratom’s withdrawal symptoms can be difficult, they are not as painful as the opioid withdrawal symptoms experienced by users and they usually subside after three days (Singh et al., 2016). This may prove to be a benefit of substituting Kratom for opioids and can explain why it is used to wean off of them. Clinical interactions between Kratom and other varying unknown substances in the worst of cases may lead to unintentional death with untraceable and inexplicable links, as was the case of 27 year old Matthew Dana in Tupper Lake, New York, who was found to have extremely high levels of Kratom in his blood at the time of his death, but who's death could not be attributed to the herb itself (Smith, 2019). Cases like his cause a lot of uncertainty not only about the true pathology of death, but about the safety of everything Dana was possibly taking, the interactions between them and what else may have been at play. Kratom does not appear in regular urine drug screens and may be undetected during routine screening of acute drug intoxication, overdose, or withdrawal, and may only be found if disclosed during a patient history intake (Sethi et al., 2020). This scenario also poses the pertinent question of how safe historically safe herbs truly are when used in modern ways. “In Thailand and Malaysia, the identity of the supplier and the quality of their products are known to the buyer, [whereas] in the West, the largest volume of Kratom is sold anonymously over the internet” (Singh et al., 2016) A 58 year old man with schizoaffective disorder admitted to the hospital with jaundice and liver injury from Kratom use admitted to purchasing a bulk package of “pure maeng da Kratom leaf,” described as “100% effective and 100% natural” from a novelty store (Dorman et al., 2015). He had previously taken Kratom at 1tsp per dose daily for 3 months to relieve anxiety, at which point he developed jaundice and was advised to cease ingestion by his psychiatrist. After discontinuing use, he returned to normal health and eventually resumed taking his Kratom supplement, at which time he was again admitted to the hospital again with jaundice, dark urine and abnormal liver enzymes, bilirubin and ammonia; he was discharged when his labs returned to normal (Dorman et al., 2015). The adverse events in this case appear to be dose related and to occur from the direct effects of Kratom use, since it is known to cause liver injury. His jaundice appears to be idiosyncratic, but its association with Kratom is convincing since it presented with use and disappeared with cessation, only to reappear with restarting the same Kratom formula purchased in bulk (Dorman et al., 2015).

Kratom’s effects on the body aren’t all negative. Aside from the stimulant and sedative effects that Southeast Asians have traditionally used Kratom to achieve, data analysis shows it offers additional positive benefits: it seems to inhibit pro-inflammatory mediator release and vascular permeability, it can enhance immunity, it may work as an antidepressant, and it acts as an anorectic (Fluyau & Revadigar, 2017).

Animal studies offer us some information, but the picture is still unclear. Researchers have had successful results in tracing the metabolism of mitragynine and Kratom’s other constituents in animal tests, but have been unsuccessful in reproducing the toxic or deathly affects Kratom is accused of. The similarity of the gastrointestinal tract in rodents, humans, and dogs as well as comparable opioid pharmacology of mitragynine and/or 7-hydroxymitragynine may have resulted in a multiple peak phenomenon of mitragynine across these species (Maxwell et al., 2020) Dogs are the closest species to humans in terms of total liver cytochrome content and cytochrome P3A4-mediated hydroxylase activity (Maxwell et al., 2020) so using them to study drug metabolism gives researchers reliable information for understanding how the same drugs are metabolized in human bodies. Research on beagles showed mitragynine actually appears to be a promising treatment for opioid self-administration without any abuse or addiction potential (Maxwell et al., 2020) In this study, there were concerns with levels of an increase in the binding affinity of the μ-opioid receptor compared to mitragynine, which indicated the potential for opioid-mediated abuse or addiction potential. The active constituent mitragynine was tested on female Beagle dogs at single 5mg/kg doses orally and 0.1mg/kg doses intravenously in order to investigate its safety and pharmacokinetic properties in dogs, which are "commonly used as a ‘second, non-rodent’ species for toxicological and pharmacokinetic studies during medication development” (Maxwell et al., 2020). No major adverse events were noted in the subjects in either study, although all subjects experienced mild transient sedation immediately after dosing that lasted approximately 2 to 4 h after the oral 5 mg/kg dose and for up to 1 h following the 0.1 mg/kg intravenous dosing (Maxwell et al., 2020). Stress-related frenetic signs commonly observed such as pacing, barking, jumping, and spinning were reduced, alluding to a calming effect on the dogs, and excessive drooling deemed a side effect subsided after food was given (Maxwell et al., 2020). No significant changes in vital signs, physical examinations or clinical changes in labs were reported, nor were signs of toxicity (Maxwell et al., 2020). The rodent studies mentioned by Maxwell et al. examining mitragynineʼs abuse liability did not support the alleged high abuse potential, though mitragynine administration did result in a reduction of morphine and heroin intake in the rodents (Maxwell et al., 2020). This supports the theory that mitragynine has potential therapeutic value for opiate addiction and withdrawal.

The nematode worm Caenorhabditis elegans is a test organism for toxicity screening similar to rodents that is gaining popularity for its comparability of responsiveness to a variety of substances that are commonly abused by humans, including cocaine, methamphetamine, morphine, and alcohol (Hughes et al., 2022). A study conducted on C. elegans exposed them to 45 μg/mL doses of Kratom, equivalent to a 5g dose in humans, through a variety of solvents with morphine as the control substance. The results did not yield in any significant toxic effects, except for in the elevated doses of methanol and ethanol extracts test which did adversely impact the worms, however this result was not considered a parallel result in humans use since Kratom users typically consume water based extractions (Hughes et al., 2022). However, if humans are consuming methanol or ethanol extract knowingly or unknowingly, the correlation would be explained. There were striking differences noted in the effects between the Kratom varieties though: the White Borneo Kratom consistently had a more severe impact on the health parameters tested in the C. elegans compared to the Bali and Red Maeng Da Kratom varieties (Hughes et al., 2022). The phytochemical investigation was solely focused on the alkaloids mitragynine and 7-hydroxymitragynine in this study since they are the most potent, though the other alkaloids present in Kratom are recognized as affecting both opioid and non-opioid pathways as well. Their extent is less studied though. Locomotor activity is observed in animal tests to measure the effects of morphine on the body. Food intake is affected by opioid agonists as well and is another marker for measuring opioid regulation in the body. In this study and with these parameters, “there was no significant impact on nematode mobility upon exposure to other Kratom extracts [and]… the impact on body bending was minimal compared to the morphine control, suggesting that Kratom is unlikely to impact the opioid-like signaling pathway in the same way as morphine” (Hughes et al., 2022). Interestingly, this study’s data suggests that Kratom is not toxic and that it acts through an alternative pathway to opioid signaling (Hughes et al., 2022), which is different than presumed. The results from the worm studies brings up the question of which Kratom variety have the higher potentiality for toxicity, and how do consumers know which variety they are getting?

The variability in the commercial Kratom products available to consumers in store or online complicates the determination of the active principles responsible for the chosen self-treatment indication (Hughes et al., 2022). This can manifest in part because of varying growing methods which result in different potencies in the constituents of the plants. Greenhouse grown Kratom plants both in sun and in shade grow taller, wider, and have bigger and more numerous leaves than field grown plants in full sun, but what is most critical is that greenhouse Kratom contains a 31-40% higher mitragynine count, higher miscellaneous alkaloid counts, and a higher chlorophyll count which speaks to its nutrient profile and ultimate accumulation of light harvesting complexes and proteins (Zhang et al., 2022). Historically regarded as a field crop, data from the Zhang et al. study indicates that greenhouse production of Kratom may be more economically valuable given its yield of significantly increased alkaloid concentrations and greater total alkaloids (Zhang et al., 2022). This means that if greenhouse Kratom becomes something growers invest in, the phytochemicals of this new Kratom harvest would be even more powerful than the one we currently find in toxicology reports, and to what we have in data studies thus far- we would be looking at something completely different and potentially more dangerous.

The Kratom and its constituents themselves may not the problem, or at least not the full problem; the other part of the equation is the fact that Kratom is highly adulterated, especially when bought over the internet (Kronstrand et al., 2011) Though it has been available in the US for the better part of a decade, the Center for Disease Control and Prevention have reported an increase in significant Kratom-related calls to poison control centers between 2011 and 2015, with 7.4% of them serious to life threatening (Grundmann, 2017). It seems something is changing in how Kratom is being manufactured that is different from how it is found in nature, or the abuse potential in the West is so much higher than in the East, or perhaps both are the case. Kratom is often found to be mixed with adulterants, sometimes disclosed and sometimes not, and/or mixed with other substances to purposefully make it stronger. The preparation of Kratom plus O-desmethyltramadol called Krypton, for example, is sold in large quantities of 50g a package, even though the recommended website dose is 0.5 g. (Kronstrand et al., 2011). The risk for unintentional overdose in products such as these is high to almost guaranteed. An analysis by Kronstrand et al. identified 9 cases of fatal overdoses where toxicology reports were positive for both mitragynine and O-desmethyltramadol, the active metabolite of tramadol, without the parent drug, leading them to believe that the intake of Krypton was the cause of these deaths (Kronstrand et al., 2011). Significant autopsy findings between these deaths were common: congestion of lungs, lung edema, brain edema, and liver steatosis; the autopsy report for the previously mentioned police officer’s Kratom related death stated lung hemorrhage as his cause of death too (Kronstrand et al., 2011; Smith, 2019). Kronstrand et al.’s analysis states that femoral blood concentrations of tramadol higher than 1.0 μg/g are considered toxic and possibly fatal, and that considering the higher potency of O-desmethyltramadol, the metabolite of tramadol, the concentrations in the reported cases seem to be in the high range but without tramadol showing up, suggesting overdose of Krypton (Kronstrand et al., 2011). The absence of tramadol strongly suggests that the ingested drug was O-desmethyltramadol because tramadol has a longer half life and would show up on blood reports, but it doesn’t; this finding is significant because toxicologists know it plays a role in the overdoses, and therefore certify Krypton’s role because that’s where users would get it (Kronstrand et al., 2011). The contributions of mitragynine and its isomers in these cases is unclear- no reference data on blood concentrations are yet available, but we know it has agonist effects the μ-receptor suggest that may have contributed to the deaths, and this makes Kratom dangerous (Kronstrand et al., 2011). It’s important to note that taking Kratom as a whole leaf as it’s traditionally been used in its native setting is considered safe, and that consuming its isolated phytochemicals, changing them by extraction processes, mixing the herb with other substances, or purifying it not only changes the plant itself, but the dosage ingested becomes altered as well (Sharma & McCurdy, 2020). This must be taken into account when considering it it is intrinsically or idiosyncratically toxic. It may not be toxic on its own as historical data shows, but how it is extracted for use may make it toxic.

In their paper titled “Intrinsic versus Idiosyncratic Drug-Induced Hepatotoxicity,” Roth and Ganey define intrinsic toxicity as “reproducible in animals and occurs dose-dependently at sublethal doses” (Roth & Ganey, 2010). Idiosyncratic reactions on the other hand “present themselves very differently than intrinsic ones; they happen in a minority of patients, with variable time of onset and no obvious relationship to drug dose, and they are not reproducible in usual animal tests” (Roth & Ganey, 2010). Fundamental principles of dose response are the main difference between intrinsic and idiosyncratic toxicity (Roth & Ganey, 2010). Upon instigating an inflammatory stimulus to rodents in studies, drugs associated with human idiosyncratic reactions rendered hepatoxicity, hypothesizing that inflammation in the body may be what takes a drug in idiosyncratic reactions to a toxic level (Roth & Ganey, 2010). Kratom is highly dose dependent, so how much of it is taken is just as significant as how it is metabolized in individual systems (Dorman et al., 2015; Cinosi et al., 2015). Therapeutic drug monitoring (TDM) is generally defined as “the clinical laboratory measurement of a chemical parameter that, with appropriate medical interpretation, will directly influence drug prescribing procedures” (Kang & Lee, 2009). Drug monitoring allows for the individualizing of drug dosages in order to maintain therapeutic effect, monitoring of adverse reactions and toxicity, linking pharmacokinetic mathematical theories to patient outcomes, drug concentration-response relationships, the mapping of drug pharmacokinetic characteristics, and even the mapping of the human genome (Kang & Lee, 2009). When considering TDM, patient characteristics such as age, weight, organ function, and concomitant drug therapy are taken into account because these factors affect drug metabolism, as do the sampling time in relation to drug dose, dosage history, patient response, and the desired medicinal targets (Kang & Lee, 2009). We know that mitragynine is metabolized in liver microsomes, but due to the cytochrome-related genetic variations in humans, these enzymes play a role in the individual differences in the metabolism and toxicity of mitragynine (Kamble et al., 2019). Furthermore, Kratom and mitragynine are highly dose-dependent, but this dose can affect people differently; this makes its potential toxicity idiosyncratic, because how an individual reacts to it cannot be necessarily anticipated. This can be said for anything when it comes to everything, but for substances with high addiction rates that affect neurochemistry, it may be beyond the possibility of measuring how someone might respond or crave a substance over someone else. The substance in question also changes considerably when you compare purchasing it freshly brewed cup from a traditional tea shop versus a concentrated extract from an unknown internet provider or smoke shop; they are certainly not the same thing, and they cannot be considered to be the same substance. We are looking at different concentrations of phytochemicals capable of altering neurochemistry and physiology in very different ways when dose is critical to toxicity, where one is stimulating and one is narcotic-level sedating, with unknown interactions in between. These complex pharmacokinetics place patients at further risk of side effects and drug interactions (Coonan & Tatum 2021).

The FDA’s stance is that “Kratom should not be used to treat medical conditions, nor should it be used as an alternative to prescription opioids. There is no evidence to indicate that Kratom is safe or effective for any medical use. And claiming that Kratom is benign because it’s “just a plant” is shortsighted and dangerous” (Gottlieb, 2018). “Increasing use of the botanical Kratom to self-manage opioid withdrawal and pain has led to increased Kratom-linked overdose deaths” (Tanna et al., 2022). It has yet to be determined if the biochemical benefits of Kratom outweigh its toxicity and risks, and according to Fluyau and Revadigar, its potential side effects outweigh the benefits, and severe and real health hazards can, insidiously, lead to death (Fluyau & Revadigar, 2017).

Ultimately, Mitragyna speciosa is a substance who’s safety and toxicity is dose-dependent, and the problem is that we don't know when one dose becomes the other, or what may push it either which way. Even if Kratom is proved to be safe for consumption, there is scientific reason for toxicity concerns from a convergence of risk factors (Coonan & Tatum 2021). Taking all of this into consideration, the conclusion is that Kratom and its phytochemicals are idiosyncratically toxic. Kratom can certainly be intrinsically toxic on its own, but it depends on how it it taken. Being dose-dependent makes the complex pharmacokinetics even riskier when it is mixed with other substances, or purchased over the internet where it may be spiked or adulterated (Coonan & Tatum, 2021). Anything can be abused however, and anything beneficial can become harmful if too much is taken, or taken incorrectly. The use of substances to enhance human abilities and experiences can be traced back to our early origins; we have always experimented with plants. Predictions of novel psychoactive drug trends in Western countries specifically suggest that Kratom use will increase in the coming years (Cinosi et al., 2015) It is therefore imperative to standardize Kratom products and mitragyna extracts so that doses can be measured, and some level of herbal safety can be implemented to its street use. Research and development of a Kratom as a drug must be demonstrated in more than one animal species in order to predict accurate human pharmacokinetics (Maxwell et al., 2020) which may mean investigating better animal models or ways of testing since thus far they have not shown to reproduce toxic effects experienced with human abuse. Designing well-informed clinical studies with Kratom at concentrations to test pharmacological effects is necessary as well (Tanna, 2022). Standardizing Kratom may not be possible however due to the nature of plant variability, unless the species was grown in greenhouses and monitored carefully which may be worth exploring as an option for combatting the opioid addiction crisis the West is experiencing. Authorities may not be able to stop its popularity, but by legalizing and standardizing it, scientists can measure, study, and understand its effects more fully- and perhaps one day, eliminate the unintended toxic reactions that are taking people’s lives. Sadly, it is when Kratom is not ingested as occurs naturally that idiosyncratic toxicity arises. The most important part of the Kratom equation is to keep in mind that there is a relationship between dose and response, how it is metabolized, the presence of other chemicals, individual rates of absorption, genetics, previous drug use, how much is taken and how it is taken. The user must also be certain they are actually taking pure Kratom, and not a product that has been adulterated or spiked. If its use is “in alignment with “drug instrumentation” theories, in which a substance is utilized in a purposeful, goal-directed manner” as Eastlack et al. mentions, then there should be no issues with its recreational or even medical use (Eastlack et al., 2020). The best approach would be to standardize Kratom to provide the public with a safe way of consuming it, but in a dose regulated manner to prevent the possibility unknown interactions since its idiosyncratic toxicity is not fully preventable.

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