Accurate Education - Kratom

The use of kratom is not encouraged due to potential safety concerns.

Kratom

Kratom (Mitragyna speciosa) is a plant indigenous to Thailand and Southeast Asia and belongs to the same plant family as coffee.

Kratom leaves produce complex stimulant and opioid-like analgesic effects. In Asia, kratom has been used to ward off fatigue and to manage pain, diarrhea, cough, and opioid withdrawal.

Recently, kratom has become widely available in the United States and Europe by means of smoke shops and the Internet and people are increasingly using kratom for the self-management of pain and opioid withdrawal.

Neither kratom, nor any of its constituents nor metabolites have been approved as safe and effective for any therapeutic use. This narrative does not recommend the use of kratom or any substance that is not approved by the FDA.

Opening Comments

Based on pre-clinical data and case reports published in scientific literature as well as anecdotal experiences posted online, it is not entirely safe to use kratom. Its use can be associated with serious adverse and life-threatening effects, especially in a multi-drug scenario. Even if not directly contributed to kratom, fatal overdoses related to kratom use have occurred. Use of kratom can lead to cravings for the drug, the development of withdrawal symptoms after sustained use and addiction, particularly in those with vulnerability to addiction.

Recreational drug use history is a complex history of human desire to relieve suffering, to enhance feelings of pleasure and to satisfy other desires. The line between socially acceptable and unlawful use of psychoactive products is culture-bound. Even if it is officially banned, kratom is a plant with well-established traditional social and medicinal uses in the local cultures of South Asia. At the same time, kratom’s rapid diffusion into Western societies, where it is often considered a “natural” option to illicit drugs or an alternative to opioid treatment, is not free of risks.

Caution is advised regarding the use of Kratom. Overdoses have occurred and it is a potentially addictive drug. Purchasing Kratom is confounded by lack of product consistency and the potential for the presence of additives and contaminants that may be harmful or dangerous.

Demographics of Kratom Use

Traditionally, in certain regions of Southeast Asia, the chopped fresh or dried leaves of the tree are chewed or made into tea by local manual labourers to combat fatigue and improve work productivity. In addition, kratom preparations have also been used for centuries during social activities and religious ceremonies and to treat various medical conditions, such as morphine dependence in Thailand, and as opium substitute in Malaya.

Kratom is exceptionally complex in terms of its chemistry which adds complexity regarding its pharmacological effects. There is a lack of data relating to the toxicology of these materials, and even less regarding their interactions with conventional drugs of abuse and pbarmaceutical medications. This is further complicated by the possibility of adulteration processes which are not uncommon and which have led to accidental deaths. The level of complexity, variability, and the unknown nature of these samples, coupled with the risks associated with taking psychoactive materials, offers further risks of ill health, with potentially life-threatening consequences.

Kratom Use in Southeast Asia

This herbal plant is also known as “kratom,” as “ketum” or “biak” (Malaysia), or as “krathom” (Thailand, “thom” in Southern Thailand) and has been used for millennia:

- As a stimulant;
- As a remedy in traditional medicine for pain, diarrhea, depression and anxiety;
- As a social practice.

Historically, manual laborers (e.g., fisherman, farmers, and rubber-tappers) in northern Malaysia and southern Thailand commonly used kratom leaves to improve their work productivity under the sweltering sun and to relieve fatigue. Rural folk have traditionally ingested kratom leaves to self-treat common medical problems (e.g., diabetes, diarrhea, fever, and pain).

In kratom’s native lands, people commonly chew raw although kratom can also be smoked, vaporized, or consumed as a powder. Typically, only the kratom leaves are consumed, including chewing the whole leaves, ingesting or smoking dried and pulverized leaves, or drinking water extracts based on steeping or boiling of the leaf material. In Malaysia, kratom is primarily consumed as a decoction, where the leaves are boiled for several hours and the resulting liquid is consumed several times throughout the day.

The use of kratom is most commonly divided into two main groups of users: the first includes those who solely use kratom to improve physical tolerance to laborious work and the second polydrug users who attempt to manage drug withdrawal symptoms or reduce the intake of other opiates like heroin. A recent study showed that out-of-treatment opiate users in Malaysia often use kratom to reduce their dependence on illicit opiates as well as to reduce opiate withdrawal symptoms.

Thailand

A survey performed in 2007 investigating kratom use in Thailand (26,633 respondents aged 12–65 years) indicated that the lifetime, past year, and past 30 days use for kratom were 2.32%, 0.81%, and 0.57%, respectively. These figures, with the exception of lifetime use, were significantly higher than those for cannabis making kratom the most widely used illicit drug in Thailand.

Thailand was the first country to criminalize kratom under the Kratom Act of 1943. Today, Kratom is listed as a category V substance under the Thai Narcotics Act, similar to cannabis and psychotropic mushrooms, with penalties of up to 1- or 2-year imprisonment for possession and production or disbursement of the substance, respectively.

Since the Kratom Act, M. speciosa has been federally regulated in countries including Denmark, Latvia, Lithuania, Poland, Romania, Sweden, Myanmar, Malaysia, Australia, and New Zealand.

Kratom Use in Western Countries

In western countries kratom use has be exponentially growing as a means of treating pain and/or opioid withdrawal. Many different formulations are available, including raw leaves, capsules, tablets, powder, and concentrated extracts. Leaves may be chewed (1-3 leaves at a.time) or made into a tea but because of their bitterness sweeteners such as sugar or honey are often added. The leaves can also be smoked or vaped but not typically due to the large amount of kratom needed to be smoked to achieve effects.

United States

An estimated 10–16 million people in the United States take kratom, though current prevalence ranges of 1.3%–6.1% from national representative surveys (Henningfield et al., 2019; Covvey et al., 2020) may underestimate regular kratom users. Whereas in Southeast Asia users typically buy kratom leaves directly from a grower, in the U.S. it is purchased capsules, powders, or extracts via the internet, specialty smoke shops, and gas stations.

Reasons for kratom use in the U.S. include to self-treat acute and chronic pain, to reduce or avoid the use of illicit opioids and/or heroin and to cope with anxiety, depression and post-traumatic stress disorder.

Online surveys show that almost half of United States consumers are female and the majority of Western consumers are middle- aged, middle-income, Caucasian, and college-educated with private insurance. Most kratom consumers discover kratom through the internet or social media, about 25% from an acquaintance/ friend. Only 3% of survey respondents learned of kratom from a healthcare provider and only about 40% of kratom consumers informed their healthcare providers about their use.

Generally, motives for use in the West are the same as those in SE Asia and include improvements in health, well-being, and productivity. Survey respondents overwhelmingly report that regular kratom consumption produces desired effects, including relief of symptoms such as pain (68%) or anxiety (65%), allowing them to live functional lives and meet daily obligations. Additionlly, others report use of kratom as a means of treating opioid withdrawal.

Kratom – Safety

There is considerable ambiguity on the potential harms from kratom use. Case studies, poison control center briefings, and coroner and medical examiners’ reports have disproportionately emphasized, as these forms of inquiry often do, extreme and rare events, including seizure, liver damage, and death. As noted in a 2018 editorial directed at DEA’s consideration of scheduling kratom as a Schedule I drug, “In the United States, proposed regulatory responses to kratom appear overmatched to evidence of harms.” The authors went on, “It is our opinion that the evidence does not support such conclusions regarding the risks of kratom.”

Although the Food and Drug Administration’s (FDA) Commissioner recently referred to kratom as “a narcotic-like opioid with respect to ‘potential for abuse, addiction, and serious health consequences; including death.” This statement by the FDA is based primarily on isolated adverse event reports and an in-silico receptor binding model: the Public Health Assessment via Structural Elucidation (PHASE). Based on this model, the FDA statement concluded that “we feel confident in calling compounds found in kratom, opioids.”

Although in-silico models can provide valuable insights, an isolated receptor interaction study does not reflect the complexity of a living organism and has never been considered an acceptable replacement for experimental human-based research data for FDA drug evaluations and approval. The physiological consequences of opioid receptor bindings vary widely, from the deadly effects of fentanyl to the relatively innocuous effects of the non-scheduled dextromethorphan.

Most importantly, research shows mitragynine binding to mu-opioid receptors occurs without recruitment of beta-arrestin 2, which is causes many adverse effects associated with classical opioids, including respiratory depression, euphoria and tolerance development. The authors add that “available scientific evidence indicates that the kratom alkaloids mitragynine and 7-hydroxymitragynine are not functionally identical to opioids; their molecular and pharmacodynamic mechanisms of action are distinctly different.”

Kratom-related calls to poison control centers

From 2010 to 2015, U.S. poison control centers received 660 calls related to kratom exposures, ranging from 26 in 2010 to 263 calls in 2015. These 263 calls represented roughly 0.000091% of the total of 2,792,130. From 2011 through 2017, 1807 kratom exposures were reported to United States poison control centers. Almost two-thirds (65.0%) of these exposures occurred during 2016–2017 and it is anticipated that these numbers continue to increase. Most exposures occurred among adults ≥20 years (88.9%), mostly males (70.8%), and were related to intentional use(74.3%).

The majority of kratom-related calls to poison control centers are categorized as minor or moderate in severity, with only 7% classified as major severity. This is consistent with recent user surveys, including a 2016 study showing that fewer than 1% of respondents sought medical or mental health treatment related to consumption. Most side effects reported are minor and self-limited, resolving with discontinuation of kratom use. The most common dose-dependent adverse effects are constipation, nausea/vomiting, stomach irritability and drowsiness.

In the cases of major severity, the mere presence of mitragynine in victims’ blood only provides evidence of presumed kratom consumption but does not determine the plant’s role in toxicity, especially given that most cases involve polypharmacy.

Finally, there is no clear mechanism by which mitragynine alone and ingested even at high doses would directly cause death. Deaths attributed to the use of Kratom have been reported in Europe and the United States but not in Southeast Asia. Although kratom use was deternined by the presence of mitragynine in the blood of the decedents, causality could not be established in almost all cases because of poly-drug exposures.

Kratom Side-Effects

Almost everyone describes tongue numbness after drinking Kratom tea. As for the clinical and safety aspects, no serious adverse effect was found during a study. This is probably because the doses used in the study were less than 30 mg. However, the daily intake dose of regular users was reported to be as high as 276.5 mg in Malaysia. Every subject in this study developed tongue numbness after having finished drinking Kratom tea. All of the participants also confirmed that it was the same experience as when they took Kratom.

Agitation, irritability and tachycardia are the most common complaints made to poison control centers regarding kratom. Other side effects include fatigue, nausea and vomiting, constipation, dry mouth, changes in urination, insomnia, temporary erectile dysfunction, itching, and sweating.

With long term use, some users describe hair loss and hyperpigmentation. Loss of appetite and weight loss can also occur, as well as tremor and nystagmus, possibly related to daily use of kratom. Adult Respiratory Distress Syndrome, hypothyroidism and psychosis have been described in chronic users.

Multiple-substance exposures are associated with greater odds of admission to a health care facility and a serious medical outcome compared with single-substance exposures. There have been 11 deaths reportedly associated with kratom exposure, including two that occurred after exposure to kratom only.

Kratom alone, or in combination with other substances, has also been shown to cause physical and psychological dependence including withdrawal symptoms following repeated use of kratom.

Kratom Toxicity

Opioid Receptor-related Toxicity

Mitragynine and 7-hydroxymitragynine have partial affinity for the mu opioid receptor, so binding of kratom to this receptor largely activates G-protein coupled pathways and not the beta-arrestin pathway which responsible for the deadly side effect of respiratory depression. This suggests why kratom alone does not provide high risk for overdose death. That being said, interaction of kratom with other sedative medications may be dangerous.

By comparism, the partial opioid agonist buprenorphine (Suboxone), carries a far lower risk of lethal respiratory depression when used alone, but has been identified as contributing to overdose deaths when used in combination with Valium and other sedatives. The degree of risk associated with kratom use in combination with benzodiazepines and other sedatives may be similar, greater, or less compared to buprenorphine but is likely dose-related. It would be prudent to avoid such combinations and minimize intake levels when combination consumption occurs.

Serotonin-Related Toxicity

There are multiple mechanisms in which mitragynine may interact with other drugs which are covered below. However, one common potential for drug interactions associated with mitragynine is serotonin syndrome because mitragynine elevates serotonin levels in the brain. Serotonin syndrome is a condition that can be fatal in extreme cases but commonly consists of a flu-like syndrome, with low grade fever, nausea and vomiting, confusion and muscle stiffness, especially in the lower extremities.

Taking mitragynine with medications that raise serotonin levels adds risk for serotonin syndrome, including antidepressants but also opioids including tramadol (Ultram), tapentadol (Nucynta) and methadone.

Noradrenaline-Related Toxicity

Furthermore, because mitragynine raises noradrenaline levels, it may at higher doses trigger anxiety and feeling jittery which may be worsened when mitragynine is taken with other medications that raise noradrenaline, including the opioids tramadol (Ultram), tapentadol (Nucynta) and methadone.

Kratom-Related Fatalities

The deaths associated with kratom are likely due to potential kratom-drug interactions. Evidence also suggests that kratom might be a deadly substance when mixed with other compounds.

The majority of kratom-related fatalities test positive for opioids and/or benzodiazepines in addition to kratom. Risk of kratom-opioid interactions could be on the rise paralleling the opioid epidemic dominated by illicitly manufactured fentanyl and its analogs (https://www.cdc.gov/drugoverdose/epidemic/index.html). In fact, fentanyl and its analogs are listed as causing unintentional overdose deaths in approximately 65% (99 of 152) of kratom-related deaths.

Fatalities have been reported when kratom was mixed with these other medications:

O-desmethyltramadol (tramadol/Ultram); propylhexedrine (Benzedrex); 
Over-the-counter cold medications and benzodiazepines (Valium, Xanax, Klonopin);
Venlafaxine (Effexor), diphenhydramine (benadryl), and mirtazapine (Remeron); 
Zopiclone (Lunesta), citalopram (Celexa), and lamotrigine (Lamictal)

Krypton

Fatalities resulting from the use of a kratom-based product known as “Krypton” have also been reported with 9 documented cases in Sweden. Subsequent forensic studies revealed that Krypton contained high amounts of the exogenous pharmaceutical agent O-desmethyltramadol, an opioid analgesic and the main active metabolite of tramadol, which had been added to the plant material. The presence of this contaminant in some online products is well documented.

Other “deadly cases” have been reported: one article described a fatal reaction that appeared to be associated with mixing with propylhexedrine (a TAAR1 agonist and amphetamine-like stimulant, used as decongestant inhalers); another case indicated that a mix of kratom, over-the-counter cold medications, and benzodiazepines was responsible for the death of a 17-year-old boy; a postmortem detection of kratom together with venlafaxine, diphenhydramine, and mirtazapine was found in a 24-year man found unresponsive in bed; a middle aged man in therapy with zopiclone, citalopram, and lamotrigine was found dead at home and postmortem analysis of peripheral blood revealed high concentrations of kratom (mitragynine and 7-hydroxymitragynine) and therapeutic values of the other prescribed compounds. The nature and prevalence of potentially lethal drug interactions is unknown at this time.

Case Reports

More serious adverse effects and intoxication cases across various countries have also been reported.

Liver Toxicity (intrahepatic cholestasis with jaundice and Itching)

In 2011, a case report was published that described a case of a young man who presented with jaundice and itching after intake of kratom for 2 weeks in the absence of any other identified causative agent.

In this case, the patient reported ingestion of a powdered substance obtained via the internet in Thailand, where it was advertised as an additive for foot baths. He ordered two kinds of powder (so-called Thai Pimp and Malaysian Green, both powder from ground up kratom. Samples of the kratom powders used by the patient were analyzed by gas chromatography–mass spectrometry (GC–MS) which confirmed them to be kratom and excluded other toxic ingredients.

He took both powders on a daily basis orally. The ingested amount started with one to two teaspoons (one teaspoon is about 2.3–3.5 g, corresponding to approximately five to eight dried leaves) twice daily. In the course of 2 weeks, he increased the intake to four to six teaspoons daily. It should be noted that this dosing is considered “massive,” with six teaspoons (about 14–21 g, approximately 32–49 dried leaves), compared to 15 grams considered to be a high dose. No further illicit drugs, medication (e.g., antibiotics, analgesics), dietary supplements, or alcohols were reportedly consumed.

The patient described the effect of the products as mildly relaxing, causing tiredness without any stimulating effects, but he noticed a loss of appetite after 2 weeks. After discontinuing the products, he developed subjective fever and chills on day 2 after stopping, which lasted for about 1 week. On day 5 after stopping, he noticed slight abdominal discomfort, which developed into intense abdominal pain on day 8 associated with brown discoloration of the urine followed the next day by jaundice and itching.

Viral hepatitis (hepatitis A, B and C) and autoimmune diseases were ruled out with blood tests. Ultrasound and computed tomography (CT scan) of the abdomen showed signs of fatty liver.

A biopsy of the liver was performed on day 2 after admission which identified a drug-induced liver injury, (intrahepatic cholestasis or so-called pure cholestasis) without cellular damage. Over several weeks the condition resolved and the patient returned to normal health.

Why this patient developed intrahepatic cholestasis remains unclear, but the massive dosing daily for 2 weeks may have been the contributing factor.

Treatment of kratom intoxication is supportive in nature, with no specific antidotes. Toxicity can arise from noradrenergic overstimulation (see neurobiology of kratom below) which can be treated with benzodiazepines to suppress seizures and reduce agitation plus beta blockers (propranolol and others) to slow the heart rate and reduce blood pressure. Toxicity can also arise from opioid effects which can be treated with naloxone to block the opioid receptors although response to naloxone is likely to partial at best.

Safety Conclusion

In conclusion, although the medical literature and long-standing traditional use suggests an acceptable risk profile, kratom is not totally benign especially if used in combination with other medications. Regulatory oversight of marketing and quality needs to be engaged to protect public health. Although caution regarding the kratom alkaloids that bind to opioid receptors is warranted and important, equating kratom with more dangerous known opioids may result in premature judgments of an herbal product used by millions as an opioid substitute. For some of these consumers, if access to kratom becomes restricted it will have the potential to increase risk of illicit opioid use with the consequent potential for overdose and death.

Caution must be used when combining kratom use with other medications which can induce enhanced symptoms of toxicity.

Drug Interactions Related to Kratom

Besides the toxicity that may occur directly from kratom exposure, another aspect of safety concerns regards the potential of drug interactions with medications or drugs in one’s system. As noted above most major adverse effects related to use of kratom occurs in combination with use of other medications. Deaths related to kratom use in (almost?) every case appear to be exclusively related to its use combined with other medications.

In some cases drug interactions may be predicted based on how other drugs act or are metabolized. So when the action of two drugs are both sedating their interactions give rise to greater sedation. This type of interaction is generally obvious and predictable and doesn’t require much attention here.

However, when the metabolism of two medications taken together are affected the interaction is not obvious and only predictable when one is well informed. In the case of kratom there are important metabolic interactions that must be considered for optimal safety when taking kratom, so one must be well informed.

Kratom’s influence on the metabolism of other medications

The metabolism of medications can be complicated, but an important mechanism is the breakdown that begins in the intestines and continues in the liver and can even continue in the blood. A family of enzymes, the cytochromes P450 enzymes (CYPs), are important in the metabolic breakdown of the majority of medications. Kratom alkaloids including mitragynine and 7-hydroxymitragynine, have been found to inhibit certain CYP enzymes that metabolize many common medications, including opioids and benzodiazepines.

A 2019 publication evaluated blood levels of drugs and medications found in 15 kratom-related deaths in Colorado that suggest the possibility that kratom-induced inhibition of the breakdown of these various drugs and medications triggered their toxic levels which contributed or caused the deaths.

See: Major enzymes involved in the metabolism of opioids and/or other drugs detected in postmortem blood samples obtained from kratom-related death cases in Colorado

Kratom alkaloids strongly inhibit CYP2D6 and modestly inhibited CYP3A and CYP2C9 in the liver in a concentration-dependent manner. Likewise, they also show concentration-dependent inhibition of CYP3A in the intestines, with relatively stronger effects compared to the liver (24%–87% vs. 18%–66% inhibition).

Mitragynine and CYP enzymes

Mitragynine inhibits certain CYP enzymes in the liver and intestines, with the most potent inhibition against CYP2D6, followed by CYP3A and CYP2C9. Mitragynine can be a clinically relevant reversible CYP2D6 inhibitor that could lead to potentially dangerous drug interactions, but likely only with high doses of kratom (9 grams or more), with the average content of mitragynine in a 1-g dose of kratom to be 10 mg.

CYP2D6 Enzymes

Potential medications at risk for interactions with kratom based on the inhibition of CYP2D6 include the opioids tramadol, codeine and possibly hydrocodone and oxycodone. Because both tramadol and codeine are pro-drugs, meaning that their therapeutic actions require metabolism by CYP2D6 to form the active drug, it is possible that high doses of kratom would inhibit the clinical effects of these two medications.

Research suggests that doses of more than 9 grams of kratom extract containing 83 mg mitragynine can cause significant interactions with drugs primarily metabolized by CYP2D6.

Hydrocodone and oxycodone are partially metabolized by CYP2D6 to other opioids (hydromorphone and oxymorphone, respectively) that may provide additive effects to the two parent drugs. Thus one may see an impact on the clinical effects of hydrocodone and oxycodone when their use is combined with high dose kratom.

CYP3A Enzymes

The potency of mitragynine’s inhibition of CYP3A enzymes is similar in the liver and the intestines. With high concentrations of mitragynine, the inhibition can be >50%. Unlike with CYP2D6, due to a time-delay phenomenon with the inhibition of CYP3A enzymes in both the liver and intestine, even a low dose of kratom (2 grams of kratom powder containing only 21 mg mitragynine) may precipitate a CYP3A-mediated drug interaction. Similarly, about half-glass (∼150ml) of traditionally prepared Malaysian kratom juice daily could progressively increase the blood levels of some medications (i.e. midazolam) by ∼ 6 fold.

The impact of this is huge because roughly 40% of clinical drugs are substrates for CYP3A4 metabolism.

Due to CYP3A inhibition in the liver and/or intestine, build-up of toxic concentrations of quetiapine (Seroquil), a CYP3A substrate, is possible. A case report was published in 2019 regarding a kratom-related death associated with its combined use with quetiapine (in which quetiapine overdose was not suspected). Quetiapine is extensive metabolized in its first-pass through the liver after ingestion. It is predicted that a ∼2.5-fold increased blood level could occur when taken with a 2-g dose of kratom, supporting the possibility that the kratom-related death was due to time-delay inhibition of CYP3A.

CYP2C9 Enzymes

Mitragynine is only a modest reversible inhibitor of liver CYP2C9 and is considered to offer only a minimal risk for drug interactions with kratom.

Interaction risks for CYP enzyme substrate medications include:

Opioids: Fentanyl, tramadol, codeine, hydrocodone, oxycodone
Benzodiazepines: Clonazepam (Klonopin), diazepam (Valium)
Antidepressants: Mirtazapine (Remeron), Sertraline (Zoloft), Citalopram (Celexa), fluoxetine (Prozac) and other SSRIs
Others: Diphenhydramine (Benadryl), Quetiapine (Seroquil), topiramate (Topamax), zolpidem (Ambien)

P-glycoprotein (P-gP) Transporters

In another study, mitragynine and 7-hydroxymitragynine also showed an inhibitory effect on P-glycoprotein (P-gP), a transporter that moves medications from the gut and brain into the blood. As such, these alkaloids may both interfere with the absorption of P-gP substrate medications from the gut but they can also help sustain higher levels of these medications in the brain and central nervous system.

Several opioid medications (i.e., morphine, methadone, buprenorphine (Suboxone), loperamide (Lomotil) and fentanyl) and associated metabolites (i.e., morphine-6-glucuronide) have been identified as P-gp transport substrates. In contrast, other opioids (i.e., codeine, hydrocodone, oxycodone) are not effectively transported by P-gp.

Coupled with the inhibitory effects of these alkaloids on the CYP enzymes and P-gP transporters, their impact on the metabolism of other medications may be significant. This especially applies to overdoses related to the use of illicit opioids imcluding fentanyl and heroin (whose active metabolites include morphine and morphine-6-glucuronide). This potential danger of drug interactions of kratom with these other medications likely have contributed to the mixed overdose reported deaths.

Kratom – Commercial Product Safety

A 2021 Canadian study found that the quality of information presented across the majority of online vendor’s websites specifically focused on selling kratom products to consumers was poor. Many failed to provide sufficient information about the benefits, risks, and uncertainties of kratom needed for consumers to make an informed decision about its purchase and use.

A variety of Mitragyna speciosa related products are easily accessible from local smart shops and increasingly available for sale on the Internet, in particular on web based “legal highs” pharmacies, but their exact content is not always verified.

Because kratom is currently not recognized as a dietary supplement in the United States by the Food and Drug Administration (FDA), it has not issued guidance or regulatory standards for kratom regarding allowable product contents, alkaloid concentrations, packaging, labeling, or marketing of kratom products.

This absence of regulatory policy and the potential for adulteration of kratom products prompted the American Kratom Association (AKA) to develop voluntary industry guidelines through a Good Manufacturing Practice (GMP) Standards Program that tests for purity and contaminants. The AKA requires producers of kratom products to meet strict manufacturing standards verified by a third-party auditor if they want to be certified by the AKA.

But the potential for adulteration of kratom products remains a concern. There is evidence that some of the kratom sold in the United States is adulterated to make it more potent. It is therefore advised that one purchase only AKA certified kratom products.

7-Hydroxymitragynine Contamination

Some kratom products have been found to contain artificially high levels of 7-hydroxymitragynine (See pharmacology of kratom below), one of the naturally occurring alkaloids in kratom that act on opioid receptors in the brain but is usually present in only very small amounts in the plant, roughly 2% of the plant’s alkaloid content. In a 2016 publication, the kratom supplements Phoriatm red, Phoriatm green, Phoriatm regular, Phoriatm Borneo white vein, Phoriatm Borneo red vein, Phoriatm Borneo green vein, Phoriatm maeng da blue lotus, Phoriatm maeng da kava, Green vein extra strength Kratom shot, and Viva Zen were purchased from a local market and tested for 7-hydroxymitragynine content. The authors found multiple packaged commercial kratom products contained substantial artificially elevated concentrations of 7-hydroxymitragynine. The amount of 7-hydroxymitragynine exceeded that found in naturally occurring material by up to 500% making the products more potent with a greater side effect profile.

Opioid Contamination

Kratom products have reportedly been laced with opioids (fentanyl and tramadol). Fentanyl contamination is anecdotal with no apparent publications to support this. A 2014 publication identified the active metabolite of tramadol (O-desmethyltramadol) in some commercial kratom products sold in Sweden that resulted in 9 deaths, but there does not appear to be any reports of this since. All nine patients had pulmonary congestion on autopsy, suggestive of respiratory failure . Because pure kratom does not appear to cause respiratory depression, these fatalities were likely due to O-desmethyltramadol alone and/or synergism with mitragynine or 7-hydroxymitragynine.

Heavy Metal Contamination

Contamination of raw-leaf kratom with the heavy metals lead and nickel has been reported. The source of the lead and nickel in these contaminated samples is uncertain. One possibility is that the metals may break off or leach from the equipment that is used to grind, process, transport and store the kratom leaf material. A second possibility is that the metals might be absorbed from the soil in which kratom is grown.

Most of the kratom sold in the United States is imported from sources in Indonesia and the volcanic soil in many parts of Indonesia are known to contain high levels of metals, particularly nickel. Also, lead pollution is a widespread problem in many regions of Indonesia. Noteworthy is that the samples tested that did not contain metals were concentrated extracts, suggesting the extraction procedure removes the metals. Further studies are warranted.

Salmonella Contamination

In May, 2018, 199 people were infected with outbreak strains of Salmonella as reported from 41 states. Illnesses started on dates ranging from January 11, 2017, to May 8, 2018. However, no deaths were reported and this outbreak appears to be an isolated series of events.

Kraton – Legal Status

Kratom is illegal in many countries with punishments of up to 70 years or more but it is still legal in most states in the United States. While kratom is still legal in Louisiana, this may not remain so. The DEA has announced intent to classify kratom as a Schedule 1 substance, defined as a substance with risk for addiction and with no legitimate medical purpose. Like LSD, heroin and marijuana, classification as a Schedule 1 substance will mark use of kratom as a felony and will severely limit medical research on the potential benefits of kratom.

Additionally, the DEA has classified kratom as a “drug and chemical of concern,” given the apparent lack of identified legitimate medical use and the potential risk to those who abuse it. At this time, there is no definitive timetable presented by the DEA as to when or if the federal ban on kratom will take place.

2/6/18

FDA ramps up warnings about kratom, calling unregulated herb an ‘opioid’

Kratom is largely uncontrolled in the U.S. at a federal level but at the state level there are some exceptions. DEA withdrew its initial scheduling request in October 2016 (See: Update – 10/12/16).

As of 2022, it is illegal in these parts of the United States:

Kratom Legal Status by State

As of 2022, it is illegal in these countries:

Australia, Bhutan, Denmark, Malaysia, Poland, Sweden, Thailand (since 1943), and Vietnam

Kratom Effects and Benefits

Westerners are increasingly using kratom to improve occupational functioning, much like the common use of coffee. Three Western online surveys (over 16,000 respondents combined) revealed increased energy and improved focus as main reasons for kratom consumption.

In a 2019 Western survey of 2,867 current and 157 former kratom users, 22% reported using kratom to alleviate symptoms of anxiety, post-traumatic stress disorder (PTSD), or depression. In another US-based survey of 8,049 users, 66% used kratom to treat emotional or mental conditions. Another survey of 6,150 kratom consumers by Pain News Network (2017) showed 14.5% of respondents used kratom to treat anxiety, 8.83% to treat depression, and 1.40% to treat insomnia. The most recent 2020 urvey of kratom users showed that depression (67%) and anxiety (65%) were the motivation for kratom use.

Pain Management

Although kratom’s long-term use in SE Asia is directed at a variety of ailments, reduction of pain is among the most common. An interview study of 562 kratom users in Malaysia revealed pain relief as a main motivation for kratom use. Large-scale United States online surveys have shown that pain relief is the most common motivation for kratom use.

The Pain News Network (2017) survey of pain conditions that people managed with kratom most commonly identified back/spine pain, followed by acute pain from injury, fibromyalgia, migraine or headache, and rheumatoid arthritis. Other pain conditions people reported treating with kratom included multiple sclerosis, neuropathy, osteoarthritis, inflammatory bowel disease, lupus or other autoimmune diseases, complex regional pain syndrome, Ehlers-Danlos syndrome, trigeminal neuralgia, and cancer.

Over 90% of the survey respondents indicated that kratom is “very effective” in treating their pain or medical condition, while approximately 7% reported it to be “somewhat effective” (Pain News Network survey, 2017).

Kratom and Opioid Use

In one of those surveys, nearly half of 8,049 respondents indicated that kratom enabled them to reduce or discontinue the use of opioids. Ten percent of 3,017 respondents to another survey were taking kratom to cut down on opioid use and/or relieve withdrawal. Of those using kratom in place of opioids, 90% indicated that it was helpful to relieve pain, reduce opioid use, and relieve withdrawal.

An analysis of 170 kratom threads during a 12-month period (2004–2005) on a Western online pharmacy indicated that a vast majority purchased kratom to treat opioid withdrawal. In an internet forum of 161 respondents in the U.S, over 10% reported using kratom to successfully decrease or abstain from an unwanted substance.

Unfortunately, other than the self-reported beneficial effects for pain with kratom, no peer-reviewed studies have evaluated this in rigorously controlled clinical trials with humans.

Kratom and Acute Pain

Adding to data from these observational studies, results from a recent randomized, double-blind, placebo-controlled trial showed that kratom significantly increased acute pain tolerance, as measured in the laboratory using the cold-pressor task in a sample of 26 male kratom users. This task is a standardized test commonly employed to measure an individual’s tolerance of acute pain associated with the time between the pain onset and the hand withdrawal from an ice bath. Arguably this type of test has limited application for understanding the benefit of kratom for acute or chronic pain.

Kratom Dosing

According to online reports and traditional experiences, subjective effects of kratom depend on the dosage: at low to moderate dose (1–5 g) it has a mild pleasant stimulant effect; at moderate-high dose (5–15 g) the compound has opioid-like analgesia and sedation. No studies have been conducted so far to determine the blood concentration in patients, and in the event of excessive dosing, there may be no response to naloxone.

Traditionally, the fresh or dried leaves of kratom are chewed or brewed into tea or smoked. Kratom is bitter and sugar or sweet beverages are commonly added to mask its taste. To experience vigor and euphoria, traditional kratom users chew one to three fresh leaves at a time. Regular and addicted users chew 3–10 times a day. It is reported that an average green leaf weighs about 1.7 g and a dry leaf about 0.43 g and twenty kratom leaves contain about 17 mg of mitragynine.

While kratom can be smoked, according to users this has no advantage over chewing or making a tea and the amount of leaves that constitutes a typical dose is too much to be smoked easily.

Dosing Effects

Five to ten minutes after kratom consumption, users describe themselves as feeling happy, strong, and active. Generally, the effects of kratom last for approximately five to 7 hours, with the strongest effect within two to 4 hours of ingestion, though after-effects (e.g., fatigue) can be felt even the next day.

In general, users report that at low doses kratom is a stimulant in which the mind is “more alert,” physical energy and sometimes sexual arousal are increased, and ability to do physical work is improved. It has often been compared to caffeine.

The stimulant effect at low doses (1-5 grams) reportedly acts as a mood booster.

At higher doses (>5 grams), it is described as more sedative and analgesic; users seem to be less sensitive to physical or emotional pain, to feel and look calm, and to have a general feeling of comfortable pleasure. Higher doses induce relaxation that may alleviate anxiety. These higher doses may be necessary for successful opioid substitution.

There is also preliminary evidence that kratom has empathogenic effects, suggesting that kratom may enhance sociability beyond what would be accomplished with anxiety reduction alone.

Kratom consumers sometime also describe euphoric effects at higher doses. Some people find the euphoric effect “edgy” rather than pleasant. Of note, only 2% of 6,135 kratom-users in the Pain News Network (2017) online survey responded “yes” to the question “Can you get high from kratom?”

People who decide to initiate taking kratom should begin with a very small amount to test for adverse reactions before slowly increasing. It is important to understand that the potency of any medicinal plant can vary based on factors such as geographical source, the season, age of the sample, and post-harvest handling as well as the strain, which is commonly referred to as vein type (red, green, or white) and likely corresponds to the age of the leaf. The red vein variety may be more potent than the older, green vein. Patients are advised to purchase kratom from the same manufacturer to be as consistent as possible in the product.

Kratom – Addiction and Dependency

In Southeast Asia it is estimated that 55% of regular users become dependent. However, findings show that regular kratom users do not seem to experience major impairments in their social functioning, despite being dependent on kratom for prolonged periods. On the other hand, evidence shows that kratom can generate addiction problems and lead to other social issues.

Regular kratom use is associated with drug dependency, development of withdrawal symptoms, and craving. Many regular users acknowledge difficulty abstaining from kratom use and experience unpleasant symptoms during abstinence periods. Physical withdrawal symptoms include anorexia, weight loss, decreased sexual drive, insomnia, muscle spasms and pain, aching in the muscles and bones, jerky movement of the limbs, watery eyes/nose, hot flushes, fever, decreased appetite, and diarrhea.

Psychological withdrawal symptoms commonly reported are nervousness, restlessness, tension, anger, hostility, aggression, and sadness. Long-term addicts are known to become thin and have increased skin pigmentation on their cheeks, due to the capacity of mitragynine to increase the production of melanocytes-stimulating sustance. Regular kratom use is also reported to cause psychotic symptoms such as mental confusion, delusion, and hallucination.

Kratom Withdrawal

Kratom tolerance, dependence, and withdrawal have been reported with daily and heavy use, though these symptoms are generally milder and of shorter duration than those of classical opioids. The physical dependence that can develop over time generally with three or more daily servings has been described as similar to that of coffee or mild opioid dependence.

The half-life of mitragynine half-life is 7-24 hours depending on alkaloid, requiring dosing every 6-12 hours. Longer duration of use and higher average doses may extend the duration and increase the severity of withdrawal, however, and only a small number of individuals find kratom very difficult to quit.

Withdrawal symptoms typically begin ~12 hours after last use, and may represent either serotonin or opioid withdrawal, or both. Withdrawal symptoms resolve within one to 3 days for most people.

Serotonin withdrawal symptoms

Typical symptoms of serotonin withdrawal include flu-like symptoms, insomnia, nausea, imbalance, sensory disturbances, and hyperarousal. These symptoms usually are mild, lasting one to two weeks, and are rapidly reversed with use of an antidepressant medication (even just a 2-3 day course), such as paroxetine.

Opioid withdrawal symptoms

Opioid-like withdrawal symptoms from mitragynine are also common, including muscle aches and jerking, irritability, mood disturbances, runny nose, diarrhea, and nausea. Kratom consumers sometime experience tolerance (requiring the consumption of higher doses to achieve the same effects) and may also include a “cross-tolerance” to opiates.

Pharmacology of Kratom Constituents

The clinical effects of kratom are dose dependent, with qualitatively different effects between low and high doses.

Low dose (1-5 grams)

1. Stimulatory due to neuroamines
2. Antidepressant-like effect similar to those with MAO (monoamine oxidase inhibitors) due to increased levels of serotonin, noradrenaline and dopamine

High dose (>5 grams)

1. Sedative and analgesic properties due to opiate receptor activation: 7-hydroxymitragynine has greater activity than mitragynine on the mu opioid receptor whereas only mitragynine has activity on the alpha-2 adrenergic receptors.
2. Counteracts opioid withdrawal: Mitragynine’s action as an alpha-2 adrenergic agonist may explain its use in treatment for opioid withdrawal, much like clonidine and lofexidine (See: Alpha-2 adrenergic agonists).

There are at least 40 chemically similar alkaloids in kratom with pharmacological properties, but the main psychoactive components in kratom leaves are the alkaloids mitragynine (MG) and 7-hydroxymitragynine (7-HMG), both found only in Mitragyna speciosa.

The phytochemicals isolated from various parts of the kratom tree include over 40 structurally related alkaloids of which mitragynine is the most important, with up to 66% purity in the extract of leaves from Thailand, and only 12% in kratom leaves from Malaysia. These additional alkaloids have not been extensively evaluated and presently there is no evidence to indicate which, if any, of these other compounds cross the blood-brain barrier or have any potential analgesic or other medicinal properties.

Mitragynine (MG)

Mitragynine, the dominant alkaloid found in kratom is yet to be fully understood in its mechanisms of action. It pharmacologic activities are complex and appear to involve multiple receptors and pathways.

Activity at Opioid Receptors

Mitragynine is likely responsible for some of the analgesic activity that has been linked to kratom, mostly due to its stimulation of opioid receptors in the brain, but this is dose-dependent. At lower doses, MG acts as an antagonist at the mu-opioid receptor, in that it binds to the receptor but does not trigger any response by the receptor. At higher doses, MG functions as an agonist, triggering a response by the mu-opioid receptor. As an agonist, however it has a low degree of efficacy, meaning it has low potency. In fact, in mice, MG is 2.6-fold less potent than codeine.

It is interesting – and important – to note that although MG and 7-HMG can act as an agonists on all three opioid receptors, the structural and chemical properties of both MG and 7-HMG are very different from morphine and other members of the opioid family. This has important ramifications for the potential of kratom alkaloids towards the development of new analgesics that may be safer than traditional opioids (see below).

Mu-opioid Receptor Pathways

When opioids stimulate the mu-opioid receptors, two separate pathways are engaged, one that results in analgesic effects (the G-protein-coupled receptor pathway) and one that results in reduced drive to breath (respiratory depression), the beta-arrestin pathway. The kratom alkaloids MG and 7-HMG do not appear to trigger the beta-arrestin pathways. As a result, respiratory depression leading to respiratory failure and death with an isolated overdose of kratom should not occur.

There remain concerns however that if kratom is taken with other drugs that trigger respiratory depression, an overdose death may occur, as has been reported, despite that a cause and effect concerning kratom has not been established. Nevertheless, one should avoid mixing kratom with other opioids, benzodiazepines or alcohol. In the event of a kratom-related overdose situation, it would still be advised to consider treatment with naloxone as one would with conventional opioids.

Additionally, mitragynine has a very high affinity for the mu-opiod receptor, stronger than fentanyl, morphine, buprenorphine and naltrexone. This means it binds more strongly, like a magnet, than these other opioids and theoretically could displace these other opioids off the mu-receptors if given simultaneously. This suggests that if MG was taken at a high enough dose by someone already taking fentanyl or morphine, this displacement could not only reduce the pain benefit provided by the fentanyl or morphine, but might trigger opioid withdrawal symptoms. This would be analogous to the same effect that occurs when buprenorphine (Suboxone) is given to someone taking other opioids for which buprenorphine has greater affinity.

Delta- and Kappa-Opioid Receptors

Compared to fentanyl and morphine, mitragynine has the lowest affinity at the delta- and kappa-opioid receptors and it has antagonist effects of at the delta- and kappa-opioid receptors

Alpha-2 Adrenergic Receptors

Mitragynine also has activity as an alpha-2 adrenergic agonist, which may explain its effectiveness for treating opioid withdrawal symptoms, much like clonidine (See: Alpha-2 adrenergic agonists). The adrenergic alpha-2 receptors also have effects on heart rate and blood pressure.

Stimulation of adrenergic pathways in the central nervous system is a mechanism common to many medications that are effective in treating neuropathic pain. A 2020 study in rats confirmed that mitragynine may be effective in treating chemotherapy-induced neuropathic pains through α- adrenoceptor mechanisms.

Dopamine Receptors

There are 5 dopamine receptor subtypes (D1, D2, D3, D4, D5) that regulate emotion, movement, memory and learning, sleep, decision making and the reward system in the brain. The dopaminergic receptors are involved in the anti-psychotic, anti-anxiety, anti-depressant and anti-addiction activities of kratom and mitragynine.

Research suggests that mitragynine’s anti-anxiety activity is partly mediated by D1 and D2-like receptors. However, much more research is needed to determine the specific dopamine receptor binding profiles of mitragynine and other kratom alkaloids.

Serotonergic Pathways

Serotonin (5-HT) receptors are a class of G-protein-coupled receptors (GPCRs) and that regulate physiological functions including mood, cognition, sleep, sociability, blood pressure, body temperature, and sexual behavior, through their natural ligand serotonin. Serotonin receptors are associated with psychological functions such as aggression, anxiety, and depression.

Kratom has long been used in Malaysia and Thailand as a mood enhancer, mild stimulant, or aphrodisiac.

Serotonergic pathways may also be involved in the effects of mitragynine, further contributing to the complexity of this drug. It has been reported that mitragynine has a suppressive effect on the central serotonin neurotransmission system by acting as a competitive antagonist, blocking the stimulation of the 5- HT2A receptor. Along with the 5-HT2A receptor, mitragynine has also been shown to interact with the 5- HT1A receptor as a 5-HT1A agonist or partial agonist.

It is theorized that the traditional use of kratom as a mood enhancer is due at least in part to its interaction with the 5-HT1A and 5-HT2A receptors.

Cyclooxygenase 2 (COX-2) Pathway

Among its potential benefits, in addition to analgesic activity, mitragynine seems to be a key component for the anti-inflammatory properties of kratom by suppressing prostaglandin E2 (PGE-2) production in the cyclooxygenase 2 (COX-2) pathway.

Mitragynine and the Blood Brain Barrier

Cellular barriers lining blood vessels create tissue compartments that play important roles in maintaining homeostasis and protecting the tissue microenvironments. These barriers, along with the action of transporter proteins that transport essential nutrients, function as gatekeepers to regulate the passage of substances across the tissue compartments including keeping out certain drugs or harmful substances. Examples of these cellular barriers are the intestinal gut barrier (IGB) and the blood brain barrier (BBB).

Mitragynine has a higher capacity to cross both the IGB and the BBB (approximately 1.2–2.1 times higher) than 7-HMG. However, while in the brain, 7-HMG is more available with a higher affinity for binding with μ opioid receptors than MG.

Barrier Transporters

There are transporter molecules that function to either facilitate or impede transcellular permeability across the IGB and BBB barriers. The P-glycoprotein (P-gp) is an important transporter that affects the pharmacokinetics of many medications by limiting intestinal absorption or impeding central nervous system penetration, thus influencing drug delivery and targeting. Evidence whether P-gp transporters affect MG and 7-HMG efflux are conflicting.

However, studies are in agreement that MG and 7-HMG both can inhibit P-gp-mediated efflux of known substrates of this transporter. This means that these alkaloids can affect the absorption of P-gp sensitive medications from the gut as well as suppress their elimination from the brain, potentially significantly impacting their therapeutic effects. This inhibition of P-gp-mediated efflux by kratom alkaloids needs careful monitoring for potential interactions with drugs that are substrates of the P-gp (See: P-gp Drug Interactions above).

Recent research also suggests that mitragynine may alter the expression of P-gp by downregulation of mRNA and protein expression of the P-gp in a concentration-dependent manner. This reduced functionality of P-gp transporter by another mechanism than inhibition further reduces P-gp functioning with additional impact on the effects of P-gp substrate medications.

Mitragynine Metabolism

Recent research shows that MG is metabolized in the intestines and liver into 7-HMG by CYP3A4 enzymes. However, a 2020 study determined that unlike that in rodents and other animals, 7-HMG is metabolized in human blood by an indeterminate mechanism into mitragynine pseudoindoxyl (MG-pseudoindoxyl).

7-Hydroxymitragynine (7-HMG)

7-hydroxymitragynine is a minor constituent alkaloid (2% or less) found in kratom (M. speciosa). Unlike MG, it is a partial agonist at the opioid receptors. 7-HMG provides potent pain relieving benefits. The analgesic potency of 7-HMG is reportedly 13x higher than morphine and 46x higher than MG. Despite that very little 7-HMG is found in the kratom plant itself, because MG is metabolized in the body into 7-HMG, it nevertheless is likely the dominant contributor to the analgesic properties of kratom due to its activity at opioid receptors.

7-Hydroxymitragynine also demonstrates the development of analgesic tolerance, including cross-tolerance to morphine, as well as physical dependence. It is likely the major contributing factor to the addictive potential of kratom.

Oxidation of mitragynine to 7-HMG significantly strengthens the binding affinity at the mu opioid receptor but weakens affinity at the adrenergic and serotonin receptors.

Mitragynine Pseudoindoxyl (MG-pseudoindoxyl)

Mitragynine pseudoindoxyl (MG-pseudoindoxyl) is 20- fold more potent than morphine and 100-fold more potent than mitragynine. Although it remains uncertain whether the observed pharmacological activity of kratom is due to MG or its metabolite, 7-HMG, the role of MG-pseudoindoxyl adds additional uncertainty.

Preliminary research suggests that after kratom ingestion a reasonable amount of 7-HMG is present in the blood that could be further metabolized to MG-pseudoindoxyl, although the absolute conversion rate of 7-HMG to MG-pseudoindoxyl is unknown. This raises the possibility that kratom’s opioid-like effects may be mediated by a combination of MG, 7-HMG, and MG-pseudoindoxyl, which is even more potent than MG and 7-HMG.

It is also possible that this metabolism of 7-HMG into MG-pseudoindoxyl may be catalyzed by an enzyme or enzymes that have genetic variants. This would potentially lead to variability in an individual’s relative exposure to 7-HMG vs MG-pseudoindoxyl following use of kratom. Given the difference in potency between these two metabolites, such differential exposure could result in individual variability in the pharmacological effects of kratom.

The abuse potential of MG-pseudoindoxyl has not been well characterized. However, since 7-HMG is reported to have high abuse potential and given that MG-pseudoindoxyl is even more potent, it is likely to also be highly abusable.

Pharmacokinetics of Mitragynine and 7-Hydroxymitragynine

The major active constituent alkaloids of kratom (MG and 7-HMG) are highly bound to plasma proteins (>90%).

CYP3A4, predominantly found in the liver and intestines, is the major CYP isoform enzyme esponsible for the metabolism of mitragynine, with small or negligible contributions from CYP2C9, CYP2C19, and CYP2D6. Individuals with genetic variants of these enzymes may experience atypical responses to mitragynine. Similarly, those individuals taking medications that modify activities of these enzymes may also experience atypical responses.

Depending upon the individuals natural levels of enzymes and other factors, but a terminal half-life of one day (terminal half-life is the time required to divide the blood concentration by two after reaching pseudo-equilibrium, and not the time required to eliminate half the administered dose).

7-Hydroxymitragynine has quite a bit shorter duration, with an average half-life of @2.5 hours.

Recent evidence suggests that mitragynine has poor water solubility, is acid degradable in the stomach and has high variability of drug release in biological fluids. These characteristics of mitragynine further influence the large variability of its pharmacological responses reported in the literature.

References:

Following (the Roots) of Kratom (Mitragyna speciosa):  The Evolution of an Enhancer from a Traditional Use to Increase Work and Productivity in Southeast Asia to a Recreational Psychoactive Drug in Western Countries
Pharmacokinetics of mitragynine in man

Kratom – New

Kratom – Overviews

Kratom – Medicinal Use

Kratom – Commercial Products

Kratom – Dependence and Abuse

Kratom – Drug Interactions

Kratom – Legality

Kratom – Neurobiology & Pharmacokinetics

Kratom – Toxicity

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Accurate Education – Kratom