The use of kratom is discouraged due to safety concerns.

Kratom

Kratom (Mitragyna speciosa) is a plant indigenous to Thailand and Southeast Asia. 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.

 

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.

 

Kratom is illegal in many countries 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. At this time, there is no definitive timetable presented by the DEA as to when the federal ban on kratom takes place.

 

2/6/18

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

10/12/16

The DEA’s latest action is to postpone the rescheduling of kratom and for the time being, kratom remains legal.

See: Update – 10/12/16

 

The following information is provided for educational purposes only, with no intent to encourage the use of kratom.

 

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The use of kratom is discouraged due to safety concerns.


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 uncomom 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:

(a) as a stimulant;

(b) as a remedy in traditional medicine for pain, diarrhea, depression and anxiety;

(c) in social context.

 

Historically, manual labourers (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, diarrhoea, fever, and pain).

 

The use of kratom can commonly be divided into two main groups: 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.

 

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 [3]. 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.

 

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.

 

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.

 

Legality

Kratom is largely uncontrolled in the U.S. at a federal level but at the state level there are some exceptions. DEA withdrew its scheduling request in October 2016. As of 2018, it is illegal in several states and countries:

(1) Alabama, Arkansas, Indiana, Ohio, Rhode Island, Vermont, Wisconsin (Illegal in certain counties / cities)

(2) Denver CO; San Diego CA; Sarasota FL, Washington DC §Illegal in Certain Countries

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


Effects

Five to ten minutes after kratom consumption users describe themselves as feeling happy, strong, and active. Regarding desired/recreational effects of kratom, users report that at low doses it is rather stimulant, mind is “more alert,” physical energy and sometimes sexual arousal are increased, and ability to do physical work may be improved and they also described “entactogenic” effects, like empathy and euphoria. Some people find this level edgy rather than pleasant. At higher doses, 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. Others report an increase of empathy feelings.

 

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 overdose, there may be no response to naloxone.

 

Traditionally, the fresh or dried leaves of kratom are chewed or brewed into tea or smoked. Ketum is bitter and sugar or sweet beverages are commonly added to mask its taste. To experience vigour and euphoria, traditional “kratom eaters” chew one to three fresh leaves at a time. Regular and addicted users chew 3–10 times a day.  In “Following “the Roots” of Kratom” (below), Amattayakul 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. No information is available on other active compounds of the plant.

 

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.

 

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 abusers 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.

 

Side effects frequently include fatigue, nausea and vomting, constipation, dry mouth, changes in urination, insomnia, temporary erectile dysfunction, itching, and sweating and also hyperpigmentation and tremor, nystagmus and anorexia and weight loss in long term. Some users describe hair loss, possibly related to daily use of kratom. Agitation, irritability and tachycardia are the most common complaints made to poison control centers regarding kratom.

 

From 2011 through 2017, 1807 kratom exposures were reported to United States poison control center. 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 intentional (74.3%).  Multiple-substance exposures were associated with greater odds of admission to a health care facility and a serious medical outcome compared with single-substance exposures. There were 11 deaths associated with kratom exposure, including two that occurred after exposure to kratom only.

 

Adverse effects and intoxications cases across various countries have also been reported, including liver toxicity, seizure, and coma. There are reports of patients suffering from intrahepatic cholestasis after two weeks of kratom use, Adult Respiratory Distress Syndrome, and hypothyroidism. Loss of appetite, weight loss, hyperpigmentation, and psychosis are described in chronic abusers. Kratom alone, or in combination with other substances, has been shown to cause physical and psychological dependence including withdrawal symptoms following repeated use of kratom.

 

Treatment of kratom overdose is supportive in nature, and no antidotes are known. Response to naloxone is partial at best.

 

Addiction and Dependency

Findings showed 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.

 

Findings show that regular kratom use is associated with drug dependency, development of withdrawal symptoms, and craving. Many regular users acknlowledge 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.

 

Withdrawal

The half-life of mitragynine half-life is 7-24 hours depending on alkaloid, requiring dosing  every 6-12 hours. Withdrawal symptoms typically begin ~12 hours after last use, and may represent either serotonin or opioid withdrawal, or both.

 

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. Users describe tolerance (requiring the consumption of higher doses to achieve the same effects) and also a “cross-tolerance” to both kratom and opiates after repeated intake.


Drug Interactions

There are multiple mechanisms in which mitragynine may interact with other drugs which are covered below and in the Pharmacology section 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.

 

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

 

Fatalities

Evidence also suggests that kratom might be a deadly substance when mixed with other compounds. 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 asso- ciated 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.

 

Pharmacology and Identification 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 inhibiors) due to increased leves of serotonin, noradrenaline and dopamine

 

High dose (>5 grams)

  1. Sedative and analgesic properties due to opiate receptor activiation: 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 (See: Alpha-2 adrenergic agonists).

 

There are at least 25 chemically similar alkaloids in kratom with pharmacological properties, but the main psychoactive components in kratom leaves are the alkaloids mitragynine and 7-hydroxymitragynine, both found only in Mitragyna speciosa. Kratom has both opioid-like and psychostimulant-like subjective effects, depending on the dose. 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.

 

Mitragynine alkaloid is likely responsible for some of the analgesic activity that has been linked to kratom, mostly due to its potent stimulation of opioid receptors. Although mitragynine can act as an agonist on all three opioid receptors (kappa > mu > delta), it is structurally different from morphine and other members of the opioid family. When opioids stimulate these 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, or respiratory depression (the beta-arrestin pathway). Kratom alkaloids appear not to trigger respiratory depression and are therefore not likely to result in overdose death unless taken with other drugs that trigger respiratory depression such as opioids, benzodiazepines and alcohol. In the event of a kratom-related overdose, it would still be advised to consider treatment with naloxone as one would with conventional opioids.

 

7-hydroxymitragynine, a minor constituent (2%) of M. speciosa, when isolated demonstrates a potent antinociceptive (pain relieving) activity in mice. It is now considered to be a major contributory factor for the analgesic properties of M. speciosa due to its selectivity for mu- and kappa-opioid receptors. The potency of 7-hydroxymitragynine is 13- and 46-fold higher than morphine and mitragynine, respectively. This might be one of the main pharmacological markers of kratom’s quality and potency. Recent studies further revealed how complex is kratom’s pharmacology, involving a ????-opioid and dopamine D1 receptors interaction in its various effects.

 

Serotonergic and adrenergic pathways have also been involved in the effects of mitragynine, mostly due to its broad affinity to different receptors, further contributing to the complexity of the drug. Indeed, the pharmacological mechanisms responsible for stimulant activity are yet to be clearly established.

 

The standard half-life of mitragynine is 3.85 ± ∼1 hr, depending upon the individuals natural levels of enzymes and other factors but a terminal half-life of one day. 7-Hydroxymitragynine has quite a bit shorter duration, with an average half-life of 2.5 ± 0.7 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.

 

Pharmacological Properties

Mitragynine is metabolized in the liver by CYP3A4 and CYP2D6 and CYP2C9 enzymes. 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.

 

The active ingredients of kratom (mitragynine, 7- hydroxymitragynine, and mitraphylline) exhibit high plasma protein binding (>90%). Kratom has the potential herb–drug interaction on cytochrome P450 (CYP) liver enzyme activity, with potent inhibitory effect for CYP3A4 and CYP2D6, moderate effect for CYP1A2, and weak effect for CYP2C19, whereas in another study, mitragynine and 7-hydroxymitragynine also showed the inhibitory effect on P-glycoprotein (P-gP). These enzymes and P-gP are involved in the metabolism of many opioids including methadone and oxycodone, thus predicting the danger of opioid overdose if kratom is taken along with other opioids.  These inhibitory effects on the metabolism of other medications contribute to the potential danger of drug interactions of kratom with other medications as well and likely contributed to the mixed overdose reported deaths.

 

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.

 

There are possible serious adverse effects of kratom under investigation. Different studies have shown elevated blood pressure, kidney toxicity, impaired cognition and behaviour,  potential for physical and psychological dependence (addiction), and liver failure. The onset of liver injury is described to occur within 2 to 8 weeks of starting regular use of kratom powder or tablets, with initial symptoms of fatigue, nausea, itching, and dark urine followed by jaundice. The pattern of liver injury seems to be typically cholestatic and can be severe with serum bilirubin levels rising above 20 mg/dL. Kratom has also been identified as potentially toxic to the heart.

 

Quick Summary:

Short time use effects

Nausea, constipation, sleep problems, temporary erectile dysfunction, itching, or sweating

 

Withdrawal symptoms

Hostility, aggression, aching of muscles and bones, jerky movements of the limbs, anorexia and weight loss, and insomnia.

 

Infrequent side effects

Seizures (individuals using high doses of kratom, either alone or combined with other drugs), intrahepatic cholestasis, psychotic symptoms, Adult Respiratory Distress Syndrome, and hypothyroidism.

 

Long time use effects

Anorexia, dry mouth, problems in diuresis, darker skin, and hair loss

 

Fatalities

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

  1. O-desmethyltramadol (tramadol/Ultram); propylhexedrine (Benzedrex);

  2. Over-the-counter cold medications and benzodiazepines (Valium, Xanax, Klonopin);
  3. Venlafaxine (Effexor), diphenhydramine (benadryl), and mirtazapine (Remeron);

  4. Zopiclone (Lunesta), citalopram (Celexa), and lamotrigine (Lamictal)

 

Conclusions

Drug addiction history is the complex history of human desire, trying in every way to relieve sufferings, to enhance feelings of pleasure, and to satisfy other inexhaustible and incessant desires. The line between socially acceptable and unlawful use of a variety of psychoactive products is culture-bound. Kratom is a plant with a well-established traditional use in South Asia to enhance work abilities as well as support traditional medicine and culture, even if officially banned. 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.

 

Comments

Based on preclinical data and case reports published in scientific literature as well as anecdotal experiences posted online, kratom is not a safe drug. Its use is associated with drug dependency, development of withdrawal symptoms, craving, serious adverse effects, and life-threating effects, especially in a multi-drug scenario.

 

References:

  1. 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
  2. Pharmacokinetics of mitragynine in man

 

Kratom – Overviews

  1. Following “the Roots” of Kratom (Mitragyna speciosa) – 2015
  2. Neurobiology of Kratom and its main alkaloid mitragynine – 2016
  3. Legally Lethal Kratom: A Herbal Supplement with Overdose Potential. – PubMed – NCBI – 2019
  4. Current perspectives on the impact of Kratom use – 2019
  5. Mitragyna speciosa – Clinical, Toxicological Aspects and Analysis in Biological and Non-Biological Samples – 2019
  6. Long-Term Cognitive Effects of Kratom (Mitragyna speciosa Korth.) Use. – PubMed – NCBI – 2019
  7. Kratom exposures reported to United States poison control centers: 2011-2017. – PubMed – NCBI – 2019

 

Kratom – Dependence and Abuse

  1. Novel case of maternal and neonatal kratom dependence and withdrawal – 2018
  2. Kratom Withdrawal: A Systematic Review with Case Series. – PubMed – NCBI – 2019

 

Kratom – Legality

  1. DEA – no-timetable-for-kratom-ban pain-news-network
  2. DEA-reverses-decision-on-kratom-10-12-16

 

Kratom – Pharmacokinetics

  1. Pharmacokinetics of mitragynine in man – 2015

 

Emphasis on Education

 

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