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.
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.
The use of kratom is discouraged due to safety concerns.
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 socioreligious ceremonies and to treat various medical conditions, such as morphine dependence in Thailand, and as opium substitute in Malaya.
Natural products often used as enhancers are exceptionally complex in terms of their chemistry. This adds complexity of their pharmacological effects, with a lack of data relating to the toxicology of these materials, and even less regarding their interactions with conventional drugs of abuse. This is further complicated by the possibility of adulteration processes. The level of complexity, variability, and the unknown nature of these samples, coupled with the risks associated with taking psychoactive materials, could offer further risks of ill health by misadventure, 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;
(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 opiate 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 . 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
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. Many different formulations are available, including raw leaves, capsules, tablets, powder, and concentrated extracts.
Kratom is largely uncontrolled in the U.S. at a federal level but at the state level there are some exceptions such as Indiana, Iowa and Massachusetts.
The possession of kratom leaves has been illegal in Thailand since 1943. Kratom is also controlled in a few other countries in the region (Malaysia and Myanmar) and elsewhere (Australia, Bhutan).
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.
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. 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.
All subjects described tongue numbness after they finished 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 nausea and vomting, constipation, dry mouth, changes in urination, sleep problems, 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.
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.
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 symptoms are also common, including muscle aches, irritability, mood disturbances, runny nose, diarrhoea, and muscle jerking. 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.
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 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 (an ????-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 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. 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 on all three opioid receptors (the mu (????), kappa (????), and delta (????) opioid receptors), it is structurally different from morphine and other members of the opioid family. In the event of a kratom overdose, it is likely to respond to naloxone like 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 ????- and ????-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.
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.
Short time use effects
Nausea, constipation, sleep problems, temporary erectile dysfunction, itching, or sweating
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 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)
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.
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.
- 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 – Overviews
Kratom – Legality
Kratom – Pharmacokinetics
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