Mitragyna speciosa

Mitragyna speciosa (commonly known as kratom[2]) is a tropical evergreen tree in the coffee family native to Southeast Asia. It is indigenous to Thailand, Indonesia, Malaysia, Myanmar, and Papua New Guinea,[3] where it has been used in traditional medicines since at least the nineteenth century.[4] Kratom has opioid properties and some stimulant-like effects.[5][6]

Mitragyna speciosa
Scientific classification
Kingdom: Plantae
Clade: Tracheophytes
Clade: Angiosperms
Clade: Eudicots
Clade: Asterids
Order: Gentianales
Family: Rubiaceae
Genus: Mitragyna
Species:
M. speciosa
Binomial name
Mitragyna speciosa
Synonyms[1]
  • Nauclea korthalsii Steud. nom. inval.
  • Nauclea luzoniensis Blanco
  • Nauclea speciosa (Korth.) Miq.
  • Stephegyne speciosa Korth.

As of 2018, the efficacy and safety of kratom are unclear, and the drug was unapproved as a therapeutic agent due to the poor quality of the research.[7][8] In 2019, the United States Food and Drug Administration (FDA) stated that there is no evidence that kratom is safe or effective for treating any condition.[9] Some people take it for managing chronic pain, for treating opioid withdrawal symptoms, or for recreational purposes.[3][7] The onset of effects typically begins within five to ten minutes and lasts for two to five hours.[3]

Common minor side effects include appetite loss, erectile dysfunction, hair loss and constipation.[10] More severe side effects may include respiratory depression (decreased breathing), seizure, addiction, and psychosis.[3][5][11][12] Other side effects may include high heart rate and blood pressure, trouble sleeping, and, rarely, liver toxicity.[3][13][14][15] When use is stopped, withdrawal symptoms may occur.[7][6] Deaths have occurred with kratom both by itself and mixed with other substances.[5][16] Serious toxicity is relatively rare and generally appears at high doses or when kratom is used with other substances.[3][7]

Kratom is a controlled substance in 16 countries[5] and, in 2014, the FDA banned importing and manufacturing of kratom as a dietary supplement.[17] As of 2018, there is growing international concern about a possible threat to public health from kratom use.[5][7][18] In some jurisdictions, its sale and importation have been restricted, and several public health authorities have raised alerts.[7][18][19]

Description

Mitragyna speciosa is an evergreen tree that can grow to a height of 25 m (82 ft). Its trunk may grow to a 0.9 m (3 ft) diameter.[20] The trunk is generally straight, and the outer bark is smooth and grey.[20] The leaves are dark green and glossy[7] and can grow to over 14–20 cm (5.5–7.9 in) long and 7–12 cm (2.8–4.7 in) wide when fully open, are ovate-acuminate in shape, and opposite in growth pattern, with 12–17 pairs of veins.[20] The flowers grow in clusters of three at the ends of the branches. The calyx-tube is 2 mm (0.08 in) long and has five lobes; the corolla-tube is 2.5–3 millimetres (0.098–0.12 in) long.[20]

Mitragyna speciosa is indigenous to Thailand, Indonesia, Malaysia, Myanmar, and Papua New Guinea.[3] It was first formally described by the Dutch colonial botanist Pieter Korthals in 1839, who named it Stephegyne speciosa; it was renamed and reclassified several times before George Darby Haviland provided the final name and classification in 1859.[20]:59

Uses
Main article: Mitragynine § Uses
Mitragyna speciosa
Powder produced from unspecified tissues of the plant
Product namekratom
Part(s) of plantLeaves
Geographic originSoutheast Asia[18]
Active ingredients
Main producers
Main consumersWorldwide (No. 1: Thailand)[18][4]
Retail price€6–15 per 10g (EU; as of 2011)[18]
Legal status
Kratom leaves

As of 2013, kratom has been studied in cells and in animals, but no clinical trials have been conducted in the United States.[4] The United States Drug Enforcement Administration (DEA) stated in 2013: "There is no legitimate medical use for kratom".[11] In April 2019, the United States Food and Drug Administration (FDA) stated that there is no evidence that kratom is safe or effective for treating any condition, and there are no approved clinical uses for kratom.[9]

Kratom leaves are commonly used by smoking or chewing, as a tea, powdered in capsules or pills, or extracted for use in liquids.[4]

Traditional use

In cultures where the plant grows, kratom has been used in traditional medicine.[25] The leaves are chewed to relieve musculoskeletal pain and increase energy, appetite, and sexual desire in ways similar to khat and coca.[7] The leaves or extracts from them are used to heal wounds and as a local anesthetic. Extracts and leaves have been used to treat coughs, diarrhea, and intestinal infections.[3][4][20] They are also used as intestinal deworming agents in Thailand.[26][18]

Kratom is often used by workers in laborious or monotonous professions to stave off exhaustion as well as a mood enhancer and painkiller.[20] In Thailand, kratom was "used as a snack to receive guests and was part of the ritual worship of ancestors and gods".[27] The herb is bitter and is generally combined with a sweetener.[21]

Opioid withdrawal

As of 2018, there have been no formal trials to study the efficacy or safety of kratom to treat opioid addiction.[5] Kratom is not approved for this or any other medical use.[18]

Data on how often it is used worldwide are lacking, as it is not detected by typical drug-screening tests.[21] Rates of kratom use appear to be increasing among those who have been self-managing chronic pain with opioids purchased without a prescription and are cycling (but not quitting) their use.[21]

In 1836, kratom was reported to have been used as an opium substitute in Malaysia. Kratom was also used as an opium substitute in Thailand in the nineteenth century.[4]

Recreational uses

At low doses, kratom produces euphoric effects comparable to coca.[28] At higher doses, kratom produces opioid-like effects.[28] The onset of effects typically begins within five to ten minutes and lasts for two to five hours.[3]

According to the US DEA and a 2020 survey, kratom is used in the public to alleviate pain, anxiety, depression, or opioid withdrawal.[11][29]

In Thailand, a 2007 survey found that the lifetime, past year, and past 30 days kratom usage rates were 2.32%, 0.81% and 0.57%, respectively, among respondents aged 12–65 years,[18] and was the most widely used drug in Thailand.[18]

Commercially available kratom may be mixed with other psychoactive drugs, such as caffeine and codeine.[6][30] Starting in the 2010s, a tea-based cocktail known as "4×100" became popular among some young people across Southeast Asia and especially in Thailand. It is a mix of kratom leaves, cough syrup, Coca-Cola, and ice. Around 2011, people who consumed the cocktail were often viewed more negatively than users of traditional kratom, but not as negatively as users of heroin.[31] As of 2012, use of the cocktail was a severe problem among youth in three provinces along the border of Malaysia and southern Thailand.[32]

In the US, as of 2015, kratom was available in head shops and over the Internet; the prevalence of its use was unknown at the time.[7] In the United States, kratom use increased rapidly between 2011 and 2017.[33]

Adverse effects

Mitragyna speciosa causes many adverse effects and in November 2017 the Food and Drug Administration issued a public health advisory for the drug.[8] A 2019 review listed as common side effects: decreased appetite, anorexia, weight loss, temporary erectile dysfunction, insomnia, sweating, hyperpigmentation, hair loss, tremor, and constipation.[10]

At relatively low doses (1–5 g of raw leaves), at which there are mostly stimulant effects, side effects include contracted pupils and blushing; adverse effects related to stimulation include anxiety and agitation, and opioid-related effects like itching, nausea, loss of appetite, and increased urination begin to appear.[3][7]

At moderate (5 to 15 g of raw leaves) doses and higher, at which opioid effects generally appear, additional adverse effects include tachycardia (an increased stimulant effect) as well as the opioid side effects of constipation, dizziness, hypotension, dry mouth, and sweating.[7][12]

Long term use of high doses of kratom may lead to development of tolerance, dependence, and withdrawal symptoms on stopping, including loss of appetite, weight loss, decreased sexual drive, trouble sleeping, muscle spasms, muscle and bone pains, jerky movement, watery eyes, hot flushes, fever, diarrhea, restlessness, anger, and sadness.[6] This may lead to return to use.[6][7][34]

Frequent use of high doses of kratom may cause tremors, anorexia, weight loss, seizures, and psychosis.[7] Serious toxicity is relatively rare and generally appears at high doses or when kratom is used with other substances.[3][7]

In July 2016, the Centers for Disease Control issued a report stating that between 2010 and 2015, US poison control centers received 660 reports of exposure to kratom. Medical outcomes associated with kratom exposure were reported as minor (minimal signs or symptoms, which resolved rapidly with no residual disability) for 162 (24.5%) exposures, moderate (non-life-threatening, with no residual disability, but requiring some form of treatment) for 275 (41.7%) exposures, and major (life-threatening signs or symptoms, with some residual disability) for 49 (7.4%) exposures.[15] One death was reported in a person who was exposed to the medications paroxetine (an antidepressant) and lamotrigine (an anticonvulsant and mood stabilizer) in addition to kratom. For 173 (26.2%) exposure calls, no effects were reported, or poison center staff members were unable to follow up regarding effects.[15]

A 2019 report from the American Association of Poison Control Centers (AAPCC) stated that kratom use was increasing rapidly, with 1807 kratom exposures and a 52-fold increase occurring over the years 2011 to 2017.[33] Most exposures occurred intentionally by adult males in their homes, with 32% of the incidents requiring admission to a health care facility and half of the admissions as a serious medical condition.[33] Multiple-substance exposures were associated with a higher number of hospitalizations than single-substance exposures, and involved 11 deaths, including two due to kratom alone.[33] Postmortem toxicology testing detected multiple substances for almost all those who died, with fentanyl and fentanyl analogs being the most frequently identified co-occurring substances.[35]

Overdoses of kratom are managed similarly to opioid overdoses, and naloxone can be considered to treat an overdose that results in a reduced impulse to breathe, despite mixed results for its utility, based on animal models.[3]

From October 2017 to February 2018 in the United States, 28 people in 20 different states were infected with salmonella, an outbreak occurring from the consumption of contaminated pills, powder, tea or unidentified sources of kratom.[36] An analytical method using whole genome sequencing applied to samples from the infected people indicated that the salmonella outbreak likely had a common kratom source.[36]

Respiratory depression

Respiratory depression is the leading cause of death from opioid use.[37] Although evidence is sparse, the risk from respiratory depression caused by taking Mitragyna speciosa appears to be low, but as of 2016 the Food and Drug Administration listed respiratory depression as a concern.[8][17]

Liver toxicity

In rare cases, though with a dangerous delay, kratom use has been linked to acute liver injury with symptoms of abdominal discomfort, dark urine, itching and jaundice.[14][13] Liver injury has been reported with a latency (time from first use to onset of symptoms) of median 20.6 days. Reported liver biopsies tend to show cholestasis, however blood biomarkers can show a range of cholestatic, mixed, or hepatocellular injury pattern.[13] The majority of users do not seem to develop liver injury, and it is unclear which users are at heightened risk. The mechanism by which kratom causes liver damage in some people is unknown and poorly studied, but a model has been proposed.[13]

Death

Kratom overdose is a subject of concern in many countries because of the rising number of hospitalizations and deaths in which chronic kratom abuse is a contributing factor.[7][14] According to clinical reviews, a kratom overdose can cause liver toxicity, seizures, coma, and death,[14] especially when in combination with alcohol abuse. Between 2011 and 2017, forty-four deaths were kratom-related.[5] However many cases could not be fully assessed because of limited information.[5] People who died from kratom use typically have taken it in combination with other substances, or have underlying health conditions.[10]

Over 18 months in 2016 and 2017, 152 overdose deaths involving kratom were reported in the United States, with kratom as the primary overdose agent in 91 of the deaths, and 7 with kratom being the only agent detected.[38][39][40] Nine deaths occurred in Sweden during 2010–11 relating to use of Krypton, a mixture of kratom, caffeine and O-desmethyltramadol, a prescription opioid analgesic.[16][41]

Chemistry
Main article: Mitragynine

Many of the key psychoactive compounds in M. speciosa are indole alkaloids related to mitragynine, which is a tetracyclic relative of the pentacyclic indole alkaloids, yohimbine and voacangine.[7] In particular, mitragynine and 7-hydroxymitragynine (7-HMG) compose significant proportions of the natural products isolable from M. speciosa; e.g., in one study, mitragynine was 12% by weight from Malaysian leaf sources, versus 66% from Thai sources, and 7-hydroxymitragynine constituted ~2% by weight.[7][42] In addition, at least 40 other compounds have been isolated from M. speciosa leaves,[21] including ~25 additional alkaloids, including raubasine/ajmalicine (originally isolated from Rauvolfia serpentina), corynantheidine (also found in Pausinystalia johimbe),[43] as well as mitraphylline, mitragynine pseudoindoxyl, and rhynchophylline.[44][45]

Detection in body fluids

The plant's active compounds and metabolites are not detected by a typical drug screening test, but can be detected by more specialized testing.[41][46] Blood mitragynine concentrations are expected to be in a range of 10–50 μg/L in persons using the drug recreationally. Detection in body fluids is typically by liquid chromatography-mass spectrometry.[41][47]

Pharmacology
Mitragyna speciosa alkaloids at opioid receptors
CompoundAffinities (Ki)RatioRef
MORDORKORMOR:DOR:KOR
7-Hydroxymitragynine13.51551231:11:9[48]
Mitragynine7.2460.31,1001:8:152[48]
Mitragynine pseudoindoxyl0.0873.0279.41:35:913[48]

As of 2017, much of the pharmacology of kratom was not well understood, having stimulant effects at low doses, an opioid-like effect at higher doses, as well as sedative and sensory-suppressive effects.[7][8]

Both mitragynine and 7-HMG have partial agonist activity at nanomolar concentrations at the human μ-opioid receptors; 7-HMG appears to have higher affinity.[49][50] Other alkaloids have antagonist activity at micromolar concentrations, so effects of whole kratom may result from the interplay of these different alkaloids.[49] Different assays on the human receptor yielded different results, and activities at mouse and guinea pig μ-opioid receptors appear to be different as well, and it is unknown which alkaloids are able to cross the blood brain barrier in humans, making in vitro and animal studies problematic to translate to humans.[49] The binding of kratom alkaloids at human and model animal δ- and κ-opioid receptor subtypes was very unclear as of 2017.[49]

Mitragynine also stimulates α2-adrenergic receptors, inhibiting the release of norepinephrine (noradrenaline); other compounds in this class include dexmedetomidine, which is used for sedation, and clonidine, which is used to manage anxiety and some symptoms of opioid withdrawal. This activity might explain why kratom can be dangerous when used in combination with other sedatives.[50]

Mitragynine is metabolized in humans via phase I and phase II mechanisms with the resulting metabolites excreted in urine.[7] In in vitro experiments, kratom extracts inhibited CYP3A4, CYP2D6, and CYP1A2 enzymes, which results in significant potential for drug interactions.[7]

Regulation

As of January 2018, neither the plant nor its alkaloids were listed in any of the Schedules of the United Nations Drug Conventions.[18]

ASEAN

As of 2013, kratom was listed by ASEAN in its annex of products that cannot be included in traditional medicines and health supplements that are traded across ASEAN nations.[51]

Australia and New Zealand

As of January 2015, kratom was controlled as a narcotic in Australia and under Medicines Regulations 1985 (Amended August 6, 2015)[52] in New Zealand.[18]

Canada

As of October 2016, it was not legal to market kratom for any use in which it was ingested. However, it could be marketed for other uses, such as incense.[53] Health Canada has taken action against companies marketing it for ingestion.[54][55]

Europe

As of 2011, the plant was controlled in Denmark, Latvia, Lithuania, Poland, Romania and Sweden.[18] In the UK, since 2016, the sale, import, and export of kratom are prohibited under the Psychoactive Substances Act.[56]

In 2017, kratom was designated a Schedule 1 illegal drug (the highest level) in the Republic of Ireland, under the names 7-hydroxymitragynine and mitragynine.[57]

Malaysia

The use of kratom leaves, known locally as ketum, is prohibited in Malaysia under Section 30 (3) Poisons Act 1952.[58] Although prohibited by statute, the use of kratom remains widely spread because the tree grows natively and tea decoctions are readily available in local communities.[59] Certain parties have urged the government to penalize the use of kratom under the Dangerous Drugs Act instead of the Poisons Act, which would carry heavier penalties.[60]

Thailand

Possession of kratom leaves (Thai: ต้นกระท่อม, RTGS: ton krathom) was illegal in Thailand until 2018.[61] The Thai government had passed the Kratom Act 2486, effective 3 August 1943, which made planting the tree illegal,[11] in response to a rise in its use when opium became very expensive in Thailand and the Thai government was attempting to gain control of the opium market.[7] In 1979, the Thai government placed kratom, along with marijuana, in Category V of a five category classification of narcotics.[11] Kratom accounted for less than two percent of arrests for narcotics between 1987 and 1992.[62]

The Thai government has considered legalizing kratom in 2004, 2009, 2013, and 2020.[63][64] In 2018, Thailand became the first Southeast Asian country to legalize kratom for medical purposes.[61]

United States

In the United States, there is consideration to make kratom a Schedule I drug.[65] In 2019, the FDA warned consumers that kratom remains unapproved for interstate commerce,[66] may be unsafe in commercially available products, and is on an import alert which can lead to confiscation of imported supplies.[9]

FDA assessment

In April 2019, the FDA issued a statement declaring that kratom was not approved for any medical use, was potentially unsafe in commercial products available in the United States, and remained on an import alert where imported supplies would be confiscated.[9] On April 4, 2018, the FDA issued the first mandatory recall in its history over concerns of salmonella contamination of several kratom-containing products.[67] Samples of the products, manufactured by Triangle Pharmanaturals, and marketed under the brand name 'Raw Form Organics', tested positive for contamination and the manufacturer did not comply with federal requests for voluntary recall.[68] FDA Commissioner Gottlieb stated that the recall was, "...based on the imminent health risk posed by the contamination of this product with salmonella" and not related to other regulatory concerns.[67] Consumers were advised to immediately discard any such products to prevent serious health risks.[68]

In February 2018, the commissioner of the FDA, Scott Gottlieb, released a statement describing further opioid-like properties of kratom and stating that it should not be used for any medical treatment or recreational use.[5] Also in 2018, the FDA supervised the voluntary destruction of kratom dietary supplements by a nationwide distributor in Missouri, and encouraged all companies involved in kratom commerce to remove their products from the market.[69] On February 26, the FDA warned a California manufacturer of a kratom product called "Mitrasafe" that the supplement was not confirmed as safe, was not approved as a dietary supplement or drug, and was illegal for interstate commerce.[24]

In November 2017, the FDA cited serious concerns over the marketing and effects (including death) associated with the use of kratom in the United States, stating that "There is no reliable evidence to support the use of kratom as a treatment for opioid use disorder; there are currently no FDA-approved therapeutic uses of kratom... and the FDA has evidence to show that there are significant safety issues associated with its use."[70]

DEA scheduling

On August 30, 2016, the Drug Enforcement Administration (DEA) announced its intention to place the active materials in the kratom plant into Schedule I of the Controlled Substances Act as a warning about an imminent hazard to public safety, citing over 600 calls to poison control centers between 2010 and 2015 and 15 kratom-related deaths between 2014 and 2016.[19] This drew strong protests among those using kratom to deal with chronic pain or wean themselves off opioids or alcohol.[71] A group of 51 members of the U.S. House of Representatives and a group of nine Senators each sent letters to acting DEA administrator Chuck Rosenberg protesting the listing and around 140,000 people signed an online White House Petition protesting it.[72][73] The DEA noted the responses but said that it intended to go forward with the listing; a spokesman said: "We can't rely upon public opinion and anecdotal evidence. We have to rely upon science."[74] In October 2016, the DEA withdrew its notice of intent while inviting public comments over a review period ending on December 1, 2016.[75][76] As of July 2016, Alabama, Arkansas, Indiana, Vermont, and Wisconsin had made kratom illegal,[77] and the US Army had forbidden soldiers from using it.[78] Between February 2014 and July 2016, U.S. law-enforcement authorities "encountered 55 tons of kratom," or roughly "50 million individual doses," according to the International Narcotics Control Board.[79]

From 2010 to 2015, kratom-related reports of poisoning in the United States increased 10-fold.[15] Because kratom was being marketed as a dietary supplement in 2014 – but had never been commonly used in the United States or confirmed to be safe – the FDA coordinated with other U.S. agencies to seize imported shipments.[17][80]

See also

References
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