Current perspectives on the impact of Kratom use

04 July 2019
Current perspectives on the impact of Kratom use

Substance Abuse and Rehabilitation

Charles Veltri 1

Oliver Grundmann 1,2

1Department of Pharmaceutical Sciences,

College of Pharmacy, Midwestern

University, Glendale, AZ 85308, USA;

2Department of Medicinal Chemistry,

College of Pharmacy, University of

Florida, Gainesville, FL, 32611, USA

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Abstract: The leaves from the tree Mitragyna speciosa, commonly known as Kratom, in the

coffee plant family (Rubiaceae) are commonly used in their native habitat of Southeast Asia

as a stimulant to sustain energy during hard day labor and as an opioid-like analgesic and

sedative. Traditional and modern uses overlap based on the effects of the leaf extract which

has also gained popularity in the United States and Europe in the last two decades. Kratom

has and is being used for the mitigation of opioid withdrawal symptoms and as a harm

reduction agent with a minority of users subsequently developing a dependence on the

extract. The respective demographic use patterns of Kratom differ between Southeast Asia

and the Western world. While pure Kratom is primarily used by day laborers and misused in

conjunction with cough medicine by youth in Southeast Asia, a majority of users in the

United States is middle-aged, has at least middle income, private health insurance, and

completed some college. Deaths attributed to the use of Kratom have been reported in

Europe and the United States but not in Southeast Asia. Although Kratom was detected as

the alkaloid mitragynine in the blood of the decedents, causality could not be established in

almost all cases because of poly-drug exposures. It is notable that Kratom can cause herb–

drug interactions, especially with other central nervous system -active substances. Given the

mostly unregulated market for Kratom products in Western countries, consumers may be

exposed to adulterated or contaminated products, especially if purchased through websites or

the darknet. A number of countries have scheduled Kratom because of its stimulant- and

opioid-like effects and the established interaction of the alkaloid mitragynine with opioid

receptors.

Keywords: Kratom, Mitragyna speciosa, use pattern, Southeast Asia, substance dependence

Introduction

Kratom (Mitragyna speciosa Korth.) is an evergreen tree in the coffee family

(Rubiaceae) that is native to Southeast Asia and cultivated especially in Indonesia,

Malaysia, and Thailand for its historical medical and recreational uses.1 Kratom is

also referred to as biak-biak, ketum, or Maeng Da in different regions and describes

both the tree and the varying extracts and preparations derived from it.2 The leaves of

the tree, that are used for their pharmacological activity, can have different colored

veins (white, green, or red) which are not distinguished in its native habitat but have

been attributed to varying effects when sold as powdered leaf extracts in Western

countries.3 The main active compounds of current interest are indole alkaloids,

primarily mitragynine and 7-hydroxymitragynine that act as partial agonists on

opioid receptors.4 Kratom products contain approximately 2% mitragynine and either

none or between 0.01% and 0.02% 7-hydroxymitragynine.5 Among other mitragyna

indole alkaloids, mitragynine presents with a unique

mechanism of action and pharmacology distinct from classical

opioids like morphine, heroin, or fentanyl. Binding to

the μ-opioid receptor causes recruitment and activation of

the G-protein-coupled signaling cascade but does not lead

to recruitment of β-arrestin 2 which has been associated

with many of the undesired effects of opioid receptor activation

such as constipation, respiratory depression, and

dependence.4,6 In animal models, mitragynine did not

cause dependence or increased self-administration and

even reduced prior administration of morphine whereas 7-

hydroxymitragynine did present with a dependence

liability.7

The use of Kratom in Southeast Asia has been documented

back for at least 150 years and described both a stimulant

effect for use in hard day labor when fresh leaves are chewed

and an analgesic and relaxing effect if brewed into a tea.3 It

also serves as a substitute and mitigation strategy for opium

that was widely used in Malaysia and Thailand from the

1830s to the 1920s.3 In addition, Kratom remains in use for

its antispasmodic, muscle-relaxant, and antidiarrheal effects

while both its brief stimulant and analgesic effects remain a

popular home remedy in Southeast Asia.8,9 The use of

Kratom is prohibited in Malaysia under Poisons Act 1952,

but its use remains widely spread because the tree grows

natively and tea decoctions are readily available in local

communities.1 Thailand lifted the ban on the use, production,

and possession of Kratom in 2018 for medicinal purposes.10

The increase of Kratom sales across Europe and North

America caused rising concerns about its safety with several

European countries banning the plant and its active

alkaloids.11 The status of Kratom as a dietary supplement

remains vague in the United States as of this writing

because the Food and Drug Administration (FDA) does

not consider Kratom a recognized supplement that has

been present on the US market prior to the enactment of

the Dietary Supplement Health and Education Act

(DSHEA) of 1994 that would have allowed for such a

provision.12 Instead, the FDA has designed mitragynine

and 7-hydroxymitragynine as opioids and recommended

placement of these compounds into the Controlled

Substances Act Schedule I by the US Drug Enforcement

Administration (DEA).13 As of this writing, this scheduling

action has not taken place despite an earlier attempt by the

agency to do so which was withdrawn based on public

comments and the action by several members of the US

congress. Several US states have either banned Kratom and

its active alkaloid compounds or enacted laws that prohibit

the sales of adulterated products that are not appropriately

labeled according to Good Manufacturing Practices.12,14

Kratom users in the West are using the leaf extract and

its varied formulations for a range of health reasons that

primarily relate to chronic pain, mood disorders, or mitigating

the withdrawal symptoms of a prescription or illicit drug

dependency.15 Although the number of Kratom users in the

United States remains vague, the estimate ranges from 3 to

5 million based on survey data and membership information

provided by the American Kratom Association.16

This review provides a current perspective on the use

pattern and impact of Kratom use on the individual and

society. The implications of Kratom use are discussed both

from the use as a traditional herb and supplement as well

as a potential future medicine, either as a pure drug or

complex natural extract.

Methods

PubMed and Google Scholar databases were searched on

April 9, 2019, for all research and review articles covering

Kratom use patterns. The initial search terms were:

“Kratom” AND “use pattern” or “Kratom use pattern” or

“Kratom” AND “misuse” or “Kratom” AND “abuse”. The

search returned a total of 2,596 sources. Of these, 91

resulted from PubMed and 2,505 from Google Scholar

searches. Both authors evaluated articles for inclusion in

the review independently. Initially, duplicates were eliminated,

reducing the total number of references to 2,364.

Further exclusion of non-English literature resulted in

further reduction of the number of references to 1,823.

Following evaluation of references, a total of 467 references

were initially deemed relevant to the topic of the

review. Exclusion of several book chapters that referred

back to primary literature and references that referred to

original research articles narrowed the references to a total

of 44 that were included in this narrative review.

Kratom use pattern in Southeast Asia

The first reported use of Kratom in the scientific literature

dates back to 1836 when it was noted that the leaves of the

tree were used by Malays as a substitute for opium.17 In

addition, other observations documented the traditional

use of Kratom leaves and its preparations as a wound

poultice, for fever, and for mitigating the withdrawal

symptoms from opium and later heroin.17 Its traditional

use has not been dated and has likely been part of the

social fabric for hundreds of years given that the tree

grows indigenously throughout Malaysia, Thailand, and

Indonesia.8 Its use in Malaysia and Thailand has been

primarily for two broad applications: as a stimulant to

increase work efficiency, endurance, and tolerance to hot

and humid climate conditions for manual laborers and as a

medical remedy for a range of symptoms. The latter practice

as a traditional medicine and home remedy primarily

uses fresh or dried leaf material to prepare a decoction by

brewing the leaves and ingesting it as a beverage either hot

or cold. In this form, the effects have been primarily

described as analgesic, relaxing, anti-diarrheal, antipyretic,

and anti-diabetic.18 Far less common is smoking of the

dried leaf although it is occasionally reported in Malaysia

and associated with a relaxing effect.18

The most recent study investigating the prevalence of

Kratom use was conducted in 2007 in Thailand among

26,633 respondents between the ages of 12 and 65 years.11

The lifetime prevalence for Kratom use among all users was

2.3% which was higher than for marijuana use while 13- to

16-year-old students reported a 9.4% lifetime prevalence in

a 2004 survey. Kratom is the most commonly used illicit

drug in Thailand, and similar percentages are likely for

Malaysia based on conducted seizures of Kratom. The

high prevalence can be explained by the long history of

use as both medicine and recreational drug, readily accessible

plant material that grows natively in the area, and

perceived safety of Kratom preparations.

Despite its traditional medical uses, Kratom dependence

has been known and observed for a long time and

is well documented.17 Unlike opium, opioid, or heroin

addiction, Kratom addiction is not associated with a significant

stigma in rural communities if a husband is taking

it to support his family. However, female Kratom use is

much less tolerated and there are far fewer female users in

local communities.8

Scientific research on Kratom and its effects on users in

Thailand and Malaysia has increased in the past 10 years

given the rising interest in Kratom extracts in other countries.

With a long use history and a socially acceptable

tradition of use among the general population, human studies

in general appear to be easier to conduct compared to

Western countries although Kratom is illegal in Malaysia.

Given the long-term use of Kratom especially by day

laborers to boost endurance and withstand physical labor

and harsh work conditions, both the stimulant and opioidlike

analgesic effects can contribute to dependence development

and addiction.19,20 Two surveys conducted in

Malaysia and Thailand reported that the average age of

long-term Kratom users was in their mid-30s and a

majority were married with lower education levels.19,20

While Kratom is both used for its stimulant and opioidlike

effects, a majority of users had a history of drug abuse

and primarily used Kratom to mitigate opioid and stimulant

withdrawal symptoms. It was not uncommon among

survey respondents to develop a dependence on Kratom.

Those with lower education attainment were more likely to

successfully stop using Kratom compared to those with a

higher level of education.20 One potential explanation for

this inverse correlation is the use of Kratom among higher

educated individuals who had previously used a prescription

opioid and are now either self-treating a pain condition

or mitigating withdrawal symptoms from the former

prescription drug. Maintaining the use of Kratom products

can be relatively expensive which can correlate higher

educational attainment with higher income to allow this

habit. Another explanation could be the use of Kratom as a

perceived “natural” alternative to prescription or “synthetic”

drugs for the self-treatment of a health condition.

The belief that “natural” equals safe is prevalent among

more educated individuals despite a lack of support for

such a statement especially in Western countries.

A cross-sectional survey investigated the correlation

between amount and frequency of Kratom consumption

and risk of dependence and addiction development in

long-term users in three northern peninsular states of

Malaysia.21 There was a correlation between increased

consumption of Kratom and risk of dependency development,

severity of withdrawal symptoms, and cravings for

the extract. Physical withdrawal symptoms manifested as

muscle spasms, diarrhea, lack of appetite, fever, pain, and

runny eyes and nose. Psychological withdrawal was characterized

by mood swings such as anger, nervousness,

restlessness, disturbed sleep, tension, and sadness.21

Despite these findings that are similar to opioid withdrawal

and craving symptoms, a majority of participants in surveys

and case studies as well as their providers and caretakers

do not characterize Kratom withdrawal and cravings

as severe as those experienced during opioid withdrawal

and those symptoms were of shorter duration.18,21,22

Although Kratom dependence is widespread, treatment

admissions for withdrawal have increased in recent years

from 1,000 in 2007 to almost 3,000 in 2011 in Thailand

where Kratom accounts for approximately 2% of all drug

treatment admissions.11 It is not yet clear if this change is

based on a stricter enforcement of drug policies and how it

will change with the legalization of Kratom for medical

purposes in 2018.

Even if Kratom dependence and withdrawal are not

perceived to be as severe as for opioids, the question of

impairment with the chronic use of Kratom remains. A

study involving 70 regular Kratom users and 25 control

participants evaluated cognitive functioning using the

Cambridge Neuropsychological Test Automated Battery

(CANTAB) found deficits with higher chronic Kratom

consumption (more than 3 glasses of kratom decoction

consumed per day) in new learning and visual episodic

memory.23 However, the authors conclude that overall

Kratom users independent of the amount they consumed

were comparable in their cognitive and executive functions

to control participants and does not impair motor,

memory, or attention function.

Kratom use and even dependence does not impair

social functioning according to several studies conducted

in Malaysia.9,24 A majority of chronic Kratom users are

employed, married, and live with their family and rarely

present with health problems. This stands in contrast to

alcohol, opioids, or amphetamine abuse that are not

accepted in society.25

Aside from the traditional uses of pure Kratom for its

medicinal properties and as an endurance enhancer for

hard labor, newer preparations of the plant have emerged

that are seen as problematic. Because of its bitter taste,

Kratom tea preparations are often sweetened or mixed

with beverages to make it more palatable.9 However, teenagers

and young adults in urban areas do mix Kratom

leaves and teas with caffeinated beverages such as Coca-

Cola and cough syrup containing codeine or diphenhydramine.

The mixture is boiled to create a syrup referred to as

4Å~100.9 In many cases, the syrup provides for a more

intense euphoria and is often consumed together with

other drugs such as an antidepressant, anxiolytic, alcohol,

or analgesic. Poly-drug use with Kratom increases the risk

of fatal additive or synergistic toxic effects whereas there

have been no reports in Southeast Asia of fatalities caused

by the ingestion of pure Kratom preparations.

Another folkloristic use of Kratom is as a potential

aphrodisiac that has been reported in several surveys of

chronic Kratom users.19,20 This activity contrasts with the

opioid-like effects since classical opioids are commonly

associated with sexual dysfunction and decreased libido.

Direct measurement of testosterone, follicle-stimulating

and luteinizing hormone did not indicate any differences

between Kratom users and non-users although there were

some non-pathological differences in blood profiles

between the low-dose and high-dose Kratom users.26

Furthermore, other studies and epidemiological data indicate

that despite its use as an aphrodisiac and the potential

for impairment, Kratom is not associated with an increased

risk for sexually transmitted diseases or needle sharing.11

Use pattern in the United States

and Europe

Unlike Kratom use in Asia, emergence into the Western

markets is a relatively new occurrence. Anecdotal reports

suggest that immigrants from Southeast Asia first

imported Kratom into the United States in the 1980s

and 1990s with an expansion of use in the United

States within the past decade.5,12 In the West, Kratom is

sold through the Internet and at herbal stores, tobacco/

smoke shops, and “head” shops where it is primarily

marketed as an herbal medicine/supplement to treat a

variety of ailments (pain, mental health, opioid withdrawal

symptoms) as well as a “legal” or “natural” high and

alternative to traditional opioids and even promoted as an

“herbal speedball.”1,11,15,27–29

Consumption of Kratom in the United States is predominantly

by liquids, but the use of powders added to food

or beverages and consumption of Kratom capsules is

growing in popularity.12 Users brew Kratom in a similar

fashion as making tea or coffee where the leaf material

(whole leaf or powder) is steeped in boiling water or cold

extracted. Acids have been used to enhance the extraction.

The resulting tea is bitter, so sugar, honey, or various

sweeteners are often added.12

Because of the route of administration as an oral supplement,

there is considerable discussion about the classification

of Kratom. To date, there have been few reports of

injections or other routes of administration that would indicate

a higher degree of abuse and dependence. Furthermore,

isolation of mitragynine or 7-hydroxymitragynine has not

been attempted for misuse or abuse purposes in a fashion

similar to morphine from opium. However, the legality of

Kratom as a supplement with limited regulatory oversight

has been challenged or restricted in several countries

because of its opioid-like effects and the presence of compounds

that interact with opioid receptors.

The legal status of Kratom varies in the West from

region to region. While the European Union has open borders

between members and a shared currency, the legal

status of Kratom varies. Kratom is an illegal drug/substance

in Denmark, Finland, Ireland, Latvia, Lithuania, Poland,

Romania, and Sweden.30 The legal status of Kratom in the

United Kingdom is complex. While Kratom or M. speciosa

is not listed as a commonly encountered Schedule 1 controlled

substance, it most likely falls under the term of

“psychoactive substance” of the Psychoactive Substances

Act 2016 in the United Kingdom.31,32

Kratom is not scheduled under the US Controlled

Substances Act; however, the DEA does not recognize

any legitimate medical use for Kratom.29 The DEA

based its stance on the FDA warning that Kratom “should

not be used to treat medical conditions, nor should it be

used as alternative to prescription opioids,” and that the

FDA finds no indication that Kratom is safe.33 As of this

writing, Kratom is legal in all US States except Arkansas,

Alabama, Indiana, Rhode Island, Wisconsin, and Vermont

and the District of Colombia. There are also city bans in

Alton, IL; Columbus, MS; Denver, CO; Jerseyville, IL;

San Diego, CA; and Sarasota, FL, as well as a county ban

in Union County, MS.34 Further legislation regulating,

restricting, banning the use of Kratom or reversing such

bans is pending in other jurisdictions.

There are relatively few studies describing Kratom

use in the West compared to studies focused on use in

Asia. An online anonymous survey in the United States

was utilized to answer three questions: 1) Who is consuming

Kratom and for what purpose? 2) What perceived

beneficial and detrimental effects are reported

by Kratom users if dose and frequency of consumption

are considered? 3) Does Kratom present with an abuse

potential and withdrawal symptoms?15 Analysis of the

demographics of this survey found that US Kratom

users are white non-Hispanic males between 31 and 50

years of age, married or partnered, employed with an

annual household income of US$35,000 or higher, have

private health insurance, had at least some college education,

and had used Kratom for more than one year but

less than five years. Respondents predominantly identified

Kratom use to relieve acute or chronic pain followed

by use for an emotional or mental condition.

Respondents identified increased energy, decreased

pain, increased focus, less depressed mood, lower levels

of anxiety, reduced or stopped the use of opioid painkillers,

reduction of PTSD symptoms, and elevated

mood as beneficial effects of their Kratom consumption.

Self-reported detrimental effects appeared to be dosedependent

and included nausea, constipation, and dizziness

or drowsiness as the most frequently identified

negative effects. Doses of up to 5 g of Kratom presented

with lower odds ratios for detrimental effects than doses

of 8 g or more. Less than half of the respondents

reported withdrawal effects within 12–48 hrs after discontinuation

of Kratom and the withdrawal symptoms

were mainly rated at a 2 or 3 on a 5-point Likert scale

(from 1-severe to 5-not severe at all). This study shows

that the US Kratom user population is diverse in demographics

and motives for Kratom consumption and that

doses of up to 5 g consumed 3 times per day were able

to provide beneficial effects while having lower rates of

negative effects.

Cinosi and colleagues evaluated literature from 1967 to

2015 to better understand Kratompharmacology, Kratomuse

cross-culturally, experience of the user, and to identify risks

and side effects related to Kratom consumption.11 Their

analysis identified a growing popularity of Kratom use in

areas outside of Southeast Asia, specifically the European

Union and United States. The increase in Kratom consumption

in the European Union and United States corresponds to

an increasing availability of Kratom for sale through the

Internet. The European Monitoring Centre for Drugs and

Drug Addiction (EMCDDA) conducted an Internet survey

of 27 European online shops in 2008 that identified Kratom

as one of the most widely offered “legal highs” along with

Salvia divinorum, Hawaiian Baby Woodrose seeds, Spice,

and stimulant-containing capsules.35 A more extensive study

by theEMCDDA in 2011 showed Kratom as themost widely

offered product with 20%of the online retailers shipping it to

the European Union.35 More studies are necessary to help

understand the impact of Kratom as its use increases in the

West, especially if Kratom follows the pattern of novel

psychoactive drugs.11,36

The increasing trend in Kratom consumption in the

West has corresponded with an increase in reports of

Kratom-related exposures to Poison Control Centers in

the United States, care received at a health care facility

due to Kratom consumption, and association with overdose

fatalities.12,37–39 A retrospective analysis of poison

center charts collected from January 1, 2002, to November

30, 2016, in the electronic database Toxicall™ using the

keywords Kratom and M. speciosa was performed to summarize

the clinical effects of Kratom.39 The study evaluated

12 cases of Kratom exposure (dose and frequency

were largely unknown) reported from health care facilities

and described the clinical effects to include altered mental

status, agitation, central nervous system depression, seizures,

and tachycardia.39 Admission to psychiatry and

benzodiazepines were the most frequent treatment methods

and no deaths were reported.39 A larger analysis of

data reported to Poison Control Centers using the National

Poison Data System database from 2011 to 2017 identified

1,174 Kratom-only exposures where 1,020 cases resulted

in one or more clinical effects.38 The most common clinical

effects reported were agitation/irritability, tachycardia,

nausea, drowsiness/lethargy, vomiting, confusion, and

hypertension.38 Serious clinical effects included seizures,

respiratory depression, coma, increased bilirubin, bradycardia,

rhabdomyolysis, renal failure, respiratory arrest,

cardiac arrest/asystole, and cyanosis.38 More than half

(51.9%) of these cases received one or more therapies

which included IV fluids, benzodiazepines, oxygen, naloxone,

and tracheal intubation.38

The national poison center reporting database documented

1,807 calls related to Kratom exposure from

2011 to 2017.37 The Centers for Disease Control and

Prevention analyzed data on unintentional and undetermined

opioid overdose deaths from the State

Unintentional Drug Overdose Reporting System.37

Kratom was detected on postmortem toxicology testing

in 152 cases of 27,338 overdose deaths from data collected

from 11 states during July 2016-June 2017 and 27 states

during July–December 2017.37 Kratom was identified as

the cause of death by a medical examiner in 91 of the 152

Kratom-positive deaths, but was the only identified substance

in just seven of these cases.37 Presence of additional

substances in these seven Kratom-only cases cannot be

ruled out.37,40 The co-occurring substances in the 91

cases where Kratom was identified as the cause of death

include fentanyl (including analogs), heroin, benzodiazepines,

prescription opioids, cocaine, and alcohol.37 Multisubstance

exposures involving Kratom, predominantly in

combination with opioids, are associated with a greater

odds ratio of admittance to a health care facility and

occurrence of a serious medical outcome when compared

to Kratom-only exposure.38 These data highlight that

Kratom use is associated with a complex population of

poly-drug users and especially with opioid use disorder.

These data further suggest that a deeper investigation into

the toxicity of Kratom is needed, especially focusing on

drug–herb interactions.

Kratom–drug interactions are further indicated in several

case reports resulting in hepatotoxicity or death.41–45

A 70-year-old man with a history of hypertension and

osteoarthritis, treated with amlodipine and oxycodone,

presented with jaundice.42 The patient admitted to consuming

Kratom twice daily for 4 days approximately 2–3

weeks before his initial presentation at a medical center for

jaundice.42 He presented with elevated creatinine (2.3 mg/

dL) and total bilirubin levels (33.7 mg/dL) and clinically

improved with supportive care, but required a readmission

at which time he received 3 units of packed red cell

transfusion to treat anemia.42 His abnormal liver tests

normalized after three months, except his creatinine level

remained slightly elevated (1.8 mg/dL).42 The liver

damage in this case is most likely due to an amlodipine–

kratom interaction involving the enzyme cytochrome P450

3A4 (CYP3A4).46,47

The elderly are not the only individuals at risk of

adverse events due to drug–kratom interactions. A 32-

year-old male with a history of hypertension, anxiety,

and lower back pain presented to an Emergency

Department with jaundice, nausea, fatigue, joint pain,

and night sweats after completing a dose of 60 Kratom

tablets over 1 week (as per recommended dose on the

bottle) and had mitragynine (47.8 ng/mL) and 7-hydroxymitragynine

present in his urine.45 The patient’s history

includes alcohol use and acetaminophen use for his back

pain, but he has no history of smoking or illicit drug use.

The patient received a loading dose of N-acetylcysteine

(150 mg/kg/hr) but developed an anaphylactic response

and further doses withheld. While the patient’s liver

enzymes were trending down, he was discharged prior to

them normalizing. The authors attributed the acute liver

injury solely to the patient’s use of Kratom;45 however, the

repeated use of acetaminophen could have attributed to the

liver injury and the consumption of Kratom could have

been overwhelming to an already damaged liver.

Hepatotoxicity associated with Kratom use is rare and

appear to be associated with chronic or high consumption

of the product.48 In animal experiments, high concentrations

of mitragynine (100 mg/kg) or a methanolic Kratom

extract (1000 mg/kg) in rats showed organ damage primarily

to the kidneys and liver with elevated liver

enzymes and hepatic cellular damage. Although these

doses exceed both acute and chronic human doses, further

research on the impact of chronic kratom consumption on

liver and kidney function is warranted.

Kratom use could have serious adverse events due to

drug–herb interactions, specifically with the antipsychotic

quetiapine. A 27-year-old male with a history of

Asperger Syndrome, bipolar disorder, and substance

abuse was found deceased.43 The postmortem analysis

of subclavian blood revealed valproic acid (8.8 μg/mL),

quetiapine (12,000 ng/mL), and mitragynine (qualitatively

positive).43 The death was ruled an accident and

due to acute toxic effects of quetiapine.43 The high levels

of quetiapine were ruled to be due to a drug–herb interaction

with Kratom since there was no evidence of significant

discrepancies in quetiapine pill quantities in his

residence.43 This case further highlights the need for

more investigation into Kratom–drug interactions, specifically

involving CYP2D6 and CYP3A4.

A better understanding of Kratom–drug interactions is

needed specifically when dealing with consumption of

Kratom to aid with withdrawal symptoms from, or as a

substitute for, traditional opioids. Individuals suffering

from opioid addiction are using Kratom out of curiosity

and ease of purchasing.49,50 These individuals are highly

variable and have an extensive substance use history.49

The variability in both user and drug use/preference will

further complicate developing a treatment plan and dealing

with patients consuming Kratom. It is necessary for scientists

to further elucidate Kratom drug–herb interactions to

aid physicians who can then better educate their patients

about the potential benefits and harms associated with

Kratom through a more open dialog.

Discussion and conclusion

The traditional and current diverse uses of Kratom in

both Southeast Asia and the Western world indicate that

the impact of the leaf and its extracts are of multidimensional

complexity including sociocultural, economic,

medico-legal, and often individual issues. Throughout

its history of use, Kratom has been known to exert stimulant-

and opioid-like effects that is raising concerns

with regulatory agencies and resulted in scheduling

actions in various countries. Although knowledge from

clinical studies is limited, epidemiological data obtained

from Southeast Asia, Europe, and the United States indicate

that Kratom has a distinct user profile and presents

with discrete effects from other stimulants or opioids. A

substance-dependent opioid user does not prefer Kratom

over another opioid but instead would utilize Kratom as a

harm reduction or mitigation agent. This has been the

conclusion from studies in Malaysia and the United

States although the current information is preliminary in

scope based on the small sample sizes and regional limitation

of the surveys. The findings do align with preclinical

observations in rodents that report a reduction in

morphine self-administration with the use of mitragynine.

This current knowledge points to a potential for further

development of mitragynine or use of Kratom as a harm

reduction agent similar to methadone or buprenorphine.

This will have to be further studied under controlled

clinical conditions.

The toxicity of Kratom remains a topic of discussion.

From the CDC report and published cases, it is clear

that Kratom has the potential to cause herb–drug interactions

and even be involved in fatalities. While a

majority of regular Kratom users in Southeast Asia

and the West alike do not experience acute or chronic

adverse effects, the incidence of unwanted side effects

remains unknown and can include both stimulant and

opioid-like sedative effects. Although some regulatory

agencies, including the US FDA, have determined that

Kratom and the alkaloids mitragynine and 7-hydroxymitragynine

are opioids and thus should not be available

without regulation, a direct causative link between the

fatalities in which Kratom was detected cannot be drawn

because nearly all of them involved poly-drug

exposures.51 The toxicity of Kratom in various animal

species is variable and has not been determined for most

of them following acute and chronic exposure. The only

clinical pharmacokinetic study in humans that provides

blood concentrations of mitragynine does not correlate

with post-mortem blood mitragynine concentrations thus

not allowing for the determination of a toxic or lethal

cut-off level. In addition, at this point, only the concentration

of mitragynine is reported as indication of the

presence of Kratom while it is not clear that mitragynine

is in fact the toxic compound.

Reports and studies of the dependence potential to

Kratom are of serious concern given the current opioid crisis

in the United States and rising abuse of opioids in other

countries. It appears that a majority of Kratom-dependent

users had a prior substance use disorder or were seeking

relief from a chronic pain condition but wanted to avoid

opioid use. The severity of Kratom dependence symptoms

appears to be milder compared to opioid use disorder and can

be treated in a similar manner with buprenorphine or methadone

and subsequent tapering. The incidence of Kratom

dependency is not known and to date no US nationwide

reporting system such as the National Survey on Drug Use

and Health (NSDUH) or Monitoring the Future have indicated

the use of Kratom in their reports.

Given the diversity in patterns of use for Kratom,

additional research is paramount to support and expand

on current findings. The labeling of Kratom products

available to consumers needs to follow appropriate

regulatory standards as well as quality good manufacturing

practices to ensure that consumers who seek out

Kratom are not exposed to adulterated or contaminated

products.51 Health care providers should be trained on

the science of Kratom and its clinical implications to

assist consumers in making the right choice and avoid

herb–drug interactions.

Disclosure

The authors report no conflicts of interest in this work.

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