Is Kratom the New 'Legal High' on the Block?: The Case of an

Kratom is an unscheduled herbal extract that contains alkaloids with opioid receptor agonist

activity. It is currently available in the form of dietary supplements and is used and abused by

chronic pain patients on prescription opioids. Active alkaloids isolated from Kratom such as

mitragynine and 7-hydroxymitragynine are thought to act on mu and delta opioid receptors

as well as alpha 2 adrenergic and 5-HT2A receptors. Animal studies suggest that Kratom

may be more potent than morphine. Consequently, Kratom consumption produces analgesic

and euphoric feelings among users. Some chronic pain patients on opioids take Kratom to

counteract the effects of opioid withdrawal. Although the Food and Drug Administration has

banned its use as a dietary supplement, Kratom continues to be widely available and easily

accessible on the internet at much lower prices than other opioid replacement therapies

like buprenorphine. There are no Federal regulations monitoring the sale and distribution of

this substance. Consumption of Kratom has been associated with hallucination, delusion,

depression, myalgia, chill, nausea/vomiting, respiratory depression, hepatotoxicity, seizure,

coma and death. A search of the pain literature shows past research has not described the

use and potential deleterious effects of this extract. Many pain physicians are not familiar with

Kratom. As providers who take care of high-risk chronic pain patients using prescribed opioids,

knowledge of all current substances with opioid receptor agonists with abuse potential is of

paramount importance. The goal of this article is to introduce Kratom to pain specialists and

identify issues for further studies that will be required to help better understand the clinical and

long-term effects of Kratom use among chronic pain patients.

Key words: Opioid receptor agonist, Kratom, Mitragynine, opioid overdose, chronic pain,

substance abuse :

Pain Physician 2017; 20:E195-E198

Case Report

Is Kratom the New ‘Legal High’ on the Block?:

The Case of an Emerging Opioid Receptor

Agonist with Substance Abuse Potential

From: Ventura County Medical

Center, Ventura CA

Address Correspondence:

George C. Chan ge Chien, DO

Ventura County Medical Center,

Ventura CA

E-mail:

[email protected]

Disclaimer: There was no

external funding in the

preparation of this manuscript.

Conflict of interest: Each

author certifies that he or

she, or a member of his or

her immediate family, has no

commercial association (i.e.,

consultancies, stock ownership,

equity interest, patent/licensing

arrangements, etc.) that might

pose a conflict of interest in

connection with the submitted

manuscript.

Manuscript received: 01-12-2016

Accepted for publication:

03-29-2016

Updated: 02-09-2017

Free full manuscript:

www.painphysicianjournal.com

George C. Chang Chien, DO, Charles Odonkor, MD, and Prin Amorapanth, MD, PhD

www.painphysicianjournal.com

Pain Physician 2017; 20:E195-E198 • ISSN 2150-1149

midst growing concerns of an opioid-abuse

epidemic in the United States (1), practicing

pain physicians can now add a newcomer to

their list of opioid receptor agonists with adverse effect

profiles and substance abuse potential (2,3). Kratom,

also known as Mitragyna speciosa, is extracted from

the leaves of an evergreen deciduous tree native to

Southeast-Asia and was originally described in 1839

by botanist Pieter Willem Korthals (3-5). For centuries,

Kratom leaves were ground up to create an herbal

tea consumed by laborers and blue collar workers in

some parts of Asia for enhanced work productivity (5-

7). In addition to possessing stimulant effects at low

doses (1-5 grams), Kratom powder and leaf extracts

were considered powerful analgesics with opioid-like

effects at high doses (5-15 grams) (8). Users reported

feeling ‘high’ after ingesting Kratom and this helped

to promote its utility as a recreational substance (9).

Kratom is the chief ingredient in a popular local drink

in Thailand, the ‘4x100’ concoction is made with

cola soft drink, and variable ingredients including

marijuana, benzodiazepines, methamphetamines,

and cough syrup containing codeine (10). Due to

worsening abuse and side effects it was legally banned

Pain Physician:January 2017; 20:E195-E198

E196 www.painphysicianjournal.com

in Thailand in 1946 and other parts of Asia (11). Kratom

made its way to the United States in the early 2000’s,

where it currently remains an unscheduled substance

without strict regulations (12).

Purveyors of Kratom swear by its health ben-

efits and suggest it can be brewed into morning tea,

chewed, or smoked (12,13). Chewing Kratom leaves

appears to produce the most immediate effect, with

feelings of euphoria occurring within 5 to 10 minutes

of consumption and lasting up to 1 hour (13). From a

medical perspective, there have been increasing reports

of emergency room visits and hospitalizations due to

Kratom withdrawal. Patients typically present with

symptoms of nausea, insomnia, irritability, restlessness,

mood swings, diarrhea, rhinorrhea, myalgia, and ar-

thralgia (14-16).Those whooverdoseon Kratom can ex-

perience seizures, psychosis, coma, hallucination, para-

noia, severe emesis, respiratory depression and in the

worst scenarios, death (13,16). Prolonged use of Kra-

tom can result in drug cravings and eventual addiction,

with resulting weight loss, anorexia, loss of libido, and

hyper-pigmentation over the face and cheeks. These ef-

fects appear to be dose dependent, although toxicity

levels are yet to be determined (13-16).

Kratom has high abuse liability and patients who

are on prescription opioids are at the highest risk for co-

dependence (16). Ease of availability and access to Kra-

tom via online stores and websites have led to a surge

in demand for this product (15). Together, these obser-

vations ought to engender a note of caution among all

pain physicians prescribing opioid analgesics for their

patients. Many opioid abusers now turn to Kratom to

ameliorate opioid withdrawal for two reasons: 1) Pro-

curement is as easy as a mouse click away and needs no

prescription, and 2) It is a less expensive than other opi-

oid replacement therapies such as buprenorphine (13).

While many pain physicians comply with the imper-

ative to appropriately screen patients for opioid abuse

and high-risk behaviors, it is equally important for them

to continue to discuss and address dangers of using un-

tested and unregulated herbal remedies and supple-

ments (15). Kratom is available as a dietary supplement

and it would be instructive when reviewing patients’

medication lists to inquire about non-prescribed sup-

plements (15-16). Pain experts would do well to expand

the traditional focus beyond illicit drugs to query the

use of other legal but unendorsed substances such as

Kratom, which is not yet criminalized in the United

States (11,13). Due to its titular benefit as a stimulant

at low doses and its incipient rise on the drug market,

there are no formalized systems for monitoring Kratom

sale and distribution (13). Public use lags any regulatory

policies by the Drug Enforcement Agency (DEA) or Food

and Drug Administration (FDA). The DEA, stated in

2013, “There is no legitimate medical use for kratom in

the United States.” In 2014, the FDA abolished its inclu-

sion in dietary supplements (17,18). In the fall of 2016,

the DEA has announced plans to add the psychoactive

compounds in kratom to the list of schedule I drugs

banned under the Controlled Substances Act. This act

was subsequently placed on hold as the DEA is waiting

for input from the FDA (19-20). Although there are no

tests currently available to detect Kratom itself, its me-

tabolites may be detected by specialized spectrometry

tests (11). Due to increasing popularity of Kratom, some

drug testing systems offer detection of these metabo-

lites yet these are not universally available (21).

Over 25 alkaloids have been identified in Kratom

extract, possessing antinociceptive, anti-inflammatory,

anti-depressant, and muscle relaxant properties (22).

Although they have activity at the opioid receptors, the

active ingredients in Kratom are not opioid compounds.

Mitragynine, the primary active alkaloid isolated from

Kratom, has been identified as a partial opioid recep-

tor agonist with similar effects to morphine (13,17). In

addition, 7-hydroxymitragynine, a minor alkaloid of

Kratom is considered to be more potent than morphine

although dose levels producing analgesia remains un-

defined (9,13,17). Mechanistically, these alkaloids are

thought to activate supraspinal mu and delta opioid

receptors (9,11,13). This explains the analgesia and eu-

phoria derived from Kratom and why abusers use it to

counteract the effects of opioid withdrawal, and suc-

cessful self-medication to treat opioid addiction (11,16-

17). Animal studies suggest that mitragynine may be

involved in noradrenergic and serotonergic pathways

and stimulate post-synaptic alpha 2 adrenergic recep-

tors, but inhibit 5-HT2A receptors (8,13).

Safety profile has not been ascertained and the jury

Table 1. Dose dependent effects of Kratom.

Kratom use Dose Effects

Low to moderate 1-5 grams

Mild stimulant effects that enable

workers to stave off fatigue.

Moderate to high 5-15 grams

Opioid-like effects including

analgesia, treatment of diarrhea,

opioid-withdrawal symptoms,

and euphoria.

Very high

Greater

than 15

grams

Sedating effects.

www.painphysicianjournal.com E197

Effects of Kratom: A New Opioid-Receptor Agonist

is still out in regards to its analgesic and opioid antidote

efficacy (8-10,16-18). In the context of Kratom overdose,

animal studies have yielded conflicting findings regard-

ing which opioid antagonists can reverse the effects of

Kratom (8,23). Naloxone, which has proven effective

in various community opioid overdose treatment pro-

grams and which is now the mandated intervention by

national guidelines, appears to be prime candidate for

consideration (13). Mortality from Kratom is on the rise

and although the exact numbers remain uncertain, one

thing is clear: pain physicians are well advised to be cog-

nizant of the perils of this new ‘legal high’ (12,13,16,24).

It is often said that ignorance is bliss, but in as much

as pain prescribers remain ignorant of Kratom, opioid

overdose treatment outcomes may be less than blissful

if Kratom abuse continues unabated. Given the dearth

of studies in the pain literature, the authors hope this

article sheds light on this important but under-recog-

nized consumption of under-regulated substances like

Kratom. As pain specialists continue to seek ways to

help curb the opioid overdose epidemic through vari-

ous programs (1,25), further studies on the clinical and

long-term effects of Kratom are required. Indeed, time

and research may demonstrate that the active sub-

stances in Kratom may be harnessed to treat pain, or

opioid addiction. Pain management specialists should

be apprised of the ongoing medical and legal develop-

ments regarding this controversial substance.

Table 2. Pharmacokinetics of Kratom.

Pharmacokinetics Time

Time to reach maximum plasma

concentration

0.83 ± 0.35 hour

Terminal half-life 23.24 ± 16.07 hours

Volume of distribution 38.04 ± 24.32 L/kg

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