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explain why administration of kratom line with those induced by morphine understand kratom’s therapeutic po-
extract inhibited acute limb edema withdrawal. tential and risks and the populations
while long-term kratom use prevented In another rat study, mitragynine most likely to benefit or experience
the growth of granuloma tissue in ani- 1, 10, and 100 mg/kg was given orally harm from its use. A search of clinical-
mal studies.13 for 28 days.18 No deaths occurred, but trials.gov using the index terms kra-
Kratom induces constipation elevated liver transaminases occurred tom and mytragyna found no studies,
through opioid and nonopioid mecha- and histological liver (hepatocyte hy- either completed or underway.22
nisms. A methanolic extract of kratom pertrophy and hemorrhage) damage Anecdotal reports suggest that
reduced defecation frequency and fecal was found in rats given moderate-to- kratom produces an unusual com-
weight in a castor oil–induced diarrhea high doses of mitragynine, and med- bination of stimulant and opioidlike
model and slowed intestinal transit ullary damage (vacuolation and ne- effects.9,23 The stimulant effects of
in rats.13 Naloxone preadministration crosis of neuronal cells) occurred with 1–5 g of raw leaves are not perceived
only partially ameliorated these gas- high doses. The day after stopping as being as potent as those of amphet-
trointestinal effects. Intestinal transit therapy (day 29), the cumulative with- amines, and some people with chronic
time was also suppressed when sub- drawal score was elevated from base- pain appreciate the stimulant effects
cutaneous 7-hydroxymitragynine was line in a dose-related fashion based on as opposed to the depressant effects of
administered to mice.13 Paynatheine, the intensity of previous mitragynine normal opioid agonists. When greater
speciociliatine, and speciogynine im- exposure. The same relationship held amounts (5–15 g of raw leaves) are in-
pede intestinal smooth muscle func- true 14 days after withholding mitrag- gested, analgesia is enhanced and the
tion.9,13 Speciociliatine inhibits ace- ynine, but the scores were substan- sedative effects overcome the stimu-
tylcholine release from presynaptic tially reduced from day 1 withdrawal lant effects. The euphoric effects of
nerves while payantheine and spe- values.18 kratom are perceived as being less
ciogynine inhibits muscarinic recep- In vitro, a methanolic extract of pronounced than those arising from
tors in ileal smooth muscles.9 kratom inhibited cytochrome P-450 traditional opioid agonists.9,23
Kratom has been used to ame- (CYP) isoenzymes 2C9, 2D6, 1A2, and Discussion threads initiated and
liorate opioid withdrawal symptoms 3A4, with the most potent blockade propagated on Drugbuyers.com (now
but also induces withdrawal. In zebra seen with CYP 2D6.2,13 Opioids such Drugs.com), a website with health in-
fish, long-term morphine administra- as codeine, hydrocodone, fentanyl, formation for the lay public, surged
tion (1.5 mg/L for 2 weeks) resulted methadone, oxycodone, and trama- in 2005 and overwhelmingly involved
in withdrawal symptoms (decreased dol are CYP substrates.19 In addition, the use of kratom for opioid addic-
exploration, erratic swimming, cor- illicit drugs such as 3,4-methylene- tion.24 In 1836 and 1895, kratom was
tisol activation, and prodynorphine dioxymethamphetamine (commonly identified as a treatment for opium
transcript production) that was at- called MDMA) and several synthetic addiction and as an opium substitute
tenuated by the administration of cannabinoids are CYP substrates, and in Southeast Asia, but a formal assess-
mitragynine 2 mg/L.13 In rats, acute reports have documented the adul- ment of its benefits is lacking.13
mitragynine administration induced teration of illegal or unregulated prod- A case report described the use of
locomotor sensitization and anxioly- ucts of abuse with opioids, MDMA, kratom in Thailand to treat 2 people
sis and impaired passive avoidance and synthetic cannabinoids.20,21 Other addicted to heroin.10 Methadone was
learning, memory consolidation, and CYP substrates, including caffein- ineffective for 1 patient, and metha-
retrieval.7 After 14 days of intraperi- ated soda, codeine, and dextrometho- done was not routinely available for
toneal mitragynine 30 mg/kg, severe rphan, are sometimes used together the other patient. Both patients felt
somatic withdrawal signs (paw trem- with kratom in the “4 × 100” prepara- that kratom was a suitable mainte-
or, shakes, piloerection, teeth chat- tion as well as the CYP 2D6 inhibitor nance medication, though 1 patient
tering) and anxiety occurred 12–24 diphenhydramine.9 The pharmacoki- felt that methadone would have been
hours after withholding a mitragy- netics of mitragynine in rats suggest better.
nine dose. The rats exhibited hyper- a time to maximum concentration of The best data on the use of kratom
sensitivity to small challenge doses 1.2–1.8 hours, an elimination half-life to manage drug withdrawal symp-
of mitragynine (3 mg/kg) for up to 14 of 3.9–9.4 hours, and a volume of dis- toms comes from a survey of 136 kra-
days after withholding therapy. Fur- tribution of 37.9–89.5 L/kg.9,13 tom users in Malaysia.25 Overall, 90%
thermore, rats treated with 28 days were using kratom to reduce addiction
of intraperitoneal mitragynine (1, 5, Published reports to other drugs and 84% to ameliorate
or 10 mg/kg) had significant impair- There are no published human the effects of withdrawal from opioid
ment of learning and memory with pharmacologic or drug interaction addiction. Before turning to kratom,
all 3 doses on days 1, 3, and 7 of with- studies on kratom or mitragynine,2,9,10,13 77% of subjects had used cannabis
drawal. These impairments were in making it virtually impossible to fully and 53% had used heroin. When giv-
en urine drug screens, 46%, 10%, 4%, phosphokinase concentrations. Ther- which led to the conclusion that the
and 1% of kratom users tested posi- apy included i.v. fluids (43%), benzo- cause of death was an accidental
tive for concomitant use of cannabis, diazepines (29%) or other sedatives overdose of kratom.27 In total, FDA
heroin, amphetamine, and metham- (14%), antiemetics (7%), antihyper- is aware of 36 deaths associated with
phetamine, respectively. Information tensives (7%), and oxygen (7%).27 the use of kratom-containing prod-
on the frequency of use of these other An assessment of calls to U.S. poi- ucts and of reports that kratom has
drugs of abuse was not collected. On son control centers from 2010 through been laced with other opioids (e.g,
average, 3.2 glasses of kratom were 2015 revealed 660 reports of kratom hydrocodone).28
consumed daily, and the average du- exposure.6 The volume of kratom- Three reported cases of seizures
ration of kratom use was 3.5 years. The related calls increased from 26 in 2010 due to kratom were reported, but 2
benefits of continuing kratom were to 263 calls in 2015, with 75% of calls cases involved the concomitant inges-
self-reported and included reduced placed by healthcare providers. Sixty- tion of an additional drug (modinafil
withdrawal symptoms, increased five percent of calls were for patients or Datura stramonium).29 D. stramo-
work capacity, and increased energy. exposed solely to kratom, 72% of pa- nium (jimsonweed), a plant native
Loss of weight, hyperpigmentation of tients were male, and the median to Mexico, is purported to have anal-
the face, dehydration, and constipa- age was 28 years. The major adverse gesic, antispasmotic, and hallucino-
tion were commonly reported adverse effects included tachycardia (25%), genic effects. In one case, the patient
effects. However, 78% of patients re- agitation or irritability (24%), drowsi- lost consciousness 30 minutes after
ported trying to stop using kratom in ness (19%), nausea (15%), and hyper- drinking kratom and D. stramonium
the past, though all had failed.25 tension (12%). Outcomes were more tea and began seizing at home and an
severe when kratom was combined hour after arrival in the emergency de-
Adverse effects with other drugs. Twenty-five percent partment. Lorazepam and phenytoin
Relatively few cases of acute tox- of patients had minimal adverse signs were administered, and the patient
icity with kratom have been reported or symptoms, 42% had moderately recovered and was discharged. His
in the Western literature, and many of severe adverse effects, and 7% experi- urine mitragynine concentration was
the cases are confounded by the con- enced life-threatening adverse effects 167 ng/mL.29
comitant consumption of other drugs. or residual disability. No outcome was Kratom has been reported to cause
It cannot be determined definitively reported in 26% of cases. One death hypothyroidism in a single case report
if the paucity of reports is because was reported in a patient taking par- and intrahepatic cholestasis in an-
of superior safety versus other drugs oxetine and lamotrigine in addition to other, with only the latter having basic
of abuse or because kratom use is kratom.6 animal data to support the event.2,18
not recognized by clinicians and law Nine deaths were reported af-
enforcement. ter the ingestion of krypton, a Addiction to kratom
In an assessment of calls to poison product containing kratom and There are case reports of patients
control center in Texas from 1998 to o-desmethyltramadol.2 Blood lev- in Europe and the United States be-
September 2013, 14 kratom-related els of mitragynine (0.02–0.18 mg/g) coming physically dependent or ad-
cases were reported, all of which oc- and o-desmethyltramadol (0.4–4.3 dicted to kratom.9 In each case, the
curred from 2009 through 2013.26 Eight mg/g) were identified in these cases. individual exhibited tolerance to the
of the cases involved kratom alone, Another death reported resulted effects of kratom and showed overt
and the rest involved the concomitant from the concomitant use of mi- symptoms of withdrawal when kra-
use of other substances (wild dagga, tragynine and propylhexedrine.2 In tom was discontinued. Symptoms in-
wormwood, alprazolam, synthetic Texas, a death attributable to kra- cluded irritability, dysphoria, nausea,
cannabinoid, tryptamine, alcohol, tom was included in a news report diarrhea, hypertension, insomnia, rhi-
and methamphetamine). Eighty-six in February 2013, but specific details norrhea, myalgia, and arthralgia.9
percent of patients were treated in a of the case were not given.26 Anoth- Much of the data on the toler-
healthcare facility and 14% at home. er death occurred in a middle-aged ance and withdrawal associated with
Overall, 29%, 36%, and 7% had mild, man who was found dead at home.27 kratom comes from Southeast Asia.
moderate, and major adverse effects, An autopsy revealed no significant In 1975, 30 kratom-addicted people
respectively; 28% of people were un- pathological findings, and drug in Thailand were studied.14 Ninety
able to be assessed for adverse-effect screening revealed normal concentra- percent of users were 30–70 years
severity. The most common adverse tions of zopiclone, citalopram, and la- old (though 73% became addicted
effects included tachycardia, hyper- motrigine. However, serum concentra- at 20–39 years), 97% were male, 87%
tension, agitation, nausea, vomiting, tions of mitragynine (1.06 mg/L) and were married, and 63% were middle
confusion, tremor, and diaphoresis. 7-hydroxymitragynine (0.15 mg/L) class. The people chewed the fresh
One subject had elevated creatinine were also found during the autopsy, leaf or ingested the crushed dried
leaf 3–10 times per day and followed or peer pressure, and 15% used kratom as destructive socially and financially
this consumption by drinking warm to wean themselves from illicit drugs as heroin or opium addiction but that
water (40%) or hot coffee (60%). The and alcohol. Eighty-nine percent of kratom was an addictive substance.31
initial dose was ~3 leaves daily but subjects tried to abstain from kratom The following is FDA’s position on
grew to 10–20 leaves daily in 40% of in the past, but all had relapsed. Physi- kratom28:
people and to 21–30 leaves daily in cal withdrawal symptoms in those
37% of people. People began chew- who tried to quit included insomnia, It’s very troubling to the FDA that
ing the leaves to overcome fatigue and anorexia, nausea, vomiting, diarrhea, patients believe they can use
weariness and increased the number myalgia, muscle spasms or tremor, kratom to treat opioid withdrawal
of leaves ingested over time to satisfy shakiness, lacrimation, rhinorrhea, symptoms. The FDA is devoted to
their addiction. People reported an and hot flashes. About 65% of people expanding the development and
onset of action of 5–10 minutes with experienced mild physical withdrawal use of medical therapy to assist
feelings of increased strength, vitality, symptoms, and 35% had moderate-to- in the treatment of opioid use
and happiness. Periodic consumption severe symptoms. These withdrawal disorder. However, an important
throughout the day allowed them to symptoms lasted for up to 3 days in part of our commitment to this
work very long hours in the fields or in 64% of subjects but longer than 3 effort means making sure patients
the sun with less achiness and fatigue. days in 36% of subjects. Psychologi- have access to treatments that are
Anorexia, weight loss, insomnia, xe- cal symptoms of withdrawal included proven to be safe and effective.
rostomia, constipation, ptosis, black anxiousness, anhedonia, restlessness, There is no reliable evidence to
small stools, darkening of the skin on anger, and tension. Seventy-three per- support the use of kratom as a
the cheeks, frequent micturition, and cent of subjects experienced multiple treatment for opioid use disorder.
limited sexual desire were commonly psychological withdrawal symptoms. Patients addicted to opioids are
reported. Five people reported devel- Those who consumed more than 3 using kratom without dependable
oping delusions, hallucinations, and glasses of juice daily (odds ratio [OR], instructions for use and more
confusion, though 2 of them were 7.05; 95% confidence interval [CI], importantly, without consultation
using other drugs (amphetamines, 4.09–12.13) or used kratom 3 or more with a licensed health care pro-
heroin, and alcohol). One patient re- times daily (OR, 5.19; 95% CI, 3.02– vider about the product’s dangers,
ported having convulsions. Withdraw- 8.92) were 7 and 5 times more likely, potential side effects or interac-
al symptoms included hostility, tear- respectively, to report severe depen- tions with other drugs.
fulness, rhinorrhea, inability to work, dence than those who consumed less
arthralgia and myalgia, and “jerky mo- kratom.30 Treatment of adverse events
tions” of the limbs.14 In 2015, another study assessed and withdrawal
In 2014, a study was conducted in the social functioning of the same 293 Table 1 summarizes the adverse
Malaysia among 293 male kratom us- Malysian kratom users.31 None of the events and withdrawal symptoms
ers (mean age, 29 years; 58% single; kratom users endured any medical reported with kratom and some po-
66% employed).29 Thirty-six percent problems requiring hospitalization tential treatments.2,6,9,13,20,21,24-34 While
were former users of other illicit drugs, directly related to kratom use, and adverse events that coincide with opi-
and half began using kratom at age none felt like they needed treatment oids can be theoretically treated with
11–21 years. The average frequency of for their kratom use during the prior naloxone, there are nonopioid mech-
use was 3.5 times daily. In Malaysia, 30 days. None of the respondents had anisms for symptoms such as con-
kratom is consumed as a fresh used other illicit drugs in the prior 30 stipation and nausea and vomiting,
squeezed juice; 13% of study partici- days, which was confirmed by urine suggesting that other therapies would
pants consumed 0.5–1.5 glasses daily, toxicology screening. Thirteen per- be superior or needed adjunctively.
42% consumed 2–3 glasses daily, and cent of subjects reported depressive Seizures are not commonly associated
44% consumed more than 3 glasses symptoms, 14% reported anxiety, with opioids but can occur at high
daily. One glass of kratom contained 17% reported trouble concentrating doses, and naloxone can reverse those
350 mL of kratom juice given alone or or remembering, 6% reported violent effects.32 However, seizures are also as-
mixed with caffeinated soda, dextro- behavior, and fewer than 1% reported sociated with overdoses of stimulants,
methorphan, or nimetazepam (a ben- hallucinations or attempted suicide which are not amenable to naloxone
zodiazepine). The mitragynine con- in the prior 30 days. While subjects therapy but may be treated with ben-
tent per glass averaged 79 mg (range, felt they could control their addic- zodiazepines and other anticonvul-
75–83 mg). The majority of people tion, none were abstinent, and only sants.20,21,29 The benefits of giving nal-
used kratom to enhance their ability 18% went more than 3 months before oxone need to be weighed against the
to work long hours with less pain and relapsing. The subjects and research- withdrawal symptoms the patient will
fatigue, 31% began use out of curiosity ers believed that kratom use was not experience. Similarly, the value of add-
Seizures Benzodiazepines, naloxone, Joint and muscle pain Nonopioid pain relievers
anticonvulsants
Sedation Naloxone ... ...
a
Treatments for adverse events and withdrawal are general treatment suggestions and were not studied in any clinical trials of kratom.
ing an a-2 antagonist to ameliorate Natural Standard Research Collabora- Sci. 2012; 57:1168-80.
adverse effects via that mechanism is tion. J Diet Suppl. 2013; 10:152-70. 12. National Institute on Drug Abuse.
3. Nelson S. Dozens of congressmen ask Monitoring the Future Study: trends
unknown.20,21 An a-2 agonist has been
DEA not to ban Kratom next week in prevalence of various drugs. www.
used to treat patients trying to achieve (September 23, 2016). www.usnews. drugabuse.gov/trends-statistics/
kratom abstinence, a strategy that has com/news/articles/2016-09-23/45- monitoring-future/monitoring-
been helpful with other opioids as congressmen-ask-dea-not-to-ban- future-study-trends-in-prevalence-
well.17 kratom-next-week (accessed 2016 various-drugs (accessed 2016 Nov
Nov 17). 16).
In one patient, the use of dihydro-
4. Boodman E. DEA reconsidering its 13. Hassan Z, Muzaimi M, Navaratnam
codeine and lofexidine (an a-2 agonist) ban on the herbal supplement kra- V et al. From kratom to mitragynine
was used to attenuate the subjective tom (October 5, 2016). www.statnews. and its derivatives: physiological
and objective withdrawal phenomena, com/2016/10/05/kratom-ban-dea- and behavioural effects related to
which have been described as similar delay/ (accessed 2016 Nov 17). use, abuse, and addiction. Neurosci
5. Brown M. States ban kratom Biobehav Rev. 2013; 37:138-51.
to those experienced with other opi-
supplement over abuse worries (May 14. Suwanlert S. A study of kratom eaters
oids.33 In another patient, the combi- 20, 2016). www.usnews.com/news/ in Thailand. Bull Narc. 1975; 27(3):21-
nation of doxepin and diazepam was us/articles/2016-05-20/states-ban- 7.
used to treat a patient dependent on kratom-supplement-over-abuse- 15. Lydecker AG, Sharma A, McCurdy
both alcohol and kratom.34 worries (accessed 2016 Nov 16). CR et al. Suspected adulteration of
6. Anwar M, Law R, Schier J. Notes from commercial kratom products with
Conclusion the field: kratom (Mitragyna spe- 7-hydroxymitragynine. J Med Toxicol.
ciosa) exposures reported to poison 2016; 12:341-9.
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Disclosures 2016 Nov 17). 18. Sabetghadam A, Ramanathan S,
9. Prozialeck WC, Jivan JK, Andurkar SV. Sasidharan S et al. Subchronic expo-
The author has declared no potential con-
Pharmacology of kratom: an emerg- sure to mitragynine, the principle al-
flicts of interest.
ing botanical agent with stimulant, kaloid of Mitragyna speciosa, in rats. J
analgesic and opioid-like effects. J Am Ethnopharmacol. 2013; 146:815-23.
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