On February 6, 2018, a statement from US
Food and Drug Administration (FDA) Commissioner Scott Gottlieb, MD, reiterated
the FDA’s concerns about the supposed dangers of leaf preparations of the
Southeast Asian tree kratom (Mitragyna
speciosa, Rubiaceae).1
“Kratom should not be used to treat medical
conditions, nor should it be used as an alternative to prescription opioids,”
the statement reads. “There is no evidence to indicate that kratom is safe or
effective for any medical use.”1
Kratom is a tropical, evergreen,
broad-leafed tree that can grow to 25 meters (82 feet) tall. It is native to
peninsular Thailand, southeastern Myanmar, Malaysia, Borneo, Sumatra, the
Philippines, and New Guinea. The species belongs to the madder (Rubiaceae)
family, a large plant family that also includes coffee (Coffea arabica, C. canephora). The name “kratom” originates from
Thailand and likely derives from the Sanskrit kadam, a name that refers to Neolamarckia
cadamba (Rubiaceae), a widespread tree that is sacred in Hinduism. Similar
names are used for various related tree species in the region.2
Preparations of kratom leaves have been
used for centuries in Southeast Asia for a wide range of purposes, including to
treat cough, diarrhea, and diabetes; to manage pain and opioid withdrawal; and
to stave off fatigue. Leaf preparations of the plant, including powders and
teas, act on the central nervous system. At low doses, they can produce
stimulant effects, while higher doses often produce sedative and intoxicating
effects.2
In a previous FDA statement from November
14, 2017, in which the FDA urged consumers not to use kratom or any compounds
from the plant, the FDA claimed it was “aware of reports of 36 deaths
associated with the use of kratom-containing products.”3 By the time
of the February statement, that number had increased to 44 deaths. Also on
February 6, the FDA released reports of the 36 deaths previously noted in
November (though only 33 appear to include any data) and stated it would release
the remaining reports soon.1,4-6
Reports of the 36 deaths “underscore the
serious and sometimes deadly risks of using kratom and the potential
interactions associated with this drug,” according to the FDA.1 But,
in most, if not all, of these cases, kratom’s involvement is circumstantial,
and it is difficult or impossible to establish a causal relationship between
kratom and the deaths. Many of these cases involved other substances and
decedents who had a history of misusing substances other than kratom.4-6
To the FDA, though, this raises concerns that potentially lethal interactions may
occur when kratom is used with other substances.7
“If you were taking an FDA-approved opioid,
you would know exactly what other drugs you’re not supposed to be taking with
it,” an FDA spokesperson was quoted as saying. “We don’t have that with kratom —
nobody does.”7
Among the 36 cases was someone who died by
suicide and struggled with bipolar disorder and depression; another who was
murdered by a gunshot to the chest; and a third person with nine other
substances in his system who fell from a window, suffered a broken arm, and
refused medical treatment.4-6 Also included are nine deaths that
occurred in Sweden between 2009 and 2010 that were linked to a product called
“Krypton.” It has been documented that kratom-containing products sold under
the name “Krypton” were also found to contain caffeine and O-desmethyltramadol, which is the main active metabolite of the
prescription opioid tramadol and is a significantly more potent agonist
(activator) of mu-opioid receptors (a class of opioid receptors) than tramadol.2,4-6
The FDA identified one case that it stated
“was of particular concern. This individual had no known historical or
toxicologic evidence of opioid use, except for kratom.” However, because the
February 6, 2018, FDA statement does
not include the case ID number, it is unclear to which case report the FDA is
referring, or whether the report for this case is even included among those
that were released.1
It is possible, or perhaps probable, that
the FDA was referring to the case of Matthew Dana. In September 2017, Franklin
County (New York) Coroner Shawn Stuart ruled that the official cause of death
of Dana, a police sergeant from Tupper Lake, New York, who died the previous
month, was hemorrhagic pulmonary edema from an accidental overdose of
mitragynine, one of the main chemical constituents of kratom. Dana reportedly
had an extremely high amount of mitragynine in his blood (3,500 nanograms per
milliliter) when he died, but no other foreign substances.8 “It’s
possible that we see more people die from drinking too much water every year.
Or taking too much Tylenol,” Stuart was quoted as saying. “All we’re doing is
reporting that in this case, kratom was the cause of death.”7 Notably,
this case may contradict the frequently mentioned claim that, at high doses,
kratom induces vomiting, thus making it difficult to overdose.2
Eight of the deaths associated with kratom
came from the Center for Food Safety and Applied Nutrition (CFSAN) Adverse
Event Reporting System (CAERS), while 25 came from the FDA Adverse Event
Reporting System (FAERS).6 Notably, both the CAERS webpage and the
FAERS webpage include disclaimers about the limitations of the data.
The CAERS webpage states: “The adverse
event reports about a product and the total number of adverse event reports for
that product in CAERS only reflect information AS REPORTED and do not represent
any conclusion by FDA about whether the product actually caused the adverse
events. For any given report, there is no certainty that a suspected product
caused a reaction…. The event may have been related to a concurrent underlying
condition or activity or to co-consumption of another product, or it may have
simply occurred by chance at that time.”9
Likewise, the FAERS webpage states: “First,
there is no certainty that the reported event (adverse event or medication
error) was due to the product. FDA does not require that a causal relationship
between a product and event be proven, and reports do not always contain enough
detail to properly evaluate an event.”10
The significance of these data perhaps is obscured
further because the deaths occurred over at least a nine-year period, and many
occurred outside the United States.4-6 In the United States, kratom
started gaining popularity about 15 to 20 years ago.2 Now, an
estimated three million to five million Americans reportedly use kratom
regularly. Some kratom proponents argue that, considering this large number of
regular kratom consumers in the United States and that people in the plant’s
native range reportedly have used it safely for centuries,11 the
number of confirmed adverse events is seemingly very low, especially when
compared to those caused by other products/substances that are widely
available, including some that remain unscheduled under the Controlled
Substances Act (CSA) of 1970.6 Still, kratom is now banned in seven
states (Alabama, Arkansas, Indiana, Rhode Island, Tennessee, Vermont, and
Wisconsin) and Washington, DC, because of disagreements about its safety and
potential for misuse.2,12
FDA Calls Kratom an
‘Opioid’ But Ignores Relevant Scientific Data
The FDA’s February 6 statement also
describes how an unpublished computer model, which the FDA developed, was used to
simulate how kratom’s constituents “are structured at a molecular level, how
they may behave inside the body, and how they can potentially affect the
brain.” Using this model, FDA scientists evaluated the 25 most prevalent
compounds in kratom and concluded: “The model predicted that 22 (including
mitragynine) of the 25 compounds in kratom bind to mu-opioid receptors.”1
Some have questioned the timing of this
proclamation and claimed it may be another attempt to stigmatize kratom in
light of the current opioid epidemic. After all, the fact that kratom contains
opioid-like compounds is not news. This has been known since at least 1996 when
an in vivo study on mitragynine was published.13 The study showed
that mitragynine inhibited pain impulses in mice in a dose-dependent manner,
and these effects were reversed by naloxone, a semisynthetic opioid receptor
antagonist (i.e., an inhibitor of receptor activity) that is used to reverse
the effects of opioids in cases of overdose or postoperative sedation.14
A study published the following year showed that, through the opioid receptor,
mitragynine inhibited the movement of isolated guinea pig intestines, and these
effects also were reversed by naloxone.15
According to Oliver Grundmann, PhD, an
associate professor of medicinal chemistry at the University of Florida College
of Pharmacy who has co-authored a review of kratom pharmacology, the FDA’s
computer model considers only whether compounds bind to opioid receptors. “It
doesn’t take into consideration the data that we have obtained that distinguish
the kratom alkaloids mitragynine and
7-hydroxymitragynine from the classical opioids,” he said (oral communication,
June 4, 2018).
“We know from studies that have been
conducted by Christopher McCurdy at the University of Florida and Andrew
Kruegel at Columbia University that, after they bind to the opioid receptor,
the downstream activation and the downstream signaling are different for the
kratom alkaloids,” Grundmann continued.16,17
That is, the kratom alkaloids do not
recruit the beta-arrestin-2 protein that seems, at least partly, to influence respiratory
depression and opioid tolerance. Instead, the kratom alkaloids seem “biased”
toward the G-protein signaling pathway and therefore do not seem to cause
respiratory depression the way that other opioids, like morphine, do.2,16-18
“I understand that the FDA has safety
concerns, but what we have seen so far with kratom is that, for one, the
extracts are not being abused in the manner that heroin or morphine or some of
the other classical opioids are being abused,” Grundmann said. “They do not
seem to be injected. The kratom alkaloids
are not being extracted and used as pure substances, like fentanyl or heroin, and
then being injected. That is not happening.”
In addition, kratom alkaloids are partial
agonists of mu-opioid receptors, meaning their maximal effect is lower than that
of a full agonist like morphine. The pharmacological actions of the kratom
alkaloids more closely resemble those of buprenorphine than those of other,
more common opioids. Buprenorphine is a semisynthetic opioid that gradually has
been replacing methadone in opioid maintenance therapy for recovering opioid addicts.2,13,17-18
“I agree that we need a better system to
allow more traditional medicines or supplements, like kratom, to undergo
clinical trials,” Grundmann added. “There needs to be a pathway for such
supplements to be recognized and have a path forward through the regulatory
system to be recognized as potential treatment options.”
There are countless anecdotal reports of
people who claim to have benefitted from kratom. These people have used kratom
for a broad variety of purposes, including to cope with post-traumatic stress
disorder (PTSD), manage fibromyalgia and other chronic pain conditions, and recover
from alcoholism.2 The FDA, however, is concerned that people are
using kratom to self-medicate, without guidance from trained medical
professionals.1,19 Instead, the FDA urges kratom users to seek FDA-approved
medications, like methadone, which have undergone extensive review and for
which the FDA continuously tracks emerging safety data.1 Kratom
proponents argue that these medications often are inaccessible to the
uninsured, don’t work for everyone, and can be dangerous.7
Methadone, for example, causes about 5,000 overdose deaths per year.2
While there is hope about the potential for
new therapeutics derived from kratom to become safe and effective
pain-relievers and opioid recovery aids, there, unfortunately, seems to be
little financial incentive to investigate kratom constituents as new drugs. In
the United States, the only paths for kratom are as a new dietary ingredient
(NDI) or a botanical drug. For NDIs, the FDA requires adequate safety data
before the ingredient can be used in supplement products, but the FDA does not
believe this requirement has been met for kratom. In addition, no company has
submitted the necessary information for a kratom product to become a botanical
drug.2,13
Herbal products can be sold as long as no
disease-treatment claims are made and as long as the FDA does not consider them
unsafe. In kratom’s case, however, the FDA has formally recommended that the US
Drug Enforcement Administration (DEA) place the kratom alkaloids in Schedule I,
the most restrictive and punitive schedule, of the CSA.6,7,19 This,
in effect, would mean that possession and distribution of any kratom
preparations would be illegal and could result in criminal prosecution. In
August 2016, the DEA announced its intention to temporarily place the compounds
in Schedule I, but significant backlash from the public and members of Congress
convinced the DEA to withdraw that proposal (covered extensively in HerbalGram
issue 112).2 Now, the
DEA has hinted it could make a decision as early as summer 2018.19
“When the FDA comes to us and says a
certain substance should be a medicine, we are bound by that,” DEA spokesperson
Rusty Payne was quoted as saying. “When something is deemed a threat, we act.”7
On February 8, 2018, two days after the
FDA’s statement, Grundmann and eight other top kratom researchers submitted a
letter to DEA Acting Commissioner Robert W. Patterson and Counselor to the
President Kellyanne Conway in which they urged them to consider the effects
that banning kratom might have on current kratom users. “We believe strongly
that the current body of credible research on the actual effects of kratom
demonstrates that it is not dangerously addictive, nor is it similar to
‘narcotics like opioids’ with respect to ‘addiction’ and ‘death,’” the scientists
wrote. “It is our collective judgment that placing kratom into Schedule I will
potentially increase the number of deaths of Americans caused by opioids
because many people who have found kratom to be their lifeline away from strong
opioids will be vulnerable to resumption of that opioid use.”20
The scientists also claimed that failure to
consider possible negative consequences of scheduling would contradict the purpose
of the enactment of the CSA (to protect the safety of consumers) and that
scheduling would have a “profound and pervasive chilling effect” on additional kratom
research.20
Salmonella
Outbreak
On February 20, 2018, the US Centers for
Disease Control and Prevention (CDC) announced it was investigating a Salmonella outbreak it claimed was
linked to kratom. Twenty-eight people from 20 states were reported to have been
infected with a type (or serovar) of Salmonella
designated I 4,[5],12:b:-. Because whole genome sequencing revealed that Salmonella samples from the infected individuals
were closely related genetically, the CDC concluded the outbreak likely was caused
by a single source. Interviews with some infected people then led the CDC to
conclude that kratom was the likely source, even though no kratom products had
been shown to be contaminated at the time.21
A CDC spokesperson explained: “Health officials use questionnaires to ask sick
people in an outbreak what they ate in the week before illness. Eight out of 11
people interviewed reported kratom use, which is a much higher percentage than
would be expected for a healthy group of people. That epidemiologic evidence is
strong enough to link the outbreak to kratom. There were no other common foods
reported at such a higher than expected frequency. In outbreak investigations,
it is normal for some people to not report eating the suspected food item,
which could be for a variety of reasons. For instance, they might forget what
they ate, it isn’t specifically asked on the questionnaire, or they got
secondary transmission from caring for someone else who was sick.”22
The Salmonella
serovar in question reportedly has been found previously in humans, reptiles,
and fish, and even in spices and dried mushrooms. Furthermore, a CDC
spokesperson confirmed that “Salmonella I 4,[5],12:b:- is often seen in countries in
Southeast Asia [where kratom is native]. We have seen other outbreaks with this
serotype linked to other products, such as frozen shredded coconut and frozen
raw tuna.”22
On March 1, the CDC announced that 12 more people
from seven states had been infected with the Salmonella serovar in question, bringing the total to 40 people
from 27 states. Notably, analyses of leftover and unopened kratom products from
ill people in North Dakota and Utah confirmed that both samples were
contaminated with the serovar in question.21
Two weeks later, the CDC announced that 47
more people from 25 states had been added to the investigation, bringing the
total to 87 people from 35 states. Notably, analysis of kratom products from
retailers where ill people purchased kratom confirmed that samples were
contaminated with additional Salmonella serovars.
By the end of the investigation on May 24, 199 infected people had been
identified from 41 states. Implicated products were recalled, but the
investigation was not able to identify a single, common source of contaminated
kratom. The CDC warns that contaminated kratom products may still be available
for purchase or in people’s homes. No deaths were reported.21
A group of scientists suggested that, by
issuing its kratom import alerts several years ago, the FDA may have
inadvertently contributed to the Salmonella
outbreak, because these alerts significantly reduced the number of
available kratom products and thus forced some kratom users to turn to inferior
products.23 In 2012, the FDA issued an import alert notifying field
personnel that they could detain kratom-containing products listed in the alert
without physical inspection because these products were considered unapproved
and/or misbranded drugs. In February 2014, the FDA issued a separate import
alert regarding kratom-containing dietary supplements and bulk dietary
ingredients.24
“This Salmonella
contamination of kratom products underscores the need for responsible
manufacture of products, implementation of current Good Manufacturing Practices
(cGMPs) in compliance with the mandatory 2007 rule for dietary supplements, and
FDA enforcement, not scheduling [under the CSA],” Paula N. Brown, PhD, director
of applied research in biosciences at the British Columbia Institute of
Technology, was quoted as saying.23
Grundmann also said: “Whenever there is a
food contamination, that doesn’t mean that all of a sudden we would prohibit
lettuce as a food item, for example. That’s not happening. If we establish
quality control measures for herbal supplements the same way we do for our food
chain products, then we can ensure that products consistently meet necessary
standards and prevent contamination.”
—Connor Yearsley
Image credits (top to bottom): Kratom leaf. Photo courtesy of Ahmad Fuad Morad
FDA logo
Mitragynine chemical structure
Kratom flower. Photo courtesy of Ahmad Fuad Morad
CDC logo
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