Your body would never get used to the
perfect painkiller, says Susruta
Majumdar, a chemist at Memorial Sloan
Kettering Cancer Center. So unlike the
case with common opioids such as
morphine or Oxycontin, you would not
need to take ever-increasing doses to
relieve the same amount of pain. The
ideal analgesic would not have the high
risk of addiction, withdrawal or fatal
respiratory slowdowns that have turned
opioid abuse into a massive epidemic.
The holy grail of painkillers would not
induce the seductive euphoria of common
opioids or their less-pleasant side
effects like itching or constipation.
A painkiller with just one of these
properties would be great, but Majumdar
thinks he has stumbled onto a class of
chemicals that might have them all. They
are found in kratom, a plant that the
U.S. Drug Enforcement Administration
intends to effectively ban from the U.S.
in an emergency move as early as
September 30. Without legal access to
it, research on some of the most
promising leads for a better painkiller
may grind to a crawl.
Kratom comes from the
Mitragyna speciosa tree
native to parts of Southeast Asia, where
people chew the leaves for a light,
caffeine-like jolt of energy or as a
traditional medicine for ailments
ranging from diarrhea to pain. Kratom
has been illegal since 1943 in Thailand,
where it is believed to be addictive.
Case studies have suggested that
suddenly stopping regular kratom use may
lead to withdrawal symptoms—but they are
widely considered milder than those
associated with opioids.
Majumdar first learned about kratom
via a Web search a couple of years ago.
By then there were stories in the West
about how kratom tea could be used to
manage pain—and to mitigate brutal
opioid withdrawal. That caught
Majmundar’s attention, and he found
research from the 1970s that described
some of the basic biochemistry of
kratom’s two primary psychoactive
compounds, mitragynine and
7-hydroxymitragynine, as well as one
more molecule called mitragynine
pseudoindoxyl, which is produced when
kratom ferments. “We got excited because
the chemical structure is almost
completely unrelated to that of commonly
used opioids,” says Andras Varadi, a
colleague of Majumdar who is a medicinal
chemist at Columbia University and Sloan
Kettering.
When Majumdar and his team started
studying the compounds in the
laboratory, they realized all three
molecules were binding to the mu-opioid
receptor—one of three known kinds of
opioid receptors in the brain—in an
unconventional way. Think of this
receptor as the ignition to a “hybrid
car,” Varadi explains, and the opioids
that bind to it as keys. A typical
opioid such as morphine turns on the
“electric engine,” and that leads to a
desired effect like pain relief. But it
also starts up the “gas engine,” causing
negative side effects. The mitragynine
molecules from kratom seem to activate
mostly the “good” systems, leaving
behind the unwanted effects yet keeping
pain relief.
Scientists have been trying to
develop next-generation drugs with this
property. There is one candidate,
pharmaceutical company Trevena’s TRV130,
in clinical trials now. That’s part of
what makes kratom exciting to
researchers, says Laura Bohn, a
biochemist at the Scripps Research
Institute who was not involved with this
work. “The more chemical structures you
have [with this property] the more you
can say, ‘here’s the right features of
these, and let’s impart that into our
drug development.’”
Majumdar noticed that the
fermented-kratom compound mitragynine
pseudoindoxyl—unlike most other drugs in
development—also blocks off another
opioid receptor, the delta receptor.
“That’s when we got excited,” Majumdar
says. Past experiments have shown that
delta receptor blockers could reduce
morphine tolerance and withdrawal
symptoms in mice. “There were signs that
delta antagonism is good,” Majumdar
says. And if mitragynine pseudoindoxyl
could both block the delta receptor and
produce favorable behavior on the mu
receptor, Majumdar says it might be
better than any other pain drug science
is currently investigating.
In an attempt to find out about these
blocking capabilities Varadi injected
mice with mitragynine pseudoindoxyl
twice a day for a month. Then he checked
if they could feel pain, using
techniques such as putting them on a hot
plate. In such experiments morphine
usually loses its painkilling effects
after five days. But after 30 days on a
consistent dose of mitragynine
pseudoindoxyl, the mice still showed
numbness to pain. “It was the most
exciting experiment I’ve ever done,”
Varadi says. In other experiments Varadi
and Majumdar reported that the mice
exhibited few withdrawal symptoms from
mitragynine pseudoindoxyl—and they
displayed no indication that they
actually enjoyed taking the drug. “[This
is] early promise it’s nonaddictive,”
Majumdar says. His team reported its
findings in The Journal of Medicinal
Chemistry last month.
Varadi says his results indicate that
mitragynine pseudoindoxyl may have the
peculiar ability to both activate the mu
receptor—possibly making it a powerful
painkiller that also reduces addictive
and potentially deadly side effects—as
well as lower withdrawal and tolerance.
“It’s a double whammy,” Varadi says.
Although the kratom compounds have
yet to be clinically studied in humans,
Andrew Kruegel, a pharmacologist at
Columbia who was not involved in
Varadi’s study, says the results hold
promise for better designer painkillers.
“Those compounds alone may already be
superior to codeine and oxycodone. At a
minimum, if you can get rid of
respiratory [problems] then you can save
thousands of lives,” Kruegel says. “But
we can tweak their properties to make
them even better than the natural
starting point.” Or they would do so if
the research were able to legally
continue, he adds.
The DEA plans to place kratom and its
psychoactive ingredients in the agency’s
most restricted controlled substance
category, Schedule I, on September 30 at
the earliest. That would place it in the
same group as heroin, ecstasy and
marijuana. All Schedule I drugs are
supposed to have a high potential for
abuse and harm, and to have no medical
use.
Scientists can obtain a license to
study Schedule I drugs but they are hard
to acquire and significantly slow down
research, says Chris McCurdy, a kratom
researcher at the University of
Mississippi. “I don’t oppose it being
regulated, I just oppose Schedule I,” he
says. “That’s where the frustration
comes in, realizing you have to shut
everything down because we don’t have a
Schedule I license.”
At the moment, neither do several
other kratom researchers, including
Majumdar. “We’ll have to destroy all our
samples in the lab,” Kruegel says. The
DEA’s emergency scheduling of kratom
will expire after two years if the
agency does not move to make the
scheduling permanent. But for that to
happen, Kruegel thinks scientists will
likely need to show further proof that
kratom is medically useful. “That we’ll
have any progress in the next two years
is very unlikely,” he says.
Russ Baer, a spokesperson for the
DEA, says the reason for putting kratom
and its psychoactive ingredients in the
most restrictive drug category is to
protect public safety and stop misuse.
“Independent of the DEA, the Food and
Drug Administration has issued a number
of public health warnings and import
alerts, most recently about July 2016,
and concerns they have about kratom
representing a health risk,” he says.
“And it’s been on our radar for awhile
as a drug of concern.”
A DEA
announcement cited 15 kratom-related
deaths between 2014 and 2016, and there
have also been accounts of kratom being
misused. “One of my [research] partners
has treated people in the emergency room
who would dissolve and then inject
kratom extract,” says Ed Boyer, a
professor of emergency medicine at
University of Massachusetts Medical
School and a kratom researcher. Most of
these incidences of abuse probably
involved other substances as well, he
adds.
Some Kratom purchased in the U.S. has
been found to be adulterated with other
compounds, including common opioids like
hydrocodone. “People think they’re
getting kratom; they could be getting
anything,” says Kavita Babu, a
toxicologist at UMass Memorial Medical
Center who was not involved with
Majumdar’s study. “In terms of death, we
really only get into that issue when
it’s combined with other substances,”
says Alicia Lydecker, also a
toxicologist at UMass. She was not
involved in the study.
Mitragynine seems to be a fairly weak
drug on its own, Majumdar says. It is
about 55 times less potent than morphine
in terms of pain relief. “I did drink
kratom tea,” he says, “and I felt
nothing.” Another compound,
7-hydroxymitragynine, is about six times
more potent than morphine—but Majumdar
says it occurs in such small amounts in
the plant that it is probably not
responsible for most effects experienced
by consumers of unaltered, natural
kratom.
The DEA’s decision on kratom has even
begun to draw critical attention from
U.S. lawmakers. Rep. Mark Pocan (D–Wis.)
has urged Congress to sign a
letter asking the DEA to delay
making it a controlled substance. But
the impending ban has left an especially
bitter taste with many researchers who
feel there is already ample evidence the
plant has clear medical potential. “It
is frustrating,” Bohn says. “I totally
empathize with trying to prevent misuse,
but it has to be thoughtful and
protective. For us, [kratom] is a
valuable, valuable research tool.”