>>I'M CATHERINE LAWS WITH NCCIH
WELCOME TO LECTURE SERIES
>> WELCOME TO THE FIRST LECTURE
SERIES FOR THE SPRING 2021 AND
NCCIH INTEGRATIVE MEDICINE
RESEARCH LECTURE SERIES.
WE'RE PLEASED THAT
DR. CHRISTOPHER MCCURDY AND OUR
VIEWING AUDIENCE COULD JOIN US
TODAY.
SEVERAL KEY RESEARCH INTERESTS
TO NCCIH INCLUDING COMPLEMENTARY
INTEGRATIVE APPROACHES TO HELP
TREAT OPIOID MISUSE ADDICTION
AND SUPPORT RECOVERY, APPROACHES
TO ENHANCE THE MANAGEMENT OF
CHRONIC PAIN, WHICH IS
FREQUENTLY CO-MORBID WITH
PROBLEMS OF OPIATE USE DISORDER,
AND TO DEVELOP TOOLS, MODEL,
MEASURES AND METHODOLOGIES TO
ADVANCE THE SCIENTIFIC STUDY OF
NATURAL PRODUCTS.
YOU CAN FIND MANY OF THESE
TOPICS OUTLINED IN OUR FY FISCAL
YEARS 2021 TO 2025 STRATEGIC
PLAN.
AND I HOPE YOU WILL TAKE A LOOK
AT THAT.
NOW IT'S MY PLEASURE TO
INTRODUCE TODAY'S SPEAKER,
DR. CHRISTOPHER MCCURDY IS A
BROADLY TRAINED MEDICINAL
CHEMIST WHOSE RESEARCH FOCUSES
ON THE DESIGN, SYNTHESIS AND
DEVELOPMENT OF DRUGS TO TREAT
PAIN AND DRUG ABUSE.
HE RECEIVED HIS PH.D. IN ME
DIDDAL
MEDICINAL CHEMISTRY FROM
GEORGIA.
DR. MCCURDY IS CURRENTLY
PROFESSOR OF MEDICINAL CHEMISTRY
AND THE FRANK A. DUCKWORTH
EMINENT SCHOLAR CHAIR, DIRECTOR
OF THE UF TRANSLATIONAL DRUG
DEVELOPMENT CORE AT THE
UNIVERSITY OF FLORIDA.
FOR OVER 20 YEARS, MUCH OF HIS
RESEARCH HAS FOCUSED ON OPIOIDS,
NEUROPEPTIDE FF AND SIGMA
RECEPTOR LIGAND, PROBE DESIGN,
SYNTHESIS, PHARMACOLOGICAL
EVALUATION AND DEVELOPMENT.
MOST NOTABLY, HE HAS DEVELOPED A
PET MRI DOES GNOSTIC AGENT FOR
INDIVIDUALIZING THE ORIGINS OF
CHRONIC NEUROPATHIC PAIN BY
INTERACTING WITH SIGMA RECEPTORS
AT THE SITE OF NERVE DAMAGE.
DR. MCCURDY IS ALSO AN
INTERNATIONALLY RECOGNIZED
EXPERT ON KRAI KRATOM, UNDER
INVESTIGATION FOR OPIATE
WITHDRAWAL SYNDROME.
HE CURRENTLY SERVED AS PRESIDENT
FOR THE ASSOCIATION OF
PHARMACEUTICAL SCIENCE AND ALSO
SERVES AS CO-CHAIR OF THE
SPECIAL INTEREST GROUP ON DRUG
DESIGN AND DISCOVERY OF THE
INTERNATIONAL PHARMACEUTICAL
FEDERATION.
HE WAS ALSO PAST DIRECTOR OF THE
NIH COBRE CENTER FOR RESEARCH
EXCELLENCE IN NATURAL PRODUCTS
NEUROSCIENCE.
DR. MCCURDY RECEIVES NIH FUNDING
FROM NATIONAL INSTITUTE ON DRUG
ABUSE AND THE NATIONAL INSTITUTE
ON NEUROLOGICAL DISORDERS AND
STROKE.
AND WITH THAT, CHRIS, WE VERY
MUCH LOOK FORWARD TO YOUR
PRESENTATION, AND I'LL TURN THE
MIC OVER TO YOU.
>> THANK YOU FOR INVITING ME TO
PRESENT TODAY.
IT'S REALLY QUITE AN HONOR TO BE
ABLE TO SHARE SOME OF THE WORK
THAT WE'VE BEEN DOING WITH YOU.
UNFORTUNATELY I CAN'T SHARE ALL
OF IT BECAUSE WE'VE REALLY DONE
A TREMENDOUS AMOUNT OF WORK IN
THIS AREA DURING THE TIME THAT
WE'VE BEEN SORT OF SEQUESTERED
TO OUR LABS.
COVID HAS NOT BEEN A TERRIBLE
THING FOR US, WE'VE BEEN VERY
PRODUCTIVE AND A LOT OF THAT IS
THANKS TO THE SUPPORT WE RECEIVE
FROM NIH.
SO I'D LIKE TO JUST TELL YOU A
LITTLE BIT ABOUT OUR JOURNEY
WITH THIS PLANT, MITRAGYNA
SPECIOSA, PROPERLY KNOWN AS
KRATOM.
WE WILL GET THROUGH MANY OF THE
ALKALOIDS AND MANY OF THE
POTENTIAL THAT'S THERE BUT I'M
ONLY SCRATCHING THE SURFACE
TODAY JUST DUE TO TIME
RESTRAINTS, AND UNFORTUNATELY,
WE DON'T HAVE ANY HUMAN DATA TO
SHARE WITH YOU JUST YET, BUT
THERE WAS RECENTLY A
PHARMACOKINETICS PAPER PUBLISHED
FROM MARY PAINE'S GROUP FUNDED
OUT OF THIS INSTITUTE, AND I'VE
NOT DIGESTED THAT COMPLETELY SO
I'M NOT GOING TO SHARE THAT DATA
WITH YOU TODAY, BUT I AM AWARE
OF AND PARTICIPATING IN A FEW
OTHER TRIALS THAT ARE GOING ON
IN CANADA, AS WELL AS ONE FUNDED
BY THE FDA THAT WILL BE STARTED
SOMETIME THIS YEAR.
SO WE'LL HOPEFULLY COME BACK
NEXT YEAR OR IN A COUPLE YEARS
AND TELL YOU WHAT WE'VE LEARNED
IN TERMS OF HUMAN SAFETY AND
PHARMACOKINETICS AS WELL AS SOME
POTENTIAL IN THE HUMAN SETTING
FROM SOY ENS.
SCIENCE.
FIRST WE'RE GOING TO TALK MORE
ANECDOTALLY AND I'D LIKE TO
SHARE WITH YOU A LITTLE ON THE
TREE AND ITS ORIGIN.
MITRAGYNA SPECIOSA COMES FROM
THE RUBIACEAE FAMILY WHICH IS
ACTUALLY THE SAME FAMILY THE
COFFEE PLANT IS IN.
WE'VE HEARD THIS COMPARISON MANY
TIMES.
AND THE MOST COMMON FORM OF
CONSUMPTION OF MITRAGYNA
SPECIOSA IS AS A BREWED TEA.
AND I'LL SHOW YOU A LITTLE BIT
OF THAT IN A FEW MINUTES.
THE TREE IS NATIVELY FOUND IN
SOUTHEAST ASIA, PARTICULARLY
THAILAND AND MALAYSIA.
IT'S REALLY IN PENINSULAR
MALAYSIA AND THAILAND WHERE THIS
TREE IS BELIEVED TO HAVE
ORIGINATED FROM.
IT HAS SINCE SPREAD THROUGHOUT
MOST OF SOUTHEAST ASIA INTO IND
KNEE SLA, WHICH
INDONESIA, WHICH IS WHERE MOST
OF THE MATERIAL COMING INTO THE
UNITED STATES IS GROWN TO THIS
DAY.
IT IS REFERRED TO AS KRATOM.
IN THAILAND IT'S ACTUALLY CRAH
TOM AND IN MALAYSIA, IT'S BIAK
BIAK OR KETUM, SO THAT SORT OF
KRATOM KETUM SORT OF VIBE TO IT,
AND WE ALL HAVE HEARD MANY
PRONUNCIATIONS.
THAT'S ONE OF THE MOST FREQUENT
QUESTIONS I'M ASKED, IS WHAT'S
THE RIGHT PRONUNCIATION.
I THINK IT'S MORE LIKE TOMATOES
AND TOMATOES, SO AS LONG AS WE
KNOW WE'RE TALKING ABOUT THE
SAME THING, THAT'S THE MOST
IMPORTANT.
THERE HAVE BEEN REPORTED OVER 40
ALKALOIDS ISOLATED TO DATE.
WE'VE JUST ISOLATED A COUPLE NEW
ONES THAT WE'RE GETTING READY TO
PUBLISH THAT HAVEN'T BEEN
REPORTED BEFORE, SO I THINK THE
LIST KEEPS GROWING, NOT TOO
DIFFERENT FROM WHAT WE SEE IN
THE CANNABIS SPACE WHERE WE KEEP
FINDING MORE AND MORE
CANNABINOIDS.
THE GENUS NAME MITT MI TRA GUY MITRAGYNA COMES
FROM THE SHAPE OF THE LEAF.
IF YOU TURN THIS 90 DEGREES
CLOCKWISE, IT TAKES ON THE SHAPE
OF A BISHOP'S OR MITER'S HAT,
AND THAT'S WHERE THE SPECIES GOT
ITS NAME, FROM MITRAGYNA.
SO I WANT TO SHOW YOU WHAT THE
SORT OF TRADITIONAL VIEW OF THIS
IS AND HOW IT LOOKS IN ITS
NATIVE SETTING.
SO KRATOM HAS BEEN USED BY FIELD
WORKERS IN SOUTHEAST ASIA TO
RELIEVE PAIN, ALSO AS A STIM
LANTD TO
STIMULANT TO IMPROVE THEIR WORK
CAPACITY IN THE HOT TROPICAL
CLIMATE, AND ALSO WHEN THEY
WOULD RUN OUT OF OPIUM, THOSE
THAT USED OPIUM, THEY WOULD USE
THIS IN A LITTLE BIT HIGHER
DOSES TO HELP REDUCE OPIOID
WITHDRAWAL.
AND THAT'S REALLY WHERE WE GOT
INTERESTED IN THIS PROJECT.
NOT JUST THE PAIN ASPECT, BUT
CAN WE SEE AN ALTERNATIVE IN
HELPING WITH OPIOID USE
DISORDERS OR EVEN OPIOID
WITHDRAWAL SYNDROME.
RECENTLY THERE'S BEEN SOME
REPORTS THAT POLYDRUG USER,
PARTICULARLY THOSE USING OPIATES
AND METHAMPHETAMINE, ARE
INTAKING KRATOM TO REALLY REDUCE
THEIR USE.
OF COURSE THIS IS INTERESTING
BECAUSE WE HAVE NOTHING TO
REALLY COMBAT METHAMPHETAMINE OR
COCAINE USE DISORDER EITHER.
SO THIS IS ANOTHER AREA WE'VE
KIND OF JUMPED INTO A LITTLE
BIT.
THE PREDOMINANT ACTIVE
INGREDIENT OR ACTIVE AGENT AT
LEAST THE THOUGHT TO BE ACTIVE
AGENT IN KRATOM IS MITRAGYNINE
THAT ACCOUNTS FOR ANYWHERE FROM
20 TO 66% OF THE TOTALING TOTAL ALKALOID
CONTENT.
I'LL TALK A LITTLE MORE ABOUT
THE TREES THEMSELVES IN A
MOMENT.
THIS IS THE STRUCTURE OF
MITRAGYNINE, AND MOST ALL OF THE
STRUCTURES IN THIS PLANT, ALL
THE ALKALOIDS HAVE THIS BASE
RING STRUCTURE.
THE SECOND THING IS THIS BOTTOM
PORTION OF THE MOLECULE, IF YOU
CAN SEE MY POINTER, WHAT WE CALL
THE BETA METHOXY ACRYLATE, WE'LL
ON THE BOTTOM LEFT-HAND SCREEN
IS THE TREE GROWING IN THE
NATIVE ENVIRONMENT IN THE
FLOWERING STATE.
WE'RE ONLY FOCUSING ON THE
LEAVES TODAY.
THE FLOWERS IS ANOTHER STORY.
AND MAYBE ANOTHER TIME.
THOSE LEAVES ARE HARVESTED FRESH
EACH DAY FROM THE TREE, THEY ARE
CUT WITH SCISSORS AND PUT INTO A
POT OF BOILING WATER, WHERE
THEY'RE BOILED FOR ANYWHERE FROM
2 TO 4 HOURS, USUALLY TWO TO
THREE HOURS MAXIMUM.
IT'S LADLED OUT AND PUT INTO
TRAVELING PACKAGES, WHICH YOU
CAN SEE DOWN AT THE BOTTOM RIGHT
CORNER THERE, EITHER IN PLASTIC
BAGGIES, WHICH IS A COMMON DRINK
CONTAINER IN MALAYSIA, OR IT'S
PUT INTO PLASTIC BOTTLES.
AND THEN I WANTED TO SHOW YOU
WHAT A STREETSIDE STAND LOOKS
LIKE, AND THAT'S PRETTY MUCH
WHAT YOU SEE THERE IN THE MIDDLE
OF THE SCREEN NEXT TO THE
MITRAGYNINE STRUCTURE.
THESE ARE NOT VERY HEAVILY
ADVERTISED.
IT'S ILLEGAL TO SELL THIS IN THE
PUBLIC IN MALAYSIA.
BUT IT'S NOT HARD TO FIND, AND
THE FINES FOR SELLING SUCH ARE
REALLY NOT PROHIBITIVE TO PEOPLE
DOING IT, BECAUSE THEY CAN MAKE
MORE MONEY SELLING.
MOST EVERY SINGLE HOUSE IN
MALAYSIA IN THIS AREA HAS A TREE
IN THEIR OWN PROPERTY.
IT'S LEGAL TO USE IF YOU GROW
YOUR OWN.
AND CONSUME YOUR OWN IN YOUR
HOUSEHOLD, BUT ALMOST EVERY
SINGLE HOUSE THAT WE ENCOUNTERED
HAD AT LEAST ONE TREE IN THE
YARD.
KRATOM USE IN THE UNITED STATES
IS A TOTALLY DIFFERENT STORY.
AND THIS IS WHAT WE SEE.
IT'S WIDELY AVAILABLE ON THE
INTERNET.
SMOKE AND VAPE SHOPS.
AND THIS DATA IS A LITTLE BIT
OLD NOW, BUT THE AMERICAN KRATOM
ASSOCIATION REPORTED BACK ABOUT
THREE YEARS AGO NOW THAT THERE
WAS ALMOST 2,000 METRIC TONS
EXPORTED INTO THE U.S. EVERY
MONTH.
AND SO IF WE DO A QUICK
CALCULATION ABOUT A TYPICAL DOSE
BEING 3 TO 5 GRAMS, IT SUGGESTS
THERE'S PROBABLY IN THE
NEIGHBORHOOD OF 15 MILLION USERS
IN THE UNITED STATES.
THERE HAVE BEEN SOME MORE
CONSERVATIVE REPORTS THAT HAVE
COME OUT RECENTLY THAT ACTUALLY
INDICATE THERE'S PROBABLY TWO TO
3 MILLION USERS.
BUT BASED ON TALKING WITH
VENDORS AND THE AMERICAN KRATOM
ASSOCIATION, I THINK THAT NUMBER
IS NORTH OF 10 MILLION FOR SURE.
THIS IS WHAT THE PRODUCTS LOOK
LIKE HERE.
WE'VE GOT CRUSHED LEAVES, WE'VE
GOT PHARMACEUTICALLY
ENCAPSULATED EXTRACTS AND
PRODUCT, WE'VE GOT ENERGY SHOTS,
AND THEN JUST FINALLY GROUND
POWDERS.
THIS IS ALL UNDER AN IMPORT BAN
FROM THE FDA, SO IT'S NOT EVEN
SUPPOSED TO BE COMING IN TO THE
COUNTRY.
YET MOST OF IT COMES IN THE
COUNTRY UNDER THE GUISE OF
SODIUM ALGINATE OR SEA WE'D, WEED, A
FOOD THICKENING AGENT USED QUITE
COMMONLY IN THE CULINARY
INDUSTRY, SO IT COMES IN AS A
GREEN POWDER, IT LOOKS JUST LIKE
SODIUM ALGINATE AS WELL, AND SO
IT'S NO SURPRISE THAT MUCH OF
IT'S GETTING THROUGH UNDETECTED.
AND IN SOME CASES, IT LITERALLY
COMES IN UNDER WET SEAWEED, AND
THAT'S BEEN A PROBLEM WITH
SALMONELLA AND OTHER ISSUES THAT
HAVE LED TO SOME RECALLS.
SO WHAT ABOUT KRATOM AND
MITRAGYNINE?
WE'RE GOING TO FOCUS ON
MITRAGYNINE, IT'S THE MOST
ABUNDANT ALKALOID IN THE PLANT
SO THE MOST EASILY EXTRACTED,
PURIFIED AND STUDIED.
WE KNOW THAT VERY FEW DEATHS ARE
ATTRIBUTABLE TO A KRATOM PRODUCT
ALONE.
AND EVEN THOSE THAT ARE
ATTRIBUTED TO KRATOM ALONE,
THERE COULD BE EXTREME
CIRCUMSTANCES.
ONE IN TERMS OF OVERDOSING OR
VERY HIGH DOSES, AND I'LL TALK
ABOUT THAT AT THE VERY END OF
THE TALK.
OR IT COULD BE ADULT RATED WITH
UNKNOWN SYNTHETIC COMPOUNDS.
WE'VE ALSO REPORTED SOME ADULT
RANGE OF MOTION OF KRATOM WITH
OXYCODONE AND MORPHINE THAT'S
BEEN AVAILABLE IN THE
MARKETPLACE.
AND WHY SOMEONE WOULD SPEND THE
MONEY TO GO THROUGH AND PUT A
MORE EXPENSIVE OPIATE INTO A
PRODUCT THAT'S VERY INEXPENSIVE
IS SOMETHING JUST SEEMING TO ME
TO BE NEFARIOUS AND SINISTER.
BUT IT HAPPENS.
MITRAGYNINE, WE KNOW IS A
PARTIAL MU OPIOID AGONIST.
IT CAUSES ABOUT 40% MAXIMAL
EFFECT IN G PROTEIN ACTIVATION,
AND THE EXCITEMENT ABOUT IT WAS
THAT IT'S ALSO A BIASED AGONIST.
IN OTHER WORDS, IT SIGNALS ONLY
THROUGH THE G PROTEIN MECHANISM,
IT DOESN'T RECRUIT BETA
ARRESTIN.
WHY IS THAT IMPORTANT?
A LOT OF MOLECULES ARE UNDER
INVESTIGATION AND DEVELOPMENT AS
OPIOIDS WITH LOW RESPIRATORY
DEPRESSIVE AND CONS CONSTIPATION
EFFECTS BECAUSE IT'S BELIEVED
THAT NOT RECRUITING BETA
ARRESTIN ACTUALLY PUSHES AWAY
SOME OF THE LIABILITIES AND SIDE
EFFECTS.
SO A LOT OF THAT WORK FIRST CAME
OUT FROM A LAB AT COLUMBIA.
THEY'VE BEEN WORK HARD ON THIS
AS WELL ,
REALLY BEEN PRODUCING SOME GREAT
MATERIAL THAT WE TEND TO GO BACK
AND FORTH IN THE LITERATURE ON.
IT'S BEEN FUN.
WHAT ABOUT THE THERAPEUTIC
POTENTIAL, THOUGH?
WE'VE LOOKED AT IT PRIMARILY
FROM THE SOURCE OF AN OPIOID
DETOXIFICATION, SO HAVING THE
POTENTIAL TO REPLACE SEVERAL
MEDICATIONS.
I'M GOING TO SHOW YOU IT'S MUCH
MORE DISRUPTIVE THAN JUST OPIOID
ACTIVITY.
IN FACT, I THINK IT'S REALLY
SOMETHING THAT IS CAUSING A LOT
OF PROBLEMS ON HOW TO DEAL WITH
THIS ON MANY LEVELS, BECAUSE OF
THE FAIRLY DISRUPTIVE
PHARMACOLOGY THAT IT'S CAUSING.
IT HAS ADD ADRENERGIC ACTIVITIES AS
WELL AS OTHERS.
BUT IF YOU COMBINE ALL OF THOSE
INTO ONE PRODUCT, YOU MIGHT BE
ABLE TO IMPROVE MEDICATION
ADHERENCE AND COMPLETION OF
DETOXIFICATION.
WE ALSO HAVE LOOKED AT IT WITH
NIDA AS A POTENTIAL MEDICATION
ASSISTED THERAPY.
IT IS USED INFORMALLY TO REDUCE
OPIOID USE AND KRATOM WITHDRAWAL
IS MILD.
REALLY ON THE SUBJECTIVE OPIATE
WITHDRAWAL SCALE, IT'S IN THE
UPPER END OF MILD BUT IT'S NOT
IMMODERATE AND IT'S CERTAINLY
NOT INSEVERE, POLYDRUG USERS
REPORT KRATOM ALSO MAY REDUCE
METH AM FEET FEATHER MEAN
METHAMPHETAMINE USE.
THE BIGGEST PROBLEM TO STARTING
EXPLORING IS HAVING A
STANDARDIZED PRODUCT TO REALLY
GET INTO CLINICAL TRIALS AND
EVALUATE ANY OF THESE
THERAPEUTIC POTENTIALS.
THERE ARE OTHER THERAPEUTIC
POTENTIAL, I THINK, THAT CAN
COME OUT OF THIS IN TERMS OF
NOVEL ANALGESIA MEASURES AS WELL
AS POTENTIAL ANTIDEPRESSANTS AND
MOOD ELEVATING ELEMENTS.
AND I'LL DISSECT A LITTLE BIT OF
THAT AS WE GO.
ONE OF THE GREAT THINGS ABOUT
THE UNIVERSITY OF FLORIDA IS
THAT WE HAVE OUR AGRICULTURAL
SCHOOL AND OUR HEALTH SCIENCES
ALL BASED IN THE GAINESVILLE
CAMPUS, WHICH IS ONE OF ONLY
THREE UNIVERSITIES IN THE
COUNTRY THAT HAS THAT ABILITY,
AND SO I'VE REALLY BEEN
FORTUNATE TO FORM A GREAT
COLLABORATIVE RELATIONSHIP WITH
BRIAN PIERSON HERE, WHO IS
LOCATED IN OUR CAMPUS JUST
OUTSIDE OF ORLANDO, AND THESE
ARE KRATOM TREES THAT WE'RE
GROWING IN THAT CENTER.
WE HAVE ABOUT 100 TREES IN
GROUND, AND WE HAVE HUNDREDS,
CLOSE TO A THOUSAND TREES IN
GREENHOUSE, WHICH IF YOU CAN SEE
MY PICTURE WHERE I'M SPEAKING
AT, IT'S A GREENHOUSE FULL OF
TREES.
INTERESTINGLY ENOUGH, WE WILL TO
WAIT UNTIL WE HAD ENOUGH BIOMASS
TO REALLY ANALYZE THESE TREES
AND WHAT WE'VE LEARNED IS WE
HAVE THREE EXISTING CHEMO TYPES.
SO NOT DIFFERENT, AGAIN, FROM
CANNABIS, WHERE WE HAVE A HIGH
MITRAGYNINE-PRODUCING CHEMOTYPE,
AND WE HAVE A CHEMOTYPE THAT
PRODUCES ALMOST NO MITRAGYNINE
AND THEN WE HAVE SOMETHING THAT
SEEMS TO BE IN BETWEEN.
WE'RE WORKING TO LOOK AT THE
BIOSYNTHETIC PATHWAYS WITHIN
THIS PLANT.
WE'RE ALSO WORKING WITH PLANT
GENETICISTS HERE AT THE
UNIVERSITY OF FLORIDA TO REALLY
START TO UNDERSTAND WHAT THE
DIFFERENCES ARE IN DOING DEEP
DIVE DNA BARCODING TO REALLY SEE
HOW CLOSELY RELATED THESE
DIFFERENT CHEMO TYPES ARE.
BUT ANYWAY, THAT BEING SAID,
IT'S BECAUSE OF THE INTEREST IN
TRYING TO GET A HOME GROWN
SPECIES SO THAT WE MIGHT BE ABLE
TO DEVELOP A PRODUCT THAT'S MORE
SIMILAR TO THE TRADITIONAL USE
FOR STUDY IN THE UNITED STATES
THAN HAVING TO RELY ON THESE
DRIED LEAF MATERIALS, WHICH BY
THE WAY UNDERGO POST HARVEST
OXIDATION AND SO YOU CAN IMAGINE
JUST THINKING ABOUT THE DRIED
LEAF VERSUS A FRESH LEAF, YOU'VE
GOT OXIDATIVE CHEMISTRIES THAT
HAVE TAKEN PLACE AND MANY TIMES
HAVE CHANGED THE COMPOSITION OF
THE ALKALOIDAL CONTENT, AND
WE'LL TALK A LITTLE BIT ABOUT
THAT AS WELL.
SO WE'VE ISOLATED MORE THAN THIS
NOW, BUT WE'VE DEFINITELY GOTTEN
ALL OF THE MAJOR ALKALOIDS OUT
OF THE PLANT, AND WE'VE GOTTEN
MANY OF THE MINOR ALKALOIDS OUT
AS WELL, AND WE'VE LEARNED A
TREMENDOUS AMOUNT ABOUT THESE.
WE'VE BEEN ABLE TO HAVE THE
LUXURY OF SCREENING EACH OF
THESE COMPOUNDS THROUGH A DRUG
TARGET PANEL AND WE'VE LEARNED A
LOT.
AND I'LL SHARE A COUPLE OF THOSE
WITH YOU, BUT NOT ALL OF THEM.
AS WE GO THROUGH THIS.
I'VE GROUPED THESE COMPOUNDS
MORE OR LESS, THESE 12 OVER
HERE, THAT ARE NATURALLY
OCCURRING IN THE PLANT, AND THEN
THE THREE ON THE RIGHT SIDE OF
THE SCREEN ARE ONES WE'VE
SYNTHESIZED TO HAVE IN LARGE
ENOUGH QUANTITY.
7 HYDROXYMITRAGYNINE, THE ONE AT
THE TOP RIGHT OF THE SCREEN, IS
THE ONE THAT'S ATTRACTED THE
SECOND MOST AMOUNT OF ATTENTION
BESIDES MITRAGYNINE.
WE DO KNOW THAT IT IS A
METABOLITE.
IT IS A METABOLITE THAT CAN BE
FORMED IN THE INTESTINE AND IN
THE LIVER.
I'LL SHOW YOU A LITTLE DATA ON
THAT.
AND WE ALSO KNOW THAT IT CAN BE
FORMED UPON DRYING OF THE
LEAVES.
SO WE DO NOT BELIEVE THAT IT
ACTUALLY EXISTS IN THE TREE IN
FRESH LEAF SAMPLES FROM NOT ONLY
OUR GROWINGS BUT THE HARVEST AND
COLLABORATIONS WE'VE HAD IN PLA
LAY
MALAYSIA, WE'VE NOT DETECTED
7 HYDROXYMITRAGYNINE IN FRESH
LEAF MATERIAL.
THAT BECOMES A LITTLE MORE THAN
LATER ON.
AND THEN MYTH PSEUDOINDOXYL WAS
FIRS REPORTED AS A FUNGAL
ISOLATE AND A VERY APPROPRIATE
MU OPIOID AGONIST, AND WE WANTED
TO SYNTHESIZE THAT.
YOU CAN SIBT SIZE SYNTHESIZE THAT FROM TH E
7 HYDROXYCOMPOUND WITH A
CLINICAL ARRANGEMENT AND WE CAN
NOW AFFORD THAT IN LARGE ENOUGH
MATERIALS AND QUANTITIES TO
STUDY AS WELL AS SOME OF OUR
COLLABORATORS OR COMPETITORS
HAVE BEEN DOING.
BUT I MENTIONED EARLIER, YOU CAN
SEE IN ALL OF THESE MOLECULES,
WE HAVE THIS BETA METHOXY
ACCUMULATE STRUCTURE.
IT MAY BE TO BENEFIT THE PLANT,
IT'S PROBABLY NOT TO BENEFIT
HUMANS.
SO WE'VE BEEN LOOKING AT SOME OF
THAT AND UNDERSTANDING WHAT
MIGHT BE GOING ON THERE.
AND I WON'T GO INTO DETAILS ON
THAT JUST BECAUSE OF TIME.
IF YOU LOOK AT MITRAGYNINE, THE
MAJOR COMPOUND THREUR THROUGH THE
EUROFIN SCREEN, IT ONLY HITS --
INTERESTINGLY ENOUGH, -- ALONG
WITH THE DREADED HERG CHANNEL
AND THAT'S IT, 10 MICROMOLAR.
IF WE TAKE THOSE HITS WHERE
WE'VE DISPLACED 50% OF THE RADIO
LIGAND AND GO DOWN TO THE
SECONDARY SCREEN THAT 100
NANOMOLAR, THIS COMPOUND LOOKS
VERY BENIGN, IT DOESN'T SEEM TO
INTERACT WITH ANY TARGET.
WE DID GO AND CALCULATE OUT FULL
KI VALUES AT ALL OF THESE
TARGETS.
I'M ONLY GO TO SHOW YOU THE
OPIOID AND ALPHA ADRENERGIC
HERE.
AND IT'S NOT SPECTACULAR.
THE KI VALUE AT MU IS 136, KAPPA
ONE WITH IT SEVEN, IT DOESN'T
BIND TO DELTA, AND ITS
MICROMOLAR AFFINITY AT
ADRENERGIC RECEPTORS.
IT DOES HAVE PARTIAL AGONIST
EFFECT AT THE MU OPIOID AS WELL
AS THE ALPHA-1 AND ALPHA
2 ADRENERGIC RECEPTORS.
WE DO HAVE SOME IN VIVO EVIDENCE
TO SUGGEST THAT IT HAS ALPHA
2 ACTIVITY, AGONIST ACTIVITY AS
WELL, AND THAT'S THROUGH DRUG
DISCRIMINATION, WHICH I DON'T
HAVE TIME TO SHOW YOU TODAY
EITHER.
INTERESTINGLY ENOUGH, IF YOU
LOOK AT POISON CONTROL DATA,
KRATOM OVERDOSES RESEMBLE
STIMULANTS, NOT OPIOIDS.
SO THEY LOOK MUCH MORE LIKE A
STIM LAND
STIMULANT OVERDOSE, A COCAINE
OVERDOSE.
THERE IS NOT THE RESPIRATORY
DEPRESSION YOU WOULD EXPECT AS A
FREQUENT CALL-IN FOR POISON
CONTROL CENTERS OR SOME OF THE
OTHER ISSUES THAT YOU MIGHT SEE
WITH OPIATE OVERDOSE.
SO WE WANTED TO PROBE THAT A
LITTLE FURTHER AND WHAT WE WERE
ABLE TO DO IS LOOK AT HOT PLATE
ASSESSMENT, SO FOR ANALGESIA,
EVERYONE HAS FOCUSED ON
MITRAGYNINE HAVING OPIOID
ACTIVITY, OPIOID ACTIVITY.
SO INDEED, IF WE TAKE WILD TYPE
C57 BLACK 6 MICE AND GIVE THEM
100 MG PER KILOGRAM, WE CAN GET
100% ANALGESIC EFFICACY IN 10
MINUTES BY SUBCUTANEOUS
INJECTION OF MITRAGYNINE.
THAT LAST FOR S FOR ABOUT AN HOUR
UNTIL IT DISSIPATES OFF.
WHAT WE WANTED WANTED TO SEE WAS WHAT
ELSE WAS GOING ON, SO WE STUCK
SOME COMPOUND IN MU OPIOID
RECEPTOR KNOCKOUT MICE, AND 100
MG PER KILOGRAM, WHICH IS GREEN,
WE SEE NO EFFECT.
AT 125 MG PER KILOGRAM, WE SEE
MAYBE A BUMP OR A TREND UP AT 10
MINUTES, BUT REALLY NOTHING.
BUT WHEN WE JUMP TO 200 MG PER
KILOGRAM, WE START TO SEE AN
ALMOST 30 TO 40% SUSTAINED
ANALGESIA THAT DROPS OFF AGAIN
RIGHT AROUND AN HOUR AND WE
WANTED TO PROBE WHAT THAT WAS
DOING.
SO WE TOOK THOSE SAME MICE AND
WE TREATED THEM AHEAD OF TIME
AND YOU CAN SEE WE ALMOST
COMPLETELY ATTENUATE THAT
ANALGESIC EFFECT.
SO THERE APPEARS TO BE A MIXTURE
OF OPIOID AND ADRENERGIC
ACTIVITY, AND HOPEFULLY BY THE
END OF THIS, WE'LL CONVINCE YOU
THERE'S SOME SEROTONERGIC
ACTIVITY WITHIN THE PLANT AS
WELL AS ANALGESIC PROMISE.
SO THIS IS JUST
MITRAGYNINE-ISOLATED.
I LIKE TO SAY THAT KRATOM IS A
COMPLEX SYMPHONY ORCHESTRA OF
ALKALOIDS AND WHAT WE GENERALLY
TEND TO DO IN SCIENCE IS PLUCK
EACH INSTRUMENT OUT AND LISTEN
TO IT AT FULL BLAST AND FORGET
ABOUT THE SYMPHONY THAT IT
NATURALLY OCCURS IN.
SO PLEASE TAKE ALL OF THIS DATA
IN THAT SORT OF CONTEXT.
WE'RE LOOKING AT THESE THINGS ON
FULL BLAST.
THESE ARE BIG DOSES,
100 MILLIGRAMS PER KG TO ACHIEVE
THAT IN ACTUAL HUMAN TAKING
KRATOM JUST STRAIGHT, IT WOULD
MAKE THEM VOMIT LONG BEFORE THEY
WOULD GET TO THAT LEVEL OF
EFFICACY.
I DO ALWAYS LIKE TO POINT OUT
THAT THE MOST COMPREHENSIVE TO
DATE STUDY OF MITRAGYNINE ITSELF
WAS DONE BY MACKO AND HIS
COLLEAGUES AT SMITH KLINE AND
FRENCH BACK IN 1972.
THIS PUBLICATION CAME OUT, THEY
WERE REALLY PURSUING THIS AS A
NEW ANALGESIC TO PUT INTO THE
MARKETPLACE TO COMPETE WITH
CODEINE, BECAUSE THEY SAW THAT
THERE WERE SOME SIMILARITIES
PARTICULARLY IN THE
ANTINOCICEPTIVE AND ANTITUSSIVE
EFFECT TO CODEINE.
SO IT HAD LESS EFFECTS ON
GASTRIC MOTILITY AND PRESS
RESPIRATORY DEPRESSION.
NSAIDS TOOK OFF AND THEY DECIDED
TO ABANDON THIS PROJECT.
IF YOU'RE INTERESTED IN THE
HISTORY OF THIS, I WOULD HIGHLY
PREM
RECOMMEND PICKING UP THIS PAPER.
I DID MENTION
7 HYDROXYMITRAGYNINE.
I'VE BEEN WORKING IN OPIOID
CHEMISTRY SINCE MY POSTDOC AT
MINNESOTA FOR -- GOSH, IT'S BEEN
ALMOST 25-PLUS YEARS NOW, AND I
NEVER HAVE SEEN AN OPIOID SCREEN
THROUGH EUROFINS PANEL THAT CAME
BACK ONLY OPIOID AT 10
MICROMOLAR.
THIS COMPOUND AT 10 MICROMOLAR
ONLY HITS OPIOID RECEPTORS.
IT HITS ALL THREE MUDDLE TA MU DELTA AND
KAPPA, AND WHEN WE GOT THE
ACTUAL KI VALUE, YOU CAN SEE
THAT JUST THE SIMPLE EDITION OF
A HYDROXY GROUP IN THE
7 POSITION COMPLETELY CHANGES
THE THREE-DIMENSIONAL STRUCTURE
OF THE MOLECULE.
SO THIS IS WHY WE'VE BEEN SO
CONCERNED ABOUT THIS MOLECULE.
AS I SAID, WE DON'T SEE IT IN
THE FRESH LEAF MATERIAL.
WE DID SEE IT IN THE HIGH LEVELS
FOR A NUMBER OF YEARS AND
PRODUCTS THAT WE ANALYZED IN THE
U.S.
I'M HOPEFUL THAT THE RESEARCH
THAT WE PUBLISHED AND MANY OF
THE THINGS THAT WE'VE DONE HAVE
REALLY GUIDED THE COMMUNITY INTO
LOOKING FOR PRODUCTS THAT ARE
ALMOST NON-DETECTABLE TO
7 HYDROXY, AND WE'VE SEEN THAT
TREND IN A LOT OF THE
MARKETPLACE NOW.
SO MANY PRODUCTS THAT WE
ANALYZE, WE CAN'T DETECT
7 HYDROXYMITRAGYNINE IN THEM ANY
LONGER.
HOWEVER, THERE'S STILL SOME
PRODUCTS OUT THERE THAT HAVE
HIGH LEVEL.
AND THIS IS THE BUYER BEWARE
SORT OF THE ENVIRONMENT THAT
WE'RE IN.
YOU JUST DON'T KNOW WHAT YOU'RE
GETTING WHEN YOU BUY THESE
PRODUCTS AND THERE'S NO
REGULATION AROUND THEM, SO IT'S
VERY HARD TO TELL.
THERE'S NO STANDARDIZATION PUT
INTO PLACE, AND THIS IS
SOMETHING THAT WE REALLY AIM TO
LEARN AND AIM TO INFORM THE
PUBLIC OF WITH THEIR TAX DOLLARS
THAT HAVE BEEN PAYING FOR A LOT
OF THIS WORK.
SO WE LOOK AT WHAT IS THE
SUBSTITUTION OF MITRAGYNINE AND
7 HYDROXYMITRAGYNINE FOR
MORPHINE, AND SO WITH SCOTT
HEMBY'S HELP, WE PUBLISHED A
NICE PAPER IN 2019 WHERE WE
LOOKED AT SELF-ADMINISTRATION OF
MORPHINE AND WE GENERATE A
TYPICAL INVERTED UNITED U-SHAPED CURVE,
THE ANIMALS ARE EITHER MORE
DRUNK OR MORE IMPAIRED AND DON'T
TEND TO ADMINISTER MORE.
WHAT WE DID WITH THESE ANIMALS
ARE HABITUATE TODAY THAT IS THEN
SUBSTITUTING MITRAGYNINE ACROSS
VARIOUS CONCENTRATIONS AND WE
DON'T REALLY SEE ANY DIFFERENCE
FROM SALINE IN THOSE INFUSIONS,
BUT WHEN WE GIVE
7 HYDROXYMITRAGYNINE, IT READILY
SUBSTITUTES AND MORE POTENTLY
SUBSTITUTES FOR MORPHINE IN
SELF-ADMINISTRATION ASSAYS,
INDICATING THAT
7 HYDROXYMITRAGYNINE IS
POTENTIALLY AN ABUSABLE AND
ADDICTIVE COMPOUND WHEREAS
MITRAGYNINE MAY OR MAY NOT BE
ABUSABLE AND ADDICTIVE, WE'VE
PROBED THIS FURTHER, BUT
JONATHAN KATZ AND HIS COLLEAGUES
AT THE NATIONAL INSTITUTE ON
DRUG ABUSE'S INTRAMURAL PROGRAM
DEMONSTRATED THAT MITRAGYNINE
ALONE COULD BLOCK
SELF-ADMINISTRATION OF HEROIN IN
RATS, AND IT DOESN'T SEEM TO BE
ABLE TO BLOCK THE INFUSIONS OF
METHAMPHETAMINE.
SO IT WORKS FOR HEROIN BUT NOT
METHAMPHETAMINE, WHICH IS A
LITTLE BIT IN CONTRAST TO WHAT
WE SAW WITH THE HUMAN REPORTS
THAT ARE HUMANS CONSUMING
KRATOM, AND AGAIN, KRATOM IS
DIFFERENT THAN JUST MITRAGYNINE.
WE'RE SEEING A REDUCTION IN
METHAMPHETAMINE USE.
SO IF WE LOOK AT MITRAGYNINE
SUBCUTANEOUSLY DOSED, IT IS NOT
NEARLY AS POTENT AS MORPHINE AS
AN ANALGESIC IN THE WARM WATER
TAIL-WITHDRAWAL TEST BUT
7 HYDROXY IS DEFINITELY MORE
POTENT THAN THIS, THAN MORPHINE.
BUT WHAT WE FOUND TO BE VERY
INTERESTING IS -- AND THIS WAS
REPORTED IN THE MACKO PAPERBACK
IN 1972, IS THAT IF MITRAGYNINE
IS GIVEN ORALLY, IT'S MORE
POTENT AND ACTUALLY EQUIPOTENT
TO CODEINE OR MORPHINE IN SOME
CASES.
AND HERE WE COULD SEE ONE
DELIVERED ORALLY, MITRAGYNINE IS
SUBSTANTIALLY MORE POTENT AND IN
FACT AT THE COUPLE HIGHER DOSES
OVERLAPS RIGHT ON TO MORPHINE'S
EFFICACY.
IN CONTRAST TO THAT, WE LOOKED
AT DELIVERING KRATOM, THE WHOLE
PLANT MATERIAL, ORALLY.
WE DO THIS AS -- WE MAKE A TEA,
WE FREEZE DRY THAT TEA SO WE
RECONSTITUTE THE TEA, WE BASE
THAT ON MITRAGYNINE CONTENTS SO
THAT THE MITRAGYNINE CONTENT IS
EQUIVALENT TO WHAT WAS GIVEN
INDIVIDUALLY AND THEN YOU CAN
SEE HERE THE ANALGESIA IS NOT
QUITE AS ROW BUST, BUT IT DOES
GET THERE.
THIS IS REALLY BECAUSE WE KNOW
THAT MYTH IS METABOLIZED IN THE
LIVER, BUT IT'S ALSO
INTESTINALLY METABOLIZED.
SO THIS KIND OF POINTS TO THE
DISTRICT OF WHICH CYTOCHROME
P50s ARE INVOLVED, WE KNOW IT
HEAVILY INVOLVED IN THE
METABOLISM OF MITRAGYNA SPECIOSA
KORTH.
WHAT YOU CAN SEE HERE IN RED IS
DEPLETION OF THE PARENT
COMPOUND, AT THE SAME TIME WE'RE
MONITORING FOR THAT IN THE LCMS,
WE'RE MONITORING FOR THE
PRESENCE OF -- FORMATION OF
7 HYDROXYMITRAGYNINE, SO WE
DIDN'T PUT 7 HYDROXYS&P IN THESE
PREPARATIONS BUT WE CAN
DEFINITELY DETECT AN INCREASING
AMOUNT OF THE LIVER MICRO SOME
AND THE INTESTINAL MICRO SOME
PREPARATIONS.
SO WE WANTED TO LOOK AT
PHARMACOKINETIC PARAMETERS
REALLY OF MITRAGYNINE AND HOWMP
7 HYDROXYMITRAGYNINE IS BEING
PRODUCED AFTER A SINGLE DOSE
OR -- EITHER ORALLY OR IV TO
RATS, IN THIS CASE THEY WERE ALL
FEMALE RATS.
WE DON'T SEE MUCH OF A SEX
DIFFERENCE IN THE
PHARMACOKINETICS.
WE DO SEE SOME SEX DIFFERENCE
BETWEEN SPECIES, BUT I DON'T
HAVE TIME TO GO INTO THAT TODAY
EITHER.
THE BOTTOM LINE IS, THE
TAKE-HOME MESSAGE, ORALLY WE
CONVERT ABOUT 9% OF THE
MITRAGYNINE DOSE TO 7 HYDROXY,
VERSUS IV, THERE'S ONLY ABOUT A
3 1/2% CONVERSION TO 7 HYDROXY.
WE ALSO FOUND THAT
7 HYDROXYMITRAGYNINE IS TOTALLY
UNSTABLE IN HUMAN PLASMA.
SO WE WERE DOING PLASMA
STABILITY STUDIES BECAUSE WE
WANTED TO DO A LOT OF STUDIES
WITH 7 HYDROXYMITRAGYNINE IN
ANIMALS.
WE WERE DOING CROSS-SPECIES
PLASMA STABILITY STUDIES.
AND THIS ACTUALLY -- WE FOUND
THAT MITRAGYNINE IS CONVERTED IN
THE LIVER TO
7 HYDROXYMITRAGYNINE.
BUT IN PLASMA,
7 HYDROXYMITRAGYNINE ACTUALLY
UNDERGOA THIS IS SEMI PINNACLE
REARRANGEMENT.
IT IS PROTEIN DRIVEN, WE DON'T
KNOW WHAT PROTEIN DOES IT YET,
BUT THIS PRODUCES MITRAGYNINE
PSEUDOINDOXYL, WHICH HAS NEVER
BEEN DETECTED FROM THE PLANT
BEFORE, AND AGAIN, IT'S NOT FROM
THE PLANT, THIS IS A METABOLITE
THAT HUMANS ARE EVEN FORMING AND
IT SEEMS TO BE A HUMAN-SPECIFIC
METABOLITE, SO IF YOU LOOK AT
THE INSERT OF THE GRAPH ON THE
RIGHT, WE WERE ACTUALLY SEEING
THIS METABOLITE PRESENT BY
TREMENDOUS AMOUNTS VERSUS MOUSE,
RAT, DOG OR MONKEY.
TREMENDOUS AMOUNTS IN HUMANS.
I ACTUALLY MADE THE LAB SCALE UP
THIS REACTION SO WE COULD
ISOLATE ENOUGH TO PERFORM NMR,
AND THAT'S WHERE WE CAME,
BECAUSE THE MASS WAS IDENTICAL
TO 7 HYDROXYMITRAGYNINE BUT THE
RETENTION TIMES CHANGED, SO WE
KNEW THERE WAS SOMETHING THERE.
ANYWAY, THEY ENDED UP PUBLISHING
THIS AND GOT US A LITTLE COVER
FEATURE.
AND THIS HAS BEEN INTERESTING
WORK WHICH LED US TO MORE
QUESTIONS.
SO WHAT'S GOING ON WHEN WE GIVE
MITRAGYNINE ORALLY, AND HOW MUCH
7 HYDROXY ARE REPRODUCING AND
WHAT'S PRESENT IN THE PLASMA
VERSUS THE BRAIN.
AND SO WE TOOK THE ED50 FROM
SOME OF OUR ANALGESIA STUDIES IN
MICE, AND WE DOSED THOSE MICE
AND WE COLLECTED PLASMA AND
BRAIN AT VARIOUS TIME POINTS,
AND WE DOSED THEM WITH
MITRAGYNINE, NOT 7 HYDROXY, B
BUT WHAT WE WANTED TO SEE WAS
HOW MUCH 7 HYDROXY WAS PRESENT
IN THOSE ANIMALS.
YOU CAN SEE THE BRAIN TO PLASMA
RATIO OF MITRAGYNINE ITSELF IS
ABOUT 2.4 AND THE BRAIN TO
PLASMA RATIO OF 7 HYDROXY IS
ABOUT 1.65.
SO THERE'S MORE 7 HYDROXY IN THE
BRAIN THAN IN THE PLASMA,
THERE'S MORE MITRAGYNINE IN THE
BRAIN THAN IN THE PLASMA.
I THINK WHAT REALLY SURPRISED US
WAS THAT WE TOOK THIS AND THEN
DECIDED TO LOOK AT THE ED50 OF 7 HYDROXYMI TRAGYNINE ORALLY, AND
WE SAW THE REVERSE.
SO 7 HYDROXYMITRAGYNINE DOESN'T
SEEM TO CROSS THE BLOOD-BRAIN
BARRIER AS EFFICIENTLY.
THE BRAIN TO PLASMA RATIO IS
LESS THAN 1, SO THERE'S MORE IN
THE PLASMA THAN IN THE BRAIN,
AND WE KNEW THAT THE METABOLITE
COULD BE GENERATED, THIS
MITRAGYNINE PSEUDOINDOXYL,
ALBEIT IN LOW AMOUNTS, WE STILL
SAW IT IN THE MOUSE AND WE SAW
IT HAVE THE SAME ISSUE, MORE OF
IT'S IN THE PLASMA THAN IN THE
BRAIN.
IN FACT, IT'S EXTREMELY LOW
RATIO.
AND WHAT WE BELIEVE THAT'S GOING
ON THERE, WHEN WE START DOING A
LITTLE BIT OF PHARMACOKINETIC
MODELING, WE LOOKED AT
MITRAGYNINE'S CONCENTRATION
VERSUS ITS EFFECT SO WE COULD
CALCULATE THE LOG BRAIN CONS 16
TRAITED OVER THE EFFECT AND WE
COULD GENERATE A RANGE OF
PHARMACOLOGICAL RESPONSE, AND
THAT MAPPED REALLY NICELY ON TO
OUR ACTUAL OBSERVED VALUES.
BUT WHAT'S MORE IMPORTANT IS,
WHEN WE LOOKED AT THE EFFICACY
OF 7 HYDROXYMITRAGYNINE VERSUS
ITS EFFECT, AND YOU CAN SEE THAT
IN THE BLUE WITH THE RED, AND
THE RED ARE THE OBSERVED, WHAT
WAS REASSURING TO US IS THAT THE
MAXIMUM 7 HYDROXY CONCENTRATION
THAT CAN BE GENERATED AFTER
MITRAGYNINE ADMINISTRATION IS
FAR BELOW WHERE THE EFFICACY
COULD BE FOUND.
SO THIS WAS JUST PUBLISHED IN
FEBRUARY.
THIS WAS SOME OF THE HOTTEST NEW
DATA.
THIS IS REFUTING SOME WORK
THAT'S COME OUT SAYING THAT
7 HYDROXYMITRAGYNINE IS
RESPONSIBLE FOR KRATOM'S
ANALGESIC EFFECTS, OR
MITRAGYNINE'S ANALGESIC EFFECTS.
AND WE DON'T BELIEVE THAT TO BE
THE CASE, WE DON'T BELIEVE THE
AMOUNT THAT'S GENERATED THROUGH
METABOLISM IS PHARMACOLOGICALLY
RELEVANT.
THERE ARE SOME QUESTIONS AS TO
WHY MITRAGYNINE -- WHEN
MITRAGYNINE IS GIVEN BY ITSELF,
YOU SEE HIGHER BRAIN TO PLASMA
RATIOS THAN WHEN 7 HYDROXYIS
GIVEN BY ITSELF, BUT WE'VE BEEN
DEALING WITH THOSE AND I'LL BE
HAPPY TO ANSWER ANY QUESTIONS
AROUND THOSE.
JUST JUMPING BACK ON THE
CYTOCHROME P450s, I KNOW WE'RE
GETTING CLOSE TO TIME AND I WANT
TO JUMP AHEAD,
7 HYDROXYMITRAGYNINE IS A
RESULTANT FROM THAT.
WE HAVE SEEN A TOTAL OF 12
METABOLITES IN MICROSOME STUDIES
AND 31 METABOLITES IN
HEPATOCYTES, AND THOSE ARE HUMAN
LIVER MICRO SOMES AND
HEPATOCYTES.
WE ALSO WANTED TO LOOK AT CYP
INHIBITION.
I HAVEN'T TALKED ABOUT ANY OF
THESE OTHER ALKALOIDS YET, SO
I'M GOING TO GO BACK HERE.
WHAT WE SAW WAS REALLY THERE'S
NOT ANY SIGNIFICANT INHIBITION
OF CYTOCHROME P450s, BUT WE DO
SEE MODERATE INHIBITION OF
CYP2D6 WITH MITRAGYNINE, THE
MAJOR ALKALOID, AND THIS COULD
BE SWA RESPONSIBLE FOR WHY WE'VE
SEEN SOME ADVERSE EVENTS WITH
OTHER CMS DRUGS THAT ARE
METABOLIZED AND CLEARED THROUGH
CYP2D6.
WE HAVEN'T DONE ANY DETAILED
STUDIES ON THAT TO PROVE THAT
THERE ARE ANY ISSUES OR
RECOMMENDATIONS TO AVOWED THOSE
THINGS.
AVOID THOSE
THINGS.
FOR THE MOST PART, ANY ALKALOIDS
WITHIN KRATOM DON'T HAVE ISSUES
EITHER.
SO JUST A QUICK TAKE-HOME OF
MITRAGYNINE, IT'S AN ATYPICAL
OPIOID WITH NON-OPIOID
PHARMACOLOGY.
IT SHARES SOME OF THE EFFECTS
BUT NOT ALL OF THE EFFECTS WITH
MU AGONISTS, AND I HAVEN'T BEEN
ABLE TO SHOW YOU ALL THE DATA WE
HAVE.
IT'S VERY LOW POTENCY AND LOW
EFFICACY.
IT HAS THE LESS TOLERANCE THAN
MORPHINE AT EQUIANALGESIC DOSES.
IT HAS LESS DEPENDENCE THAN
MORPHINE, IT HAS DIFFERENT
DISKRIM NATIVE STIMULUS EFFECTS
FROM MORPHINE, LESS TOLERANCE,
ABUSE AND DEPENDENCE LIABILITY
THAN OTHER OPIOID ANALGESICS.
IT DOES NOT APPEAR TO HAVE ABUSE
OR ADDICTION POTENTIAL AND
REDUCES MORPHINE AND HEROIN
INTAKE IN RATS, AND THESE ARE,
OF COURSE, DESIRED
CHARACTERISTICS FOR
PHARMACOTHERAPIES FOR OPIATE
ADDICTION AND WITHDRAWAL.
THAT'S JUST MITRAGYNINE BY
ITSELF AS THAT LOUD TRUMPET THAT
IT WANTS TO BE.
WHAT ABOUT 7 HYDROXYMITRAGYNINE?
IT SHOULD BE CONSIDERED A KRATOM
CONSTITUENT WITH HIGH ABUSE
POTENTIAL.
IT MAY ALSO INCREASE THE INTAKE
OF OTHER OPIATES.
I DIDN'T TALK ABOUT THAT BUT IN
THE STUDY WE HAVE PUBLISHED IN
ADDICTION BIOLOGY WITH SCOTT
HEMBY, WE DID SEE INCREASED
INTAKE OF OPIATES AFTER
ADMINISTRATION OF
7 HYDROXYMITRAGYNINE.
IT'S A VERY SELECTIVE OPIOID
LIGAND, AND THE EXTENT THAT THAT MG
IS CONVERTED -- SO WHAT ABOUT
KRATOM, THOUGH?
WE'VE BEEN TALKING ABOUT JUST A
COUPLE OF THE ONES THAT WE'VE
BEEN EASILY ISOLATED AND WHERE
CAN WE GO WITH THIS, AND I
REALIZE I ONLY HAVE A COUPLE OF
MINUTES, SO I'M GOING TO JUMP
THROUGH SOME OF THIS VERY
QUICKLY JUST TO SHOW YOU THAT IT
SEEMS TO HAVE AN ANALGESIC
SEALING, SO WE'RE LOOKING AT
ONE, TWO AND FOUR GRAMS PER KG
DOSE TO THESE MICE ORALLY.
WE DON'T SEEM TO GET ABOVE 60%
EFFICACY IN THERE.
KRATOM TEA WILL HAVE A GOOD HOUR
TO 90 MINUTES OF EFFICACY
DEPENDING ON THE DOSE THAT YOU
GIVE, AND IF YOU GIVE VERY LOW
DOSE, WE SEE REALLY NO ANALGESIC
EFFICACY.
YOU CAN READ MORE DETAILS IN
DRUG AND ALCOHOL DEEPEN DENSE ON
THESE.
DEPENDENCE ON
THESE.
WE DO KNOW THE ANALGESIA IS
MEDIATED THROUGH -- LOOKING AT
ONLY ADRENERGIC ACTIVITY OF
MITRAGYNINE IN MU KNOCKOUT MICE,
BUT HERE YOU CAN SEE IN THE WILD
TYPE MOUSE, WE CAN GET ABOUT
THAT 60% ANALGESIA, AND MU
KNOCKOUTS AND KA TA KAPPA KNOCKOUTS,
WE DON'T COMPLETELY LOSE IT.
SOMETHING WEIRD IS GOING ON IN
THE DELTA KNOCKOUT MOUSE.
AND IF WE COMBINE THE MU
KNOCKOUT MOUSE WITH NOR -- WE
CAN PRETTY MUCH ELIMINATE THE
FULL ANALGESIC EFFICACY OF THAT
1-GRAM PER KG ORALLY.
WE DO KNOW IT LACKS A
CONDITIONED PLACE PREFERENCE, IT
DOES NOT APPEAR TO HAVE ANY
SEDATIVE MEASURES AS MEASURED IN
AN ASSAY, AND IT DOES NOT APPEAR
TO REDUCE RESPIRATIONS, WHICH IS
ONE OF THE THINGS THAT HAS BEEN
TAUGHTED SORT
TOUTED ANECDOTALLY THAT IT HAS
LESS RESPIRATORY DEPRESSION,
WE'VE SEEN THAT ACTUALLY IN THE
ANIMAL PLO DELLS.
WE'VE ALSO SCENERY DUCKS OF
NALOXONE WITHDRAWAL.
I'M NOT GOING TO GO INTO THIS
BUT THERE IS SOME DEFINITE
EFFICACY THAT WE'VE SEEN, BUT I
THINK THE MOST IMPORTANT THING
TO FINISH WITH IS WHAT'S GOING
ON PHARMACOKINETICALLY, PAND
WHAT WE SEE NOW IN THE ANIMAL
MODELS, WE'RE STARTING TO NOW
GET DATA IN HUMANS, SO IT'S
GETTING TO BE A REALLY NEXUS
POINT FOR US AND AN EXCITING
TIME TO SEE IF THE ANIMAL MODELS
ARE GOING TO BE REALLY
PREDICTIVE OF WHAT'S HAPPENING
IN THE HUMAN.
WE'VE GIVEN THIS KRATOM TEA, YOU
CAN SEE 7 HYDROXYMITRAGYNINE IS
BELOW LIMITS OF DETECTION, AND
WE DO SEE SOME OF THE OTHER
ALKALOIDS THAT ARE PRESENT.
WE DO SEE MITRAGYNINE AS THE
MAJOR ALKALOID AND AS THE MAJOR
EXPOSED ALKALOID WITHIN THE
PLASMA.
WE ALSO SEE SPECIOCILLATINE, AND
TWO OTHER ALONG THE BOTTOM WHERE
IT SAYS CONTENT OF INDIVIDUAL
ALKALOIDS.
TWO OF THE MORE MAJOR ALKALOIDS
IN THIS, WE DON'T SEE THEM IN
THE PLASMA, BUT THAT'S BECAUSE
THEY DISAPPEAR WITHIN THE FIRST
HOUR.
AND SO WE REALLY DON'T HAVE DATA
TO QUANTIFY THAT THEY'RE GONE,
THEY'RE CLEARED, BUT THEY HAVE
ACTIVE METABOLITES SO STAY
TUNED.
WHAT ABOUT THE SPESH YOE
CIALATINE.
THE ONLY DIFFERENCE IS THE THREE
HYDROGEN POSITION, SO INSTEAD OF
BEING ALPHA, WE'VE MOVED TO THE
BETA POSITION.
THIS CAUSES A COMPLETE CHANGE IN
THREE DIMENSION NAT ARCHITECTURE
AND VERY SIMILAR
THREE-DIMENSIONAL ARCHITECTURE
TO THAT 7 YOU HYDROXYMITRAGYNINE
MOLECULE I TALKED ABOUT EARLIER
AS BEING PROBLEMATIC.
FORTUNATELY IT ONLY HAS PARTIAL
AGONIST EFFECT AT THE MU OPIOID
RECEPTOR AND DOESN'T APPEAR TO
HAVE EFFECT ALTHOUGH IT BINDS TO
KAPPA.
SO THIS IS SOMETHING WE'RE ALSO
PROBING AND LOOKING FORWARD TO
UNDERSTANDING.
BUT LET ME COME BACK TO THE
OTHER TWO MAJOR ALKALOIDS IN THE
PLANT --
>> CHRIS, WE HAVE ABOUT
2 MINUTES BEFORE WE GO INTO Q &
A.
>> I'LL BLOW RIGHT THROUGH THIS.
SO WE'VE GOT -- THIS MOLECULE,
PAYNANTHINE AND SPEESH YOE
GYNINE, THE ONLY DIFFERENCE IS
THE DOUBLE BOND.
THESE MOLECULES HAVE VERY HIGH
AFFINITY, IN FACT, SOME OF THE
HIGHEST AFFINITY FOR ANY TARGETS
WE'VE SEEN FROM THE NATURALLY
OCCURRING ALKALOIDS.
#-H T2 A AND B.
THESE MAY BE AN TACKNISTS WHICH
COULD BE BENEFICIAL.
35H IT 1A WE DO HAVING ANIST
ACTIVITY.
I'M NOT GOING TO SHOW YOU MUCH
IN VIVO DATA THERE BUT I DO WANT
TO SHOW YOU THAT WE LOOKED AT
ANALGESIC MEASURES OF THESE
COMPOUNDS THAT HAVE NO OPIOID
ACTIVITY AND WE SEE THAT THEY
CAN PRODUCE 100% MAXIMAL
POSSIBLE EFFECT IN ANALGESIA
MEASURES, MEDIATED COMPLETELY
THROUGH SEROTONIN 5HT1A
RECEPTORS AND THEY CAN BE
BLOCKED WITH THE SLEK TUN
100A635.
SO THIS IS AN EXCITING AVENUE
FOR NON-OPIOID ANALGESICS
POTENTIALLY.
I WON'T GO INTO THESE
CLINICAL -- -- NANOGRAMS PER
MILLILITER, REGULARLY USING THAI
GROUP OF KRATOM USERS.
WHAT WE SAW IN DEATH CASES WERE
LEVELS AT 1800-NANOGRAM PER ML,
ALMOST 200 TIMES HIGHER THAN
PEAK PLASMA CONCENTRATIONS SEEN
IN REGULAR KRATOM USERS IN
THAILAND.
AND SO FINALLY WRAPPING UP,
THERE'S A LONG HISTORY OF SAFE
USE IN THE TRADITIONAL MANNER
FROM SOUTHEAST ASIA BUT WE'VE
HAD A WIDE RANGE OF ADVERSE
EVENTS IN THE WESTERN WORLD.
THE ALKALOIDS ARE STRUCTURALLY
DIFFERENT FROM OPIATES AND,
THEREFORE, HAVE DIFFERENT
PHARMACOKINETIC AND
PHARMACODYNAMIC PROPERTIES.
PRODUCTS IN THE UNITED STATES
ARE DEFINITELY NOT THE SAME AS
THE TRADITIONALLY UTILIZED FRESH
LEAF PREPARATIONS, AND WE STILL
HAVE A LOT OF GAPS IN THE
SCIENCE AROUND THIS PLANT, AND
HOPEFULLY WE CAN CONTINUE TO
REALLY START SOLVING SOME OF
THOSE GAPS.
BUT WE FEEL THAT THIS IS A
POSSIBLE SOLUTION TO THE OPIOID
EPIDEMIC, AND IT COULD COME FROM
NATURE WHERE IT ORIGINATED FROM.
SO WITH THAT, I HAVE TO THANK
EVERYBODY THAT DID ALL THE WORK
>> ONE QUICK QUESTION ABOUT THE
MITRAGYNINE VERSUS THE TEA, THE
KRATOM EXTRACT.
I'M THINKING TO SORT OF TAKE A
PAGE FROM THE CANNABIS WORLD
ABOUT THE ENTOURAGE EFFECT, IT
DOESN'T LOOK LIKE YOU'RE GETTING
THAT, ALTHOUGH YOU'RE SHOWING
SOME CONSTITUENTS BUT OFF TARGET
ANALGESIC PROPERTIES AT THE
SAIRT NERGIC RECEPTOR.
SO WHAT DO YOU THINK IS GOING ON
THERE, AND WOULD THERE BE
COMBINATIONS OF KRATOM THAT
MIGHT HAVE THIS SORT OF
ENTOURAGE TYPE EFFECT FOR
ANALGESIA OR WHAT ARE YOUR
THOUGHTS ON THAT?
>> IT'S A GOOD QUESTION.
IN FACT, I'M A FULL BELIEVER IN
THE SYMPHONY ORCHESTRA ANALOGY,
SO I REALLY THINK THAT THE
ENTOURAGE EFFECT IS THERE.
AND WE'RE SEEING DIFFERENT
THINGS COME INTO PLAY AND I JUST
DIDN'T HAVE TIME TO GO INTO ALL
OF THE DIFFERENT ALKALOIDS AND
ALL THE PHARMACOLOGIES THAT KIND
OF GIVE YOU A LITTLE GLIMPSE OF
WHAT'S THERE.
BUT I THINK MITRAGYNINE BY
ITSELF IS A FASCINATING MOLECULE
AND IT MAY HAVE A LIMITED
THERAPEUTIC APPLICATION.
VERSUS KRATOM AS A WHOLE, MAY
HAVE A LOT MORE AVENUES TO
PURSUE IN TERMS OF MANY
APPLICATIONS.
THERE'S SO MUCH ANECDOTAL
EVIDENCE OUT THERE IN TREATMENT
OF CARDIOVASCULAR DISEASE, OF
DIABETES, YOU KNOW, OBVIOUSLY OF
PAIN, THERE'S JUST MANY AVENUES
WE HAVEN'T BEEN ABLE TO TREAD
INTO YET.
MOOD ENHANCEMENT IS ONE OF THE
THINGS THAT MAYBE SOME OF THE
SEROTONERGIC AND ADRENERGIC
EFFECTS ARE PLAYING INTO.
I'M EXCITED BECAUSE THOSE
COMPOUNDS APPEAR TO BE MUCH MORE
ENRICHED IN SOME OF THE
CHEMOTYPES THAT INDIVIDUALS THAT
ARE CONSUMING THOSE THAT DONATED
THOSE TO THE UNIVERSITY OF
FLORIDA REALLY SAID THAT THEY
HAD POSITIVE MENTAL EFFECTS FROM
THOSE TREES.
SO WE JUST HAVEN'T PURSUED THAT,
AND AS YOU MIGHT IMAGINE, WE'RE
IN THE PROCESS RIGHT NOW, OUR
R01 FUNDING IS REALLY TO START
INVESTIGATING WHAT I CALL LEAVE
ONE OUT PHARMACOLOGY.
NOW THAT WE KNOW WHAT'S PRESENT
FROM THE FULL KRATOM TEA
EXPOSURE INTO THE ANIMALS'
PLASMA AND BRAIN, WE CAN START
TAKING THOSE PURIFIED MOLECULES
IN THE SAME RATIOS AND THEN
START PLAYING AROUND WITH THAT
TO SEE IF THERE IS AN
ENTOURAGE-LIKE EFFECT.
OR IF WE'RE COMPLETELY MISSING
THE BOAT, RIGHT?
WE'RE FOCUSED ON ALKALOIDS.
WE'RE LOOKING LIKE THE GUY THAT
DROPPED HIS KEYS IN THE DARK,
WE'RE LOOKING UNDER THE LAMP
POST BECAUSE THE LIGHT IS THERE,
BUT THE KEYS MAY BE OFF IN A
DARK CORNER SOMEWHERE.
SO THERE'S TREMENDOUS AMOUNT OF
WORK TO BE DONE.
>> ABSOLUTELY.
I'LL HOLD MY SECOND QUESTION
BECAUSE I KNOW THERE'S A LOT OF
OTHERS THAT HAVE QUESTIONS.
THANK YOU, THAT WAS GREAT.
>> HELENE, DO YOU HAVE A
QUESTION OR DO YOU WANT PLE TO
MOVE TO AUDIENCE QUESTIONS?
>> WELL, SURE, I HAVE A
QUESTION.
I'M PARTICULARLY INTERESTED IN
ADRENERGIC EFFECTS, BECAUSE
TYPICALLY, RIGHT, THIS DRUG --
THE PLANT, THE TEA, AM I CORRECT
THAT IT'S PRIMARILY USED AS A
STIMULANT?
LIKE FOR PEOPLE USE THEM LIKE
FOR, YOU KNOW, IN THE FIELDS
WHEN THEY WANT TO WORK LONGER
HOURS WITHOUT GETTING TIRED, A
LITTLE BIT LIKE CHEWING COCOA
LEAVES?
>> EXACTLY.
IT'S FASCINATING BECAUSE IT
SEEMS TO BE MORE STIM LANTD-LIKE
AT LOWER DOSES AND MORE OPIATE
LIKE OR EU FORTUNATE AT HIGHER
DOSES.
WE'VE NOT REALLY BEEN ABLE TO
TWEAK THAT OR CAPTURE THAT OR
UNDERSTAND WHAT IS CAUSING THAT.
SO IT REMAINS A MYSTERY AND IT'S
SOMETHING WE'RE CONCERNED ABOUT
AS WELL.
IN FACT, I THINK THE ADRENERGIC
COMPONENT MAY BE MORE IMPORTANT
FOR THE ENTIRE PLANT THAN THE
OPIOID.
AND IF YOU LOOK AT THE POISON
CONTROL CENTER CALL US, THAT
PLAYS ITSELF OUT IN THOSE CASES.
AND SO IT IS SOMETHING THAT WE
ARE VERY INTERESTED IN.
WE HAVE A LOT OF DATA THAT WE
HAVEN'T PUBLISHED YET, SO I
CAN'T GO INTO TOO MUCH MORE
DETAIL BUT MAYBE NEXT TIME.
>> BUT PRESUMABLY THESE
ADRENERGIC EFFECTS DON'T GO AWAY
AT THE HIGHER DOSES, EVEN
THOUGH, RIGHT, AND PART OF THAT
ADRENERGIC EFFECTS CAN BE
ANTINOCICEPTIVE, YOU KNOW, AT
THE SPINAL CORD LEVEL, I
BELIEVE.
>> CORRECT.
>> SO IT COULD BE THAT SOME OF
THE ANTINOCICEPTION IS COMING
FROM THAT.
ARE YOU THINKING ALONG THESE
LINES OR --
>> WE THINK THAT IT'S MIXED
MODAL, RIGHT?
I THINK OPIOIDS ARE DEFINITELY
INVOLVED.
WE'VE SEEN THAT THROUGH RECEPTOR
BLOCKADE STUDIES, BUT WE'VE ALSO
BEEN ABLE TO TAKE KNOCKOUT
ANIMALS AND SEE ANALGESIA THAT
WE CAN BLOCK THROUGH ADRENERGIC
MECHANISMS, AND WE'VE ALSO SEEN,
AS I SHARED IN THE LAST SLIDE,
SOME SERITONERGIC ACTIVITY AS
WELL, ALL KNOWN TO BE TARGETS
FOR ANALGESIA IN THEIR OWN RITE.
SO YEAH, I THINK AS A MEDICINAL
CHEMIST, THIS IS LIKE SOMEBODY
OPENED UP THE CANDY STORE.
THERE'S SO MUCH INSPIRATION FOR
US TO MOVE FORWARD WITH.
>> THE FULL PICNIC.
THANK YOU.
>> THANK YOU.
>> SO WE HAVE A REAL RANGE OF
QUESTIONS AND COMMENTS, RANGING
FROM THANKING YOU FOR THE
WONDERFUL RESEARCH YOU'RE DOING
AND SO I THINK WE'LL START WITH
THIS QUESTION.
WHICH CAME IN WHICH IS, SO WHAT
IN YOUR OPINION IS CONTRIBUTING
TO THE ADVERSE EVENT REPORTS
AROUND KRATOM CONSIDERING DATA
THAT YOU'VE HAD OR SUGGESTIONS
THAT THERE'S A LIMITED ABUSE
POTENTIAL OR SAFETY CONCERNS.
SO THAT WAS ONE QUESTION THAT
CAME IN.
SO THOUGHTS THERE?
>> I THINK ANYTHING --
EVERYTHING SHOULD BE TAKEN
WITHIN MODERATION, EVEN
MODERATION AS WINSTON CHURCHILL
SAID.
I THINK WHERE WE START TO SEE
THE ADVERSE EVENTS IS IN A
SUBSET OF USERS, AND I LIKE TO
THINK AND I HOPE TO THINK THAT'S
A VERY SMALL SUBSET OF
INDIVIDUALS THAT ARE USING THIS.
UNFORTUNATELY THEY'RE THE ONES
THAT WE HEAR ABOUT THE MOST
BECAUSE THEY'RE THE ONES THAT
END UP IN THE HOSPITAL OR
UNFORTUNATELY IN WORSE PLACES.
BUT DEFINITELY SEEMS TO BE THIS
ADRENERGIC ACTIVITY THAT'S
REALLY CONCERNING.
FOR US.
AND WHAT WE SEE IN TERMS OF
PEOPLE THAT HAVE INGESTED TOO
MUCH MATERIAL AND END UP EITHER
IN THE HOSPITAL OR HAVE PASSED
FROM OVERDOSE, WHETHER IT WAS IN
COMBINATION WITH MANY OTHER
SUBSTANCES OR NOT, THERE'S NOT
THE OPIOID-TYPE ISSUES
ASSOCIATED WITH IT, SO THERE'S
NO RESPIRATORY DEPRESSION THAT
HAS BEEN REPORTED OR VERY
LITTLE.
MOST OF THE REPORTS ARE REALLY
AGITATION SEIZURE ACTIVITY.
THAGE DATED DELIRIUM THAT YOU
SEE IN METHAMPHETAMINE USERS IN
THE EMERGENCY ROOM THAT HAVE
OVERDOSED, THESE ARE THE TYPES
OF REPORTS THAT IF YOU JUST MINE
THROUGH THE VAERS DATABASE
SYSTEM OR POISON CONTROL
CENTERS, YOU'LL SEE SOME OF
THESE BECOMING MORE FREQUENT.
SO I THINK OUR FOCUS HAS REALLY
BEEN ON OPIATE, WHICH I THINK IS
MOST OF THE RESEARCH FOCUS.
OUR FOCUS HAS SHIFTED MORE
RECENTLY TO REALLY TRYING TO
UNDERSTAND TRANSLATIONAL ASPECTS
OF OUR WORK AND HOW CAN WE
REALLY IMPACT THOSE THAT DO
INGEST TOO MUCH.
IS NALOXONE OR NALTREXONE THE
WAY TO REVERSE THIS OVERDOSE?
I CAN'T ANSWER THAT QUESTION
RIGHT NOW, BUT I DON'T THINK
IT'S THE APPROPRIATE MEASURE TO
TAKE.
>> OKAY.
WE'VE HAD A COUPLE OF COMMENTS
REGARDING THE FACT THAT IT SEEMS
LIKE KRATOM USE IN MALAYSIA,
SOUTHEAST ASIA, IS DISTINCTLY
DIFFERENT THAN U.S.-BASED USE,
AND SO IS IS THERE SOMETHING THERE
PLAYING INTO WHAT WE'RE SEEING?
SOME PEOPLE HAVE SAID HERE IN
THEIR COMMENTS THAT THEY'VE SEEN
THINGS WHERE KRATOM HAS BEEN
COMPARED TO MORPHINE, OR THAT
IT'S SEVERAL TIMES MORE POTENT
THAN MORPHINE.
SO IT SORT OF LIKE YOU'VE GOT
THIS STRANGE SET OF
CIRCUMSTANCES WHERE YOU HAVE
TRADITIONAL USE VERSUS HOW IT'S
USED HERE, AND THEN ALSO
COMMENTARY ABOUT HOW IT COMPARES
TO THINGS LIKE MORPHINE.
SO CAN YOU IMPACT UNPACK SOME OF THAT A
LITTLE BIT?
>> I'LL TRY TO DO IT IN AS SHORT
A TIME AS POSSIBLE.
>> WE DO HAVE A FEW EXTRA
MINUTES FOR QUESTIONS SO STICK
WITH US.
>> I'LL BE HERE ALL DAY IF YOU
WANT ME.
I WILL SAY THAT WE DON'T SEE
CONCENTRATED EXTRACT PRODUCTS,
THERE ARE TREMENDOUS AMOUNTS OF
EXTRACTS AND CONCENTRATED
EXTRACT PRODUCTS THAT ARE ON THE
MARKET IN THE U.S.
AND WE DON'T UNDERSTAND EVEN IN
ANIMALS WHAT THOSE CONCENTRATED
EXTRACTS DO.
SO WE'VE DONE SOME WORK, WE'VE
REALLY BEEN TRYING TO FIGURE OUT
WHAT'S THE REAL PLANT MATERIAL
DOING, NOT WHAT ARE SOME OF THE
OTHER OPTIONS IN THE
MARKETPLACE.
SO I THINK I WOULD SAY THAT AS I
ADDRESSED EARLIER, ONE, WE HAVE
DRIED LEAF MATERIAL THAT IS
SEVERAL WEEKS TO MONTHS PAST
HARVEST.
IT'S NOT GOING TO BE CHEMICALLY
THE SAME.
THERE'S JUST NO QUESTION ABOUT
THAT.
NOW WHETHER PHARMACOLOGICALLY
IT'S THE SAME OR DIFFERENT IS
STILL QUESTIONABLE.
HOWEVER, THE EXTRACTS, THE
CONCENTRATED EXTRACTS ARE
DEFINITELY SOMETHING WE DON'T
SEE.
AND MOST OF THE ISSUES THAT ARE
COMING FROM HARM IN THE U.S., I
BELIEVE ARE PEOPLE THAT ARE
REALLY TRYING TO PUSH THE LIMIT
TO SEE IF THEY CAN GET HIGH, SEE
IF THEY CAN GET THAT REPORTED
OPIATE EFFECT, AND I CAN'T --
THAT'S SPECULATION ENOUGH.
BUT THAT'S KIND OF WHERE IT IS,
AND AS I REPORTED, WE'VE SEEN --
WE'VE ANALYZED KRATOM LEAF
MATERIAL THAT HAS HAD
HYDROCODONE IN IT, THAT HAS HAD
MORPHINE IN IT.
IT'S QUITE FRIGHTENING WHEN YOU
THINK ABOUT IT.
THOSE ARE THE THINGS WE KNOW
ABOUT.
WHAT ABOUT FENTANYL-LACED
PRODUCT, WHAT ABOUT SYNTHETIC
LACED PRODUCTS?
AND SO JUST SO MANY THINGS.
WE DON'T SEE PEOPLE IN SOUTHEAST
ASIA EXPERIMENTING TOO MUCH, BUT
I HAVE TO TELL YOU EVER SINCE WE
STARTED THIS, A YOUNGER
GENERATION OF PEOPLE IN
SOUTHEAST ASIA HAVE STARTED TO
DEVELOP ISSUES WITH COMBINING
KRATOM TEAS WITH OTHER THINGS
LIKE ARAMIN5, WHICH IS A BEN
DOUGH SIGH AZ PEEN, ALCOHOL,
COUGH SYRUPS.
THIS HAS BECOME A PROBLEM
BECAUSE OF WHAT'S HAPPENING IN
THE WEST.
AND THEN LEARNING ABOUT IT OVER
THERE.
AND SO I THINK WE'RE STARTING TO
SEE THAT GO UP.
THE LAST THING I WOULD SAY ON
THIS IS, I THINK THE USER BASE
HAS GONE UP SO TREMENDOUSLY IN
THE UNITED STATES OVER THE LAST
FEW YEARS, PARTLY PROBABLY
BECAUSE OF COVID, BUT WE HAVEN'T
SEEN THE SAME RISE IN HARM.
AND SO THERE WAS TREMENDOUS
AMOUNTS OF POISON CONTROL CENTER
REPORTS THAT WENT FROM OVER 10
YEARS OR WHATEVER IT WAS WENT UP
PERCENTAGE, BUT I DON'T THINK
WE'RE SEEING THAT TREND
CONTINUING AND I DO BELIEVE IT'S
BECAUSE WE'RE SEEING A LITTLE
BIT BETTER -- BETTER IS -- CAN
BE TAKEN WITH A GRAIN OF SALT,
PRODUCT IN THE MARKETPLACE AS
THAT PURE -- LEAF PEOPLE ARE
UTILIZING FOR THE BENEFIT THAT
THEY'RE GOING FOR, NOT TO GET
HIGH.
I THINK THAT'S -- IT'S A
POPULATION THAT'S THERE, BUT I
DON'T THINK IT'S THE LARGER
POPULATION.
THE LEGITIMATE USERS OF THIS
WILL FIGHT TO THEIR DEATH TO
KEEP IT LEGAL BECAUSE IT'S BEEN
REVOLUTIONARY FOR THEM.
>> WELL, THANK YOU, CHRIS.
THE HOUR HAS PASSED SO I THINK
WE'LL LEAVE IT THERE.
WE DID HAVE A COUPLE OF OTHER
QUESTION, AND SO WHAT WE'LL DO
IS WE'LL GATHER THOSE AND WE'LL
SHARE THOSE WITH YOU, AND THE
EMAIL ADDRESSES THAT WE HAVE IN
CASE YOU WANT TO FOLLOW UP WITH
ANYBODY DIRECTLY.
BUT WITH THAT SAID, THEN, I DO
WANT TO THANK DR. MCCURDY FOR A
WONDERFUL TALK, AND THANK
EVERYBODY WHO JOINED US AS A
VIEWER TODAY, AND FOR SHARING
QUESTIONS.
THE PROGRAM WAS RECORDED BY NIH
VIDEOCAST AND SHOULD BE
AVAILABLE LATER ON THE NIH
VIDEOCAST SITE FOR VIEWING.
AND THEN JOIN US ON MAY 18TH,
WHEN OUR NEXT IMLS LECTURE TAKES
PLACE, AND WE'RE GOING TO HEAR
ABOUT WELL-BEING IN THE ECONOMIC
BURDEN OF DISEASE, WHAT WE ARE
LEARNING FROM CANCER SURVIVORS,
AND THAT TALK IS GOING TO BE
PRESENTED BY DR. MICHELLE MARTIN
OF THE UNIVERSITY OF TENNESSEE
HEALTH SCIENCE CENTER.
SO WITH THAT SAID, THANK YOU SO
MUCH, DR. MCCURDY,
DR. SHURTLEFF, DR. LANGEVIN AND
EVERYBODY WHO'S JOINED US TODAY
AND WE WILL SEE YOU IN MAY FOR
THE NEXT LECTURE.