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| Mitragyna speciosa is barely known in the United
States, but one of the most interesting plants we have
ever found... |
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| Kratom grows in the lush rainforests in the South of
Thailand, and has the unique position of being banned in
the country it is indigenous to...true story... |
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Kratom: Possible Cure
for Drug Addiction
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Drug abuse remains a major social/health problem in Malaysia. Addiction is
mainly to morphine and cannabinoids and involves mostly males of the productive
age group. Over the last few years, Malaysia has implemented various laws and
regulations to control the problem. This has increased the street value of the
drugs and made it more difficult for addicts to obtain drug supplies.Recently,
Mitrygyna speciosa, locally known as biak or ketom, was brought to our
attention. It was reported that the plant was popular among addicts as a drug
substitute and, it was further claimed that it reduced withdrawal symptoms.
Phytochemical studies of the plants showed that the most active chemical
constituent of the leaves (the part that is commonly used) was mitragynine. This
constituent was identified by a modified thin layer chromatography (TLC)
procedure established for morphine. A survey of 54 ketom users showed that
almost all (94.3%) were former drug addicts of morphine, cannabinoids or both,
who had been using these leaves for a period ranging from 1 to more than 20
years. The leaves were consumed either in powder form or boiled in water. The
boost in energy and strength, was experienced 5-20 minutes after consumption.
The users claimed that they became dependent on ketom. None of them had tried to
stop using ketom as they developed withdrawal symptoms, although these were much
less severe than those associated with morphine. Investigation of their core
biochemistries showed that there were no significant changes from the normal
reference range. Further investigation of the neuro-pharmachological effects of
this plant extract is currently under way (Zakiah I, Mohd Isa W & Badrul AAR).
It has been reported that the use of Mitragyna speciosa (ketom) as a heroine
withdrawal suppressant, among drug users, shows a rising trend in the northern
and east coast regions of Peninsular Malaysia. Recent use of ketom can be
detected by testing for mitragynine and its metabolites in urine, and a
procedure for their isolation and analysis using solid phase extraction (SPE)
and high performance liquid chromatography (HPLC) has been established. Briefly,
urine is loaded on to the C18 SPE disk column and eluted with acetonitrile. The
extracts are chromatographed on a C8 HPLC column with acetonitrile/water as the
mobile phase, and the eluents monitored using ultraviolet (UV). The authencity
of the separated compounds is determined from their UV spectrum. Recovery of
mitragynine was in the range of 61-98 %, and no other drugs or metabolites were
noted to interfere with the procedure (Mohd Isa W, Jalilah H & Zakiah I).
Activity of several Malaysian Herbal Extract – A Preliminary Report
The function of the immune system is primarily to protect the human body against
microorganisms or other potentially injurious agents. The resulting immune
response along with all of its associated secondary phenomena is called
inflammation. Most aspects of inflammation are potentially beneficial to the
host. Excessive or inappropriate inflammatory reactions, however, can lead to
discomfort, disability, and even death. Thus, anti-inflammatory drugs and other
therapeutic measures that suppress inflammation play an important role in
medical practice. The in vitro assay, that is being employed to measure
anti-inflammatory effects of various drugs, measures chemiluminescence emitted
by neutrophils during phagocytosis. Singlet oxygen, a highly unstable and
reactive species amongst others, produced in the course of the process, combines
with bacteria or other intralysosomal elements to form electronically unstable
carboxy groups. When these groups return to ground state, light energy is
emitted, which can then be magnified and quantitated. Employing this assay we
studied the anti-inflammatory effects of varying concentrations of the extracts
of the following plants: Goniatalamus fasciculatus, Goniatalamus andersonii,
Piper aduncum, Centella asiatica, Ardisia elliptica and Eurycoma longifolia and
compared the effects with commonly prescribed anti-inflammatory drugs like
aspirin, brufen, diclofenac and indomethacin. The inhibitory effect of G.
andersonii and G. fasciculatus with RLU of 4 and 8 respectively at 5 mg/dL of
extracts on chemiluminescence appear to be markedly profound, while those of
Piper aduncum, Centella asiatica, Ardisia elliptica and Eurycoma longifolia are
as inhibitive as, if not more than that of aspirin, brufen, diclofenac and
indomethacin (RLUs between 2-60 at 10 mg/dL of extracts, as compared with
greater than70 RLU for the standard anti-inflammatory drugs). These preliminary
findings indicate the potential of the plant extracts as anti-inflammatory
agent. This study will be continued in 2001 to confirm and to isolate the
compounds with this particular activity (Nasuruddin BA, Wan Fariza BA, Zaiton
MY, Rasadah MA, Khozirah S , Ibrahim BJ, Md. Ikram MS, Mohd. Azman AB and
Shahnaz M).
In vitro studies of the anti-malaria activity of Mitragynine
The main purpose of this study is to compile a dossier on mitragynine for its
use as an anti-malarial drug. The specific objectives of this study are 1) to
evaluate the anti-malaria activity of mitragynine, 2) to evaluate the
cytotoxicity of mitragynine to establish its safety, and 3) to identify and
study the metabolites of mitragynine to obtain pharmcological data on this
compound. The anti-malaria activity of mitragynine was studied by 1) microscopy,
and 2) the parasite lactate dehydrogenase (pLDH) assay. Parasites were cultured
in varying concentrations of mitragynine and chloroquine. In the first assay,
thin blood smears were prepared from these cultures and examined under the
microscope to determine the inhibitory effect of the drugs on parasite
development. In the pLDH assay, an enzyme assay, the intensity of the colour
measured is proportional to the number of parasites present. By microscopy, the
IC50 for mitragynine and chloroquine were 4.7 m g/ml and 0.25 m g/ml
respectively. Using the pLDH assay, the IC50 of mitragynine and chloroquine for
the Gombak A strain were 11.8 m g/ml and 9.5 m g/ml respectively. Thus
mitragynine shows anti-malarial activity against the Gombak A strain (IC50 below
16 m g/ml). In order to establish the safety of mitragynine, the cytoxic effects
of this compound on 1) the MBDK cell line (normal cell line), and 2) human
erythrocytes were studied. These cells were exposed to varying concentrations of
mitragynine and chloroquine, and the cytotoxicity was determined by measuring
the amount of LDH released spectrophotometrically. The amount of LDH released
corresponded directly to cytotoxicity of the compound. Mitragynine and
chloroquine do not have any cytotoxic effect on MBDK cells in vitro, up to a
concentration of 64 m g/ml. Mitragynine was also not cytotoxic for non-infected
erythrocytes in vitro, up to a concentration of 50 m g/ml. The metabolites of
mitragynine were studied in mice. Mitragynine was given orally or via IP
injection to mice. Plasma from such mice was then subjected to three extraction
procedures and analysed by HPLC and GC-MSD. We found there were no differences
between the plasma from control and test mice, indicating that the metabolites
could not be isolated by the three extraction procedures used. This study will
be continued in 2001 (Diepens R, Mohd. Isa Wasiman, Noor Rain A & Badrul AR).
Over 25 alkaloids have been isolated from kratom. The most abundant
alkaloids consist of three indoles and two oxindoles. The three indoles are
mitragynine, paynanthine, and speciogynine - the first two of which appear
to be unique to this species. The two oxindoles are mitraphylline and
speciofoline. Other alkaloids present include other indoles, and oxindoles
such as ajmalicine, corynanthedine, mitraversine, rhychophylline, and
stipulatine.
Mitragynine is the dominant alkaloid in the plant. It was first isolated in
1907 by D. Hooper, a process repeated in 1921 by E. Field who gave the
alkaloid its name. Its structure was first fully determined in 1964 by D.
Zacharias, R. Rosenstein and E. Jeffrey. It is structurally related to both
the yohimbe alkaloids and voacangine. It is more distantly related to other
tryptamine-based psychedelic drugs such as psilocybin or LSD. Chemically,
mitragynine is 9-methoxy-corynantheidine. It has the molecular formula
C23H30N2O4 and a molecular weight of 398.5. Physically the freebase is a
white, amorphous powder with a melting point of 102-106 degrees and a
boiling point of 230-240 degrees. It is soluble in alcohol, chloroform and
acetic acid. The hydrochloride salt has a melting point of 243 degrees.
The alkaloid content of the leaves of Mitragyna speciosa is about 0.5%,
about half of which is mitragynine. An average leaf weighs about 1.7 grams
fresh or 0.43 grams dried. Twenty leaves contain approximately 17mg of
mitragynine. All leaves appear to contain mitragynine, speciogynine,
paynanthine, and small quantities of speciociliatine. Oxindole alkaloids
usually occur only in small or trace ammounts.
Alkaloid content varies from place to place and at different times. Within
each location, there is a quantitative variation in alkaloid content from
month to month. While indole content seems to be fairly stable, oxindole
content shows tremendous variation.
Kratom is traditionally only used in Thailand, although some use in Malaysia
has been reported. Besides kratom (or krathom), it also goes by the names
ithang, kakuam, and in southern regions, thom. Use dates far enough back
that its beginning can't be determined. In addition to being used as a
narcotic drug in its own right, it is often used as a substitute for opium
when opium is unavailable, or to moderate opium addiction. In folk medicine,
it is often used to tread diarrhea. A small minority of users use kratom to
prolong sexual intercourse.
Users distinguish different types of kratom, two main kinds being
distinguished by the color of veins in the leaf - red or green/white. The
green-veined variety is supposed to have a stronger effect. One study which
surveyed Thai kratom users found that most users preferred a mixture of
both, followed by red-veined alone and then white-veined alone. Growers in
Australia report that both red and white veining occurs at different times
in different plants which were all cloned from the same mother plant. They
have not yet undertaken comparisons between the two.
Nearly all kratom use is by chewing fresh leaves. Other ways it is taken
include grinding up and eating fresh, dried, or reconstituted dried leaves.
Some villagers use the leaves in cooking. When preparing fresh leaf, the
vein is extracted and sometimes salt is added to try and prevent
constipation. Consumption of the leaf is usually followed by drinking
something hot, such as warm water or coffee. Leaves can also be smoked, made
into a tea, or a crude resin extraction can be made. This resin extract is
made by preparing a water extract of the leaves, boiling it down, and then
shaping it into small balls which are rolled in a material such as flour,
then stored until use. This is apparently a quite popular method of
consumption.
Users of kratom tend to be peasants, laborers, and farmers who use the plant
to overcome the burdens of their hard work and meager existences. Female
users are apparently quite rare. Age of usage onset seems to be higher than
for other drugs. Some studies have found no addiction problems in villagers
using kratom, while others apparently have. It seems likely that if used in
doses high enough for mu receptor crossover (discussed below), addiction is
a strong possibility. Heavy users may chew kratom between 3 and 10 times a
day. While new users may only need a few leaves to obtain the desired
effects, some users find with time they need to increase doses to 10-30
leaves or even more per day.
In some parts of the country, it was said that parents would choose to give
their daughters in marriage to men who used kratom rather than men who used
marijuana. The belief is that kratom users are hard working, while marijuana
users are lazy. This belief is also maintained by many of the users
themselves, who report beginning use because of a desire to work more
efficiently, and who say using the drug gives them a strong desire to do
work.
The Thai government passed the Kratom Act 2486 which went into effect on
August 3, 1943. This law makes planting the tree illegal and requires
existing trees to be cut down. This law was not found effective, since the
tree is indigenous to the country. Today, kratom is classed in the same
enforcement group as cocaine and heroin by Thai law, and has the same
penalties. One ounce of extract is punishable by death. As with prohibition
laws elsewhere in the world, this has succeeded only at increasing black
market prices. A related species, Mitragyna javanica, is often used as a
substitute to get around the law, but it is not considered as effective. The
dominant alkaloid in this species is mitrajavine, which has not yet been
pharmacologically tested.
While the main alkaloids in kratom are structurally related to psychedelics,
there appears to be no psychedelic activity. The dominant effects seem to be
similar to opiate drugs, and include analgesia and cough suppression. These
effects are roughly comparable in strength to codeine. Mitragynine
suppresses opiate withdrawal, but its effects are not reversed by the opiate
antagonist nalorphine. These opiate-like effects appear to be mediated
mostly by delta and mu opioid receptors. In lower dosages, mitragynine
exhibits a yohimbine-like binding to alpha-adrenergic receptors, as well as
some binding to the delta opioid receptors. As doses increase, binding to
delta receptors increases, and in yet higher doses, crossover to mu
receptors occurs. Interestingly, mu crossover is increased by the presence
of opiate drugs. While delta receptor selective opiate drugs have little
abuse potential, it seems that they could be used as a primer which would
allow mitragynine to more effectively bind to the mu receptor, which
mediates the euphoric high produced by narcotics such as morphine.
Other effects of mitragynine are a reduction in smooth muscle tone, local
anesthesia, and central nervous system depression. Acute side effects
include dry mouth, increased urination, loss of appetite, and constipation
coupled with small, blackish stools. Unlike opiates, mitragynine does not
appear to cause nausea or vomiting. Heavy use can result in a prolonged
sleep.
Side effects from long term use include anorexia and weight loss, insomnia,
and a darkening of the skin, particularly on the cheeks, giving an
appearance similar to a hepatic face. Among addicts, 30% report limited
sexual desire and the need to use a combination of kratom and alcohol to
become sexually stimulated. One study found 5 people who had psychotic
conditions which may or may not have been revealed by very heavy kratom use.
As discussed earlier, addiction seems to be a possibility if high doses are
used. Some withdrawal symptoms reported by addicts include hostility,
aggression, wet nose, inability to work, flow of tears, muscle and bone
aches, and jerky limb movement.
While one study of Thai users reported that it is sedative in low doses
changing over to stimulation in higher doses, this seems to be incorrect.
Most other sources say that it is a stimulant in lower doses, becoming
sedative in higher doses, which is consistent with mitragynine's receptor
binding profile. Effects come on within five to ten minutes after use, and
last for several hours. The feeling has been described as happy, strong, and
active, with a strong desire to do work. The mind is described as calm. The
Swiss biologist Claude Rifat experimented with a low dose of three smoked
leaves and reported the effects reminded him somewhat of SSRIs, in that it
blocked motivation, induced indifference, made doing everything boring, and
brought on a strong laziness. It seems likely that these two almost opposite
results may be influenced by cultural expectations.
Inspired by traditional use, H. Ridley reported In 1897 that the leaves of
Mitragyna speciosa were a cure for opium addiction. In more recent times,
mitragynine has been used in New Zealand for methadone addiction detox.
Kratom was smoked whenever the patient experienced withdrawal symptoms, over
a 6 week treatment period. Patients reported a visualization effect taking
place at night in the form of vivid hypnagogic dreams. While working on
plans for ibogaine experiments in the USA, Cures Not Wars activist Dana Beal
suggested that mitragynine could be used as an active placebo for comparison
in the study. Acting Deputy Director of the NIDA Charles Grudzinskas
rejected the proposal, however, saying that even less was known about
mitragynine than ibogaine.
Although chemically similar, ibogaine and mitragynine work by different
pathways, and have different applications in treatment of narcotic
addiction. While ibogaine is intended as a one time treatment to cure
addiction, mitragynine used to gradual wean the user off narcotics. The fact
that mitragynine's mu crossover is increased by the presence of opiate drugs
may be exploitable in the treatment of narcotics addiction, because it
directs binding to where it is needed, automatically regulating the
attachment ratio and modulating it towards the delta receptors over a short
time. Within a few days, the addict would stop use of the narcotic they are
addicted to, and the cravings and withdrawal will be moderated by the
binding of mitragynine to the delta receptors. Mitragynine could also
perhaps be used as a maintenance drug for addicts not wishing to quit but
trying to moderate an out of hand addiction.
In 1999, Pennapa Sapcharoen, director of the National Institute of Thai
Traditional Medicine in Bangkok said that kratom could be prescribed both to
opiate addicts and to patients suffering from depression, but stressed that
further research is needed. Chulalongkorn University chemists have isolated
mitragynine which researchers can obtain for study.
In conclusion, there seems to be much more research done into this plant and
its active constituents. Although kratom has been used since time immemorial
by Thai natives, Western science hasn't paid it that much attention. What
research does exist contains some apparent conflicts. Knowledge even of the
plant's existence outside of Thailand has been limited to ethnobotanists and
a handful of pharmacology researchers. Availability of live plants and dried
leaves has been practically non-existent until very recently.
There is much to learn.
Credits
Atthakor P. "Role Seen For Traditional Herbal Stimulant": Bangkok Post
November 27, 1999
De Rienzo P, Beal D, The Statten Island Project. "The
Ibogaine Story"
Idid S Z, Saad L B, Yaacob H, Shahimi M M. "Evaluation Of Analgesia Induced
By Mitragynine, Morphine And Paracetamol On Mice": ASEAN Review of
Biodiversity and Environmental Conservation, Nov-Dec 1999
Merck & Co., Inc. "The
Merck Index": 12th edition, 1996.
Oxford University Press. "Dictionary of Organic Compounds": Volume 4, 4th
edition, 1965.
Rifat, Claude. "Mitragynine": http://www.lycaeum.org/drugs/SSRI/mitragy.html
Shaman Australis. Mitragyna speciosa catalog entry: http://www.shaman-australis.com/Website/Mitragynaspeciosa.htm
Shaman Australis. Personal email from owner: shaman@shaman-australis.com
Shellard E J. "The alkaloids of Mitragyna with special reference to those of
Mitragyna speciosa, Korth": Bulletin On Narcotics, 1974 issue 2
Suwanlert M D Sangun. "A study of kratom eaters in Thailand": Bulletin on
Narcotics, 1975 issue 3
Thongpradichote S, Matsumoto K, Tohda M, Takayama H, Aimi N, Sakai S,
Watanabe H. "Identification of opioid receptor subtypes in antinociceptive
actions of supraspinally-administered mitragynine in mice": Life Sci
1998;62(16):1371-8
Yamada R. "Re: Is Mitragynine anti-addictive?": Usenet post
199702031505.KAA21187@interport.net
from
http://www.imr.gov.my/webpage%20HMRC/foc04(1).html
Specific to Mitragyna speciosa
(Kratom):
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