life
Review
Mitragyna Species as Pharmacological Agents: From Abuse to
Promising Pharmaceutical Products
Islamudin Ahmad 1,2, * , Wisnu Cahyo Prabowo 2 , Muhammad Arifuddin 1 , Jaka Fadraersada 1 ,
Niken Indriyanti 1 , Herman Herman 2 , Reza Yuridian Purwoko 3 , Firzan Nainu 4 , Anton Rahmadi 5 ,
Swandari Paramita 6 , Hadi Kuncoro 2 , Nur Mita 1 , Angga Cipta Narsa 2 , Fajar Prasetya 2 , Arsyik Ibrahim 2 ,
Laode Rijai 2 , Gemini Alam 4 , Abdul Mun’im 7 and Sukanya Dej-adisai 8
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3
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5
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Citation: Ahmad, I.; Prabowo, W.C.;
Arifuddin, M.; Fadraersada, J.;
Indriyanti, N.; Herman, H.;
Purwoko, R.Y.; Nainu, F.;
Rahmadi, A.; Paramita, S.; et al.
Mitragyna Species as Pharmacological
Agents: From Abuse to Promising
Pharmaceutical Products. Life 2022,
12, 193. https://doi.org/10.3390/
life12020193
Academic Editor: Francois Lefort
Received: 20 December 2021
Accepted: 13 January 2022
Published: 27 January 2022
Publisher’s Note: MDPI stays neutral
with regard to jurisdictional claims in
published maps and institutional affiliations.
Copyright: © 2022 by the authors.
7
8
*
Department of Pharmaceutical Sciences, Faculty of Pharmacy, Universitas Mulawarman,
Samarinda 75119, Indonesia; marifuddin@farmasi.unmul.ac.id (M.A.); jakafadraersada@gmail.com (J.F.);
niken.indriyanti@gmail.com (N.I.); mita@farmasi.unmul.ac.id (N.M.)
Pharmaceutical Research and Development Laboratory of FARMAKA TROPIS, Faculty of Pharmacy,
Universitas Mulawarman, Samarinda 75119, Indonesia; wisnu@farmasi.unmul.ac.id (W.C.P.);
herman.mulawarman@gmail.com (H.H.); kuncoro_hadi82@yahoo.com (H.K.);
anggaciptan@yahoo.com (A.C.N.); fajarprasetya@farmasi.unmul.ac.id (F.P.); achie.ibrahim@gmail.com (A.I.);
najwankhanrjai@yahoo.co.id (L.R.)
Faculty of Military Medicine, Universitas Pertahanan RI, Bogor 16810, Indonesia; reza.purwoko@idu.ac.id
Faculty of Pharmacy, Hasanuddin University, Makassar 90245, Indonesia; firzannainu@unhas.ac.id (F.N.);
daengta007@yahoo.com (G.A.)
Department of Agricultural Product Technology, Faculty of Agriculture, Universitas Mulawarman,
Samarinda 75119, Indonesia; arahmadi@unmul.ac.id
Research Center of Natural Products from Tropical Rainforest (PUI-PT OKTAL), Department of
Community Medicine, Faculty of Medicine, Universitas Mulawarman, Samarinda 75119, Indonesia;
s.paramita@fk.unmul.ac.id
Laboratory of Pharmacognosy-Phytochemistry, Faculty of Pharmacy, Universitas Indonesia,
Depok 16424, Indonesia; munim@farmasi.ui.ac.id
Department of Pharmacognosy and Pharmaceutical Botany, Faculty of Pharmaceutical Sciences,
Prince of Songkla University, Hat-Yai, Songkhla 90110, Thailand; sukanya.d@psu.ac.th
Correspondence: islamudinahmad@farmasi.unmul.ac.id
Abstract: Mitragyna is a genus belonging to the Rubiaceae family and is a plant endemic to Asia and
Africa. Traditionally, the plants of this genus were used by local people to treat some diseases from
generation to generation. Mitragyna speciosa (Korth.) Havil. is a controversial plant from this genus,
known under the trading name “kratom”, and contains more than 40 different types of alkaloids.
Mitragynine and 7-hydroxymitragynine have agonist morphine-like effects on opioid receptors.
Globally, Mitragyna plants have high economic value. However, regulations regarding the circulation
and use of these commodities vary in several countries around the world. This review article aims
to comprehensively examine Mitragyna plants (mainly M. speciosa) as potential pharmacological
agents by looking at various aspects of the plants. A literature search was performed and information
collected using electronic databases including Scopus, ScienceDirect, PubMed, directory open access
journal (DOAJ), and Google Scholar in early 2020 to mid-2021. This narrative review highlights some
aspects of this genus, including historical background and botanical origins, habitat, cultivation, its
use in traditional medicine, phytochemistry, pharmacology and toxicity, abuse and addiction, legal
issues, and the potential of Mitragyna species as pharmaceutical products.
Keywords: 7-hydroxymitragynine; kratom; Mitragyna speciosa; mitragynine
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
1. Introduction
Mitragyna is a genus belonging to the Rubiaceae family, also known as the coffee
family [1]. There are ten species in this genus. As many as 0% of the species of this
genus are native plants and are widely found in various regions in Asia, including India,
Life 2022, 12, 193. https://doi.org/10.3390/life12020193
https://www.mdpi.com/journal/life
Life 2022, 12, 193
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Bangladesh, Malaysia, Thailand, Vietnam, the Philippines, New Guinea, and Indonesia
(Sumatra and Kalimantan) [1,2]. The remaining species are dispersed across mainland
Africa and East Asia [3,4]. Plants of this genus grow in swampy areas, along riverbanks,
and in areas often inundated by water [3]. Traditionally, the Mitragyna genus has been
trusted and used by the local community to treat various diseases such as fevers, malaria,
diarrhea, coughs, hypertension, diabetes mellitus, muscle pain, and worm infections [5].
Scientifically, it has also been reported that Mitragyna has a pharmacological effect that
has the potential to be a source of raw materials for drugs that have the following effects:
anti-inflammatory and antinociceptive [6,7]; anti-obesity [8]; analgesic [9–12]; antipyretic,
sedative, stimulant, and depressant [13–16]; antidopaminergic [17]; effects on memory [18];
antidiarrheal [19,20]; antioxidant [21,22]; and antimicrobial [21].
Mitragyna plants contain more than 40 types of alkaloids [23], especially mitragynine
(66.2%) and its derivatives, paynantheine (8.6%), speciogynine (6.6%), 7-hydroxymitragynine
(2%), and speciociliatine (0.8%) [24], which have an agonist morphine-like effect on opioid
receptors [25,26]. Mitragyna speciosa (Korth.) Havil. is the species most commonly reported
to contain psychoactive alkaloids [27]. It is native to East Kalimantan, Indonesia, where it is
known by the local name “kadamba,” known in the world market as “kratom.” This plant
is mostly grown and cultivated in Indonesia’s Kalimantan and is exported to European and
American countries.
The available products of this plant are traded online in liquid, powder, and extract
forms [27,28]. M. speciosa has a high economic value, especially in dried leaf powder and
extract forms. For 5 g of kratom extract, the price starts at $35 to $45 [24]. Kratom is
illegal in some countries, although it has been legalized in other countries [29–31]. Many
publications [32–38] have reported the abuse and addictive effects of this plant. The Drug
Enforcement Administration (DEA) of the United States has added this plant to its list
of drugs of concern, and the Food and Drug Administration (FDA) has issued a press
release identifying it as an opioid with the potential for abuse, although the literature on its
therapeutic and adverse effects is still lacking [39]. On the other hand, this plant also has
the potential to be a source of medicinal raw materials that can be processed into profitable
pharmaceutical products.
This review article aims to comprehensively examine Mitragyna plants (mainly
M. speciosa) as potential pharmacological agents through the investigation of aspects such
as historical background and botanical origins, habitat, cultivation, the application of
Mitragyna in traditional medicine and ethnomedical uses, phytochemistry, pharmacology,
and toxicity, abuse and addiction, legal issues, and the potential of Mitragyna plants as
pharmaceutical products.
2. Research Methodology
In the current narrative review study, the literature search was performed from
March 2020 to July 2021 using electronic databases such as PubMed, Embase, Scopus,
Web of Science, Directory of Open Access Journals (DOAJ), National Health Institute (NIH),
and Google Scholar. The relevant search terms for all aspects of Mitragyna plants were
(Mitragyna Korth OR Mitragyna Genus OR Mitragyna OR kratom OR mitragynine) AND
(botanical OR ethnobotany OR morphology OR taxonomy OR habitat OR cultivation) AND
(traditional medicine OR ethnomedical uses) AND (pharmacology OR pharmacokinetic
OR toxicology of Mitragyna) AND (phytochemistry OR phytoconstituent). A literature
search for relevant abuse, addiction effects used the following keywords: (Mitragyna OR
kratom OR mitragynine) AND (abuse or addiction or human effect) AND (legal status).
3. Historical Background and Botanical Origins
Mitragyna is a paleotropic genus of medium size that is widely found mainly in tropical
and subtropical areas and is native to Africa [2] and Asia [40]. The genus Mitragyna was first
described by the Dutch botanist Pieter Willem Korthlas (1807–1892), who discovered the
plants and created significant botanical collections in the Malay Archipelago. Historically,
Life 2022, 12, 193
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this genus has gone through various studies and processes of compiling and placing
sub-families into various families, finally leading to Robbrecht re-entering this genus
into the Rubiaceae family in 1993 [4]. The Rubiaceae family, commonly called the coffee
or madder family, is one of the most prominent plant families [41]. Rubiaceae can be
classified into several subfamilies, such as Cinchonoideae, Ixoroideae, and Rubioideae,
with Cinchonoideae being the smallest member (~120 genera, including Mitragyna) [42].
This family is known for features such as round petal flowers, inferior ovaries, interpetiolar
spots, and simple crossed or slightly circular leaves [43,44].
Mitragyna is one of the rubiaceous genera (Rubiaceae) that were once grouped with
the Naucleaceae family, with dense, round, head-like inflorescences [45,46]. Plants of the
genus Mitragyna are shrubs or trees characterized by a dense inflorescence system. The
flowers are arranged in compact round heads with pale interflora spathuloid bracts. The
flowers and ovaries are fused, and the fruit is abundant [44]. They have two-celled ovaries
with a cylindrical stigma, opposite leaves, and keel-shaped stalks. The flower’s head lies
on the side shoots laterally, forming a short or long tube with five lobes. The flowers have
heart-shaped stamens with heads containing lanceolate anthers [43,45–47]. Plants of the
genus Mitragyna consist of ten species (six species are found in Asia to Southeast Asia, and
the four other species are found in Africa), as shown in Table 1.
Table 1. The botanical origin of the plants of the genus Mitragyna.
No.
Species
Synonyms
Botanical Origin
References
1
M. ledermannii
(K. Krause) Risdale
M. ciliate Aubrev. & Pellegr.: Fleroya ledermannii (K.
Krause) Risdale Y.F.Deng.; and Hallea ciliate
(Aubrev. & Pellegr.) J.F.Leroy
The species spreads from eastern Liberia to the
Central African Republic, the south of Gabon,
Congo, and Angola
[48–50]
2
M. rubrostipulata
(K. Schum) Havil.
F. rubrostipulata (K. Schum) Y. F. Dengs; H.
rubrostipulata (K. Schum.) J.F.Leroy; and Adina
rubrostipulata K. Schum.
The species spreads across various regions in
Africa, including the Democratic Republic of
Congo, Ethiopia, Tanzania,
Malawi, and Mozambique
[44,47,49,50]
M. inermis (Willd.) Kuntze
M. africanum (Willd.) Hook; Nauclea africana Willd.;
N. africana var. luzoniensis DC.; N. platanocarpus
Hook.f.; N. inermis (Willd.) Baill; Cephalanthus
africanus Rchb.; Platanocarpum africanum (Willd.)
Korth; Uncaria inermis Willd.;
and Adina inermis (Willd.) Roberty
The species spreads across eastern
Mauritania to Sudan
[44,47,49,50]
4
M. stipulosa (DC.) Kuntze
M. chevalieri K. Krause.; M. macrophylla Hiern.; F.
stipulosa (DC.) Y.F. Deng.; N. stipulosa DC.; N.
bracteosa Welw.; Adina stipulosa (DC.) Roberty;
Mamboga stipulosa (DC.);
and H. stipulosa (DC.) J.F. Leroy
The species spreads from eastern
Senegal to Uganda and southern Senegal to
Zambia and Angola
[44,49,50]
5
M. hirusta Havil.
M. Africana (Willd.) Korth.; Platanocarpum Africana
(Willd.) Hook.; Cephalanthus africanus Rchb.; N.
africana Willd.; and Paradina hirusta (Havil.) Pit
The species is found in the Asian region,
mainly in Thailand, Vietnam, Laos,
China, and Cambodia
[43,44,49,50]
6
M. diversifolia
(Wall. Ex G.Don) Havil.
M. javanica Koord; Stephegyne parvifolia Vidal; S.
tubulosa Fern.; N. diversifolia Wall. Ex. G. Don; N.
adina Blanco; and Mamboga capitata Blanco
This species spreads across Asia, i.e., Indonesia,
Malaysia, the Philippines, Thailand, Vietnam,
Cambodia, Laos, and China
[43,44,49,50]
7
M. parvifolia (Roxb.) Korth.
Stephegyne parvifolia (Roxb.) Kuntze; N. parvifolia
Roxb.; and N. parvifolia Willd
The species has been found in Asia, especially in
Myanmar, Sri Lanka, India, and Bangladesh
[43,49,50]
8
M. rotundifolia
(Roxb.) Kuntze
M. brunonis (Wall. Ex. G. Don) Craib.; N.
rotundifolia Roxb.; N. brunonis Wall, Ex. G. Don.;
and Bancalus rotundifolius (Roxb.) Kuntze
This species has been found in Asia, mainly in
the regions of Thailand, Myanmar, Laos, China,
India, and Bangladesh
[43,44,49,50]
9
M. tubulosa (Arn.) Kuntze
N. tubulosa Arn
The species is endemic to Asia
(mainly India) and has spread to Kerala, Tamil,
Nadu, and Sri Lanka
[43,49–51]
10
M. speciosa (Korth.) Havil
N. luzoniensis Blanco, N. korthalsii Steud, N. speciosa
(Korth.), and Stephegyne speciosa Korth
The species is endemic to southeastern Asia and
is scattered across various regions of Myanmar,
Vietnam, Thailand, Malaysia, Indonesia, and
Papua New Guinea
[40,49,50,52]
3
M. speciosa is best known as “kratom” but is also known as giam in Vietnam, thom,
ithang, gratom, bai krathom, kakaum, and kratom in Thailand, kadamba, purik, and
keton in Indonesia, ketum, sepat, biak-biak, and kutum in Malaysia, mambog, lugug, and
polapupot in the Philippines, and beinsa, bein-sa-ywat in Myanmar. Information on this
species was first published by Pieter Willem Korthals (a botanist from the Netherlands,
Life 2022, 12, 193
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1807–1892) under the name Mitragyna. However, the proposal was considered invalid
because it was not accompanied by the required botanical descriptions according to the
International Code of Botanical Nomenclature. Similar to other genera, some experts also
renamed Mitragyna plants by grouping them into the genus Naucleae, under names such as
N. korthalsii, N. luzonionesis, and N. speciosa. Ultimately, Haviland returned the plant to the
Mitragyna genus; thus, it was accepted as M. speciosa.
4. Habitat and Cultivation of Mitragyna Plants
Naturally, Mitragyna species can grow in swampy habitats, riverbanks, inundated
soils, or non-inundated soils [52]. Plants of this species are generally tree forms that do
best in areas with wet or moist soil and also do well on rocky soils with moderate to total
sun exposure [53]. Mitragyna plants thrive in the rainy season, and their leaves will fall
off during the dry season. In less fertile to average soil conditions, these plants can grow
to a height of 4–9 m. However, if the place where they grow is on fertile soil or in their
natural habitat, they can grow to a height of 15–30 m [43,53–55]. Mitragyna’s habitat is in
watersheds and swamps. Mitragyna plants (mainly M. speciosa) grow optimally in alluvial
soil (mineral deposits) that is fertile with sufficient water. This plant has the ability to
survive under waterlogged conditions.
The above conditions can be found in several areas in Indonesia, such as land areas in
Kalimantan. M. speciosa is mostly found growing naturally in the same habitat as aquatic
plants such as Donax canniformis, Limnocharis flava, Ipomoea aquatica, and Nauclea officinalis.
N. officinalis has a morphology similar to M. speciosa, and it is often used as an adulterant of
this plant. M. speciosa is easy to grow from seeds that fall from trees and breeds quickly in
moist soil. In addition, this plant also functions as a barrier to soil erosion on the banks
of rivers.
The genus Mitragyna is very easy to cultivate. M. speciosa is one of the most widely
cultivated species in this genus. In several areas in Indonesia (especially in Kalimantan),
local people cultivate and trade the leaf part of this plant as an export commodity, which
has become the major source of income for farmers. This plant can easily be cultivated
under various conditions, such as moist, dry, or swampy soils. However, apart from
cultivation, these plants still grow naturally in forest areas, swamps, and on riverbanks [56].
Zhang et al. (2020) [57] reported that the fertility level of soil where M. speciosa grew had
little effect on the contents of secondary metabolites (mainly alkaloid content) in the leaf.
Meanwhile, low-to moderate fertilizer levels increase the levels of several compounds,
such as isocorynantheidine, corynantheidine, and speciogynine. Fertilizer is vital to further
research to determine the optimum fertilization conditions to increase the levels of target
secondary metabolites. In addition, some local farmers (in East Kalimantan) claim that
irrigation also affects the fertility level in the environment where this species is grown.
The leaves of M. speciosa are harvested for the first time when the plants are six months
old with an average height of ±1 m. Harvesting is carried out by picking the old leaves and
leaving the shoots and a few young leaves. The next harvest is carried out about 1–3 months
after the first harvest. The second and subsequent harvests will continue to experience
an increase in production of about 30%. The level of soil fertility strongly influences this
increase. M. speciosa plants that are large and about 2.5 years old have the main stem cut
out to facilitate harvesting and stimulate the emergence of branching, cutting the height to
1.5, 1, or 0.2 m from the base of the stem [58].
5. The Genus Mitragyna in Traditional Medicine Uses
Mitragyna is traditionally used in several countries where widely grown, such as in
Africa and Asia. This genus has been used from generation to generation for hundreds of
years, and some species were even recorded in traditional medicinal systems.
In Africa, most species of this genus are used by local people to treat various diseases;
M. ledermanii, M. stipulosa, M. inermis, and M. rubrostipulosa are traditionally used to treat
malaria [59], rheumatism, cardiovascular diseases, amenorrhea, inflammation, headaches,
Life 2022, 12, 193
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bronco-pulmonary diseases, and diabetes mellitus [55]. The stem bark of this plant is
traditionally combined with Garcinia cola to treat trypanosomiasis in Nigeria [60]. M. inermis
leaf decoction is used as an antidiabetic in Ivorian traditional medicine [61] and is used to
treat inflammation [62].
In Asia, the genus Mitragyna is also widely used in traditional ways, as in Africa.
Several species are widely used in traditional medicine, such as M. parvifolia, M. hirusta, M.
diversifolia, M. rotundifolia, and, controversially, M. speciosa. As for the species of M. tubulosa,
empirical use data were not recorded in the search for articles from 1990–2021, and research
publications on this species are still very limited. M. parvifolia is empirically used as an
anthelmintic [55] and antifungal [63]. In Ayurveda, traditional medicine practitioners
use bark and roots to treat fever, colic, burning, poisoning, muscle aches, edema, coughs,
gynecological disorders, and as aphrodisiacs. The leaves are used to treat wounds by
attaching them to reduce pain and swelling. Fruit juice is used to increase breast milk, as a
depurant [63,64], and as an anticonvulsant [65]. M. rotundifolia leaves [66] and M. diversifolia
bark [20] were empirically used for antidiarrhea, mainly in the Bawm tribe in Bangladesh.
The leaves of M. hirusta are used as an analgesic and to treat mental illness [55].
M. speciosa is a controversial endemic Asian plant of this genus, although it has long
been used in traditional medicine. In Thailand, Malaysia, Indonesia, and several neighboring countries, the leaves help reduce headaches, pain, and toothaches and increase stamina.
In addition, it was also noted that M. speciosa was traditionally used for hypertension,
diabetes, and fever. Traditional methods of administration include chewing, smoking,
or regular decoction [5,38,67]. The use of M. speciosa in males has been studied in rural
communities in southern Thailand and has been shown to increase work productivity,
make people stronger, less sleepy, less tired, more energetic, and more active. The number
of leaves chewed or brewed also varies, with a single dose of 0.5–4 leaves, or 10–80 leaves
per day for regular users. Some users who have routinely consumed this species for 25, 20,
and seven years can stop using M. speciosa for varying lengths of time. Moreover, users
consume it in the form of fresh leaves, and it is also used in the form of tea drinks made
from dried leaves. Users can preserve the leaves in the dry form if the plant is abundant
because the effects are the same in both the fresh and dried forms [68]. In addition, it is
also reported to be used as an aphrodisiac [69].
In Thailand, M. speciosa is more commonly used by men than women. Respondents in
Assanangkonchai’s (2007) [70] study believe that kratom can improve work performance
by increasing resistance and tolerance to sunlight and by helping the user overcome
fatigue. In particular, M. speciosa is also known to treat several conditions such as diarrhea,
cough, and hypertension [55]. A similar ethnopharmacological study was also carried
out in northern Malaysia by Ahmad and Azis (2012) [71]. The main reasons for using
M. speciosa are stamina and endurance, social and recreational use, and improving sexual
performance. In addition, based on the primary reasons for using M. speciosa provided by
users/respondents, M. speciosa is used to facilitate sleep, for its euphoric effects, and to
reduce symptoms of withdrawal from opioid drugs [71]. In Singh’s (2015) study regarding
the socio-demographics of M. speciosa users, it is known that 83% of users know that the
plant can cause addiction and dependence [67].
M. speciosa has traditionally been used in Indonesia to improve stamina, cure pain,
rheumatism, gout, hypertension, stroke symptoms, diabetes, sleeplessness, wounds, diarrhea, cough, cholesterol, typhoid, and stimulate appetite [5,58,72,73]. Several empirical
properties have been studied, including substantial analgesic effects, sedative effects, immune system boosting benefits, stimulant and anti-depressant effects, usage in pregnant
and nursing women, and possible misuse and withdrawal symptoms [10,15,26,74–76].
The action are caused by secondary metabolite contains in M. speciosa leaves (mainly
mitragynine and 7-hydroxymitragynine), which are later accountable for these pharmacological effects [77–82]. In addition, there are many other groups of secondary metabolites [21,50,80,83–85] that are interesting for further research.
Life 2022, 12, 193
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6. Phytochemistry of the Genus Mitragyna
Research on the phytochemical content of the genus Mitragyna has been widely reported for hundreds of years. As with other genera from the Rubiaceae family, the genus
Mitragyna (mainly M. speciosa) has been reported to be rich in compounds of the alkaloid
group [3,23,78–82]. So far, as many as 79 secondary metabolites from the genus Mitragyna
have been published and described in detail, including the dominant compounds of alkaloids, flavonoids, and polyphenols [21,80], terpenoids, triterpenoids [83], saponins, and
secoiroids [50,84,85] as shown in Table 2.
Table 2. Secondary metabolite compounds in leaves of the genus Mitragyna.
No
Species
Indole and Oxindole Alkaloids
Other Compounds
References
1
M. ledermannii
(K. Krause) Risdale
Mitraciliatine, rhynchophylline, rhynchociline,
ciliaphylline, rotundifoline, isorotundifoline
-
[2,50]
2
M. rubrostipulata
(K. Schum) Havil.
Hirsuteine, mitraphylline, isomitraphylline,
isorotundifoline, rotundifoline N- oxide,
isorhynchophylline, rhynchophylline N-oxide,
rhynchophylline, rotundifoline,
-
[50,86]
[2,50,87–90]
3
M. inermis
(Willd.) Kuntze
Uncarine D (speciophylline), rhynchophylline,
isorhynchophylline, rotundifoline, isorotundifoline
Quercetin, dihydrodehydrodiconiferyl
alcohol, isolariciresinol,
isolariciresinol-3α-O-β-D-glucopyranoside,
ursolic acid, oleanoic acid, betulinic acid,
barbinervic acid, quinovic acid and its derivates,
inermiside I, inermiside II,
4
M. stipulosa (DC.) Kuntze
Mitraphylline, rhyncophylline, isorhynchophylline,
rotundifoline, isorotundifoline
Ursolic acid, quinovic acid and its derivates,
sitoseterol, stigmasterol, daucosterol
[2,50,84,91]
M. hirusta Havil.
Mitraciliatine, mitraphylline, isomitraphylline,
isomitraphylline N-oxide, rhynchophylline,
isorhynchophylline, isopteropodine, isomitraphyllinol,
hirsuteine, mitrajavine, uncarine D (speciophylline),
rhynchophylline, isorhynchophylline,
rotundifoline, isorotundifoline
-
[50,92–95]
M. diversifolia
(Wall. Ex G.Don) Havil.
7- hydroxy-isopaynantheine, 3-dehydro-paynantheine,
3-isopaynantheine-N(4)- oxide, mitrafoline,
mitradiversifoline, specionoxeine-N(4)-oxide,
specionoxeine-N(4)-oxide
3α, 6β, 19α-trihydroxy-urs-12-en-28-oic acid, 3β,
6β, 19α- trihydroxy-urs-12-en-28-oic acid;
3-oxo-6β-19α-dihydroxy-urs-12-en-28-oic acid;
3β, 6β, 19α-trihydroxy-urs-12-en-24, 28-dioic acid
24-methyl ester; 3β, 6β, 19α,
24-tetrahydroxy-urs-12-en-28-oic acid; rotundic
acid; 23-nor-24-exomethylene- 3β, 6β,
19α-trihydroxy-urs-12-en-28-oic acid; pololic acid
[50,96–98]
M. parvifolia
(Roxb.) Korth.
Dihydrocorynantheol, dihydrocorynantheol N-oxide,
akuammigine, akuammigine N-oxide, 3-isoajmalicine,
mitraphylline, isomitraphylline, rhynchophylline,
isorhynchophylline, rotundifoline, isorotundifoline,
speciophylline N-oxide, uncarine F, uncarine F N-oxide,
pteropodine, isopteropodine, uncarine D
(speciophylline), 16,17-dihydro-17β-hydroxy
isomitraphylline, 16,17-dihydro17β-hydroxy mitraphylline
-
[50,64,99,100]
8
M. rotundifolia
(Roxb.) Kuntze
mitraphylline, isomitraphylline, rhynchophylline,
isorhynchophylline, isorhynchophylline
N-oxide, rotundifoline
3,4-dihydroxybenzoic acid, cathecin,
caffeic acid, epicathecin, kaempferol,
4′ -O-methyl-gallocatechin,
4-hydroxy-3-methoxybenzoic acid,
3-hydroxy-4-methyloxybenzoic acid, cincholic acid,
quinovic acid and its derivates
[50,99,101–104]
9
M. tubulosa
(Arn.) Kuntze
Mitraciliatine, rhynchociline, ciliaphylline,
rotundifoline, isorotundifoline, rhynchophylline,
isorhyncophylline, mitraphylline,
isomitraphylline, ciliaphylline N-oxide
-
[2,50,91]
M. speciosa (Korth.) Havil
mitragynine, 7-hydroxymitragynine, paynantheine,
mitralactonal, mitragynaline, speciociliatine,
speciogynine, mitrasulgynine,
3,4,5,6-tetradehydromitragynine, mitragynaline,
mitragynalinic acid, corynantheidinaline,
corynantheidinalinc acid, 3-dehydromitragynine,
9-methoxymitralactonine, 3-isopaynantheine,
ajmalicine, isocorynantheidine, mitragynine
pseudoindoxyl, mitraphylline, mitragynine oxindole A,
mitragynine oxindole B, corynoxine, corynoxine B,
mitraciliatine, 7β-hydroxy-7H-mitraciliatine,
isomitraphylline, rhynchophylline, rhyncocilline,
cilaphylline, isospeciofoleine,
isospeciofoline, isorotundifoline
Apigenin, apigenin 7-glycosides, quercetin,
quecitrin, rutin isoquercitrin, hyperoside,
quercetin-3-galactoside-7-rhamnoside, kaempferol,
kaempferol 3-glucoside, epicatecin,
caffeic acid, chlorogenic acid,
1-O-feruloyl-β-D-glucopyranoside,
benzyl-β-D-glucopyranoside, quinovic acid and
its derivates, monoterpenes
3-oxo-α-ionyl-O-β-Dglucopyranoside, roseoside,
secoiridoid, vogeloside, epigeloside
[3,23,50,71,72,
105–116]
5
6
7
10
β
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Brown et al. (2017) [50] conducted a literature survey, noting as many as 57 secondary metabolite compounds, 37 of which were unique groups of alkaloids derived from
M. speciosa. Likewise, Firmansyah et al. (2021) [24] explained that the leaves of M. speciosa
contained more than 40 types of alkaloids, with six of them having been identified and
tested to be pharmacologically active, especially as a psychoactive substances, including mitragynine, 7-hydroxymitragynine, mitraphylline, speciociliatine, speciogynine, and
paynantheine (as shown in Figure 1). The most abundant compound found in commercial kratom products (the leaf of M. speciosa) is mitragynine, which contains 2% of the
total weight and 66% of the total alkaloid content of the dried M. speciosa leaf, whereas
7-hydroxymitragynine is an active metabolite oxidized from mytraginine at 0.02% of the
total weight of the dried M. speciosa leaf [24].
Mitragynine
7-hydroxymitragynine
Mitraphylline
Speciociliatine
Speciogynine
Paynantheine
Figure 1. M. speciosa leaves contain physicochemically active indole and oxindole alkaloid compounds.
Previous phytochemical studies on the Mitragyna genus isolation found indole alkaloids (mainly mitragynine) [94,99] and triterpenoid saponins [23,103,117] to be the predominant ingredients of this plant, accounting for roughly half of the total alkaloid content. At
the same time, in vitro and/or in vivo studies, as well as clinical trials, have shown that
Mitragyna and its active components have broad pharmacological activities.
7. Pharmacology and Toxicity of the Genus Mitragyna
The Mitragyna genus has been used as a traditional medicine to treat diseases [99,100].
In this section, we discuss the pharmacological and toxicological aspects of M. speciosa.
As it gained popularity in recent years, M. speciosa consumption also increased, raising
concern for its possible development as a beneficial natural remedy and its potential risk of
abuse among the public.
7.1. Pharmacological Aspect of M. speciosa
M. speciosa contains more than 40 compounds of alkaloids, four of which have been
proven to be active, i.e., mitragynine, 7-hydroxy mitragynine, speciociliatine, and corynan-
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thidine [23,24]. Mitragynine is the most abundant component in the M. speciosa leaf, constituting 66% of the total alkaloid content, whereas others only account for 1–9% [53,118].
Mitragynine is an indole-containing alkaloid and is suggested to have approximately
13 times the potency of morphine [53,118,119].
Idayu et al. (2011) [13] reported that the administration of mitragynine at doses of
10 mg/kg and 30 mg/kg (intra peritoneal) was able to provide an antidepressant effect on
mice, as suggested by the results of two behavioral experiments, the mouse force swim
test and the tail suspension test. Overall, the results of this study are consistent with the
results obtained in a clinical setting, further implying that mitragynine plays a role in
the regulation of depression and may have psychotherapeutic value in the treatment of
depressive disorders [13]. However, it is important to note that both the mouse force swim
test and the tail suspension test are not specifically established to model the depression
condition and there are some differences between experimental animal and clinical studies
in humans. Hence, the results obtained from these experiments need to be carefully viewed
and interpreted.
Reanmongkol et al. (2007) [10] demonstrated the antinociceptive response of mice
given methanol and alkaloid extracts in hot plate tests; the mice were suspected of having
activity in the supraspinal system. It has been reported that mitragynine, the active alkaloid
in M. speciosa leaves, has antinociceptive actions on noxious mechanical stimulation by
involving the descending noradrenergic and serotonergic systems of the supraspinal opioid
system [76,120], which is primarily mediated by mu- and delta-opioid receptor subtypes
in mice [121] and has a similar effect to oxycodone and morphine [11]. In addition to its
opioid-like analgesic effect, mitragynine stimulates postsynaptic alpha-2 adrenoreceptors
and inhibits cyclooxygenase-2 messenger RNA (mRNA) and protein expression, suggesting
non-opioid receptor pain-relieving effects [53,118,122]. The inhibition of COX-2 may affect
the formation of PGE2, which can lead to anti-inflammatory effects [6,53,123]. Moreover,
mitragynine impairs neuronal pain transmission via the blockade of Ca2+ channels, which
has been proposed as another antinociceptive mechanism of M. speciosa [124].
Methanolic extract from the M. speciosa leaf has an antidiarrheal effect by reducing
diarrheal frequency, the total diarrheal score, fecal weight, and intestinal transit. The proposed mechanisms were through anti-permeability action and decreased gastrointestinal
motility. The enteric nervous system controls motility in the small intestine primarily
through excitatory and inhibitory impulses. However, these local nervous system signals
are modulated by inputs from the central nervous system, and many gastrointestinal hormones appear to affect intestinal motility. These links are parasympathetic and sympathetic
fibers that connect the central nervous system directly with the digestive tract. Thus, the
extract of M. speciosa leaves may exert its effect on other pathways in addition to the effect
of mitragynine on the opioid receptors [19].
As the primary alkaloid in M. speciosa, mitragynine undergoes metabolism in humans via phase I and II mechanisms. After the parent drug is hydrolyzed, it undergoes O-demethylation followed by oxidative and reductive transformation to form intermediate aldehydes and conjugate glucuronide formation as the final step of phase II
metabolism [53,118]. The half-life of mitragynine is about 3.5 h and it is eliminated from
the body mainly in the urine [118,125].
The onset of the effects of M. speciosa is about 10–20 min, and the full effects can be
achieved about 30–60 min after ingestion. The strongest effects of M. speciosa occur at about
2–4 h. However, generally, the effects can last approximately 5–7 h after consumption
and will weaken after 24 h [118,119,126,127]. The extract of M. speciosa inhibits various
cytochrome P450 (CYP) enzymes, notably, CYP 3A4, 2D6, and 1A2. Prescribed or overthe-counter (OTC) medicine should be taken with caution because clinically significant
interactions may appear [128].
Even though M. speciosa has potential beneficial health effects, these are based on case
reports, preclinical animal studies, and derived from its traditional use in Southeast Asia.
The effect of the real use in humans to self-treat acute or chronic pain and other psychiatric
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conditions was obtained by a user-based survey [129–131]. This method has limitations in
outcomes and health diagnosis since it is self-reported and includes small sample sizes for
specific M. speciosa uses and health conditions.
7.2. Toxicological Aspect of M. speciosa
M. speciosa can be used against fatigue and can produce stimulant effects in low to high
dosages [33,132]. Consumption of this plant under long-term and high-dose conditions
could lead to several atypical effects and other effects such as anxiety, irritability, and
enhanced aggression [69]. Frequent users report tremors, anorexia, weight loss, seizures,
and psychosis [53,118]. In addition, seizures and addiction are mainly experienced by
individuals following long-term M. speciosa consumption, and liver toxicity can occur after
M. speciosa overdose [118,133]. Individuals with long-term addiction to M. speciosa have
been reported to have hyperpigmentation of the cheeks, tremors, anorexia, weight loss,
and psychosis [33].
Several case report studies have reported M. speciosa consumption as being linked to
medical conditions and death [134], including a case report of a 32-year-old male who was
found having seizure-like movements and foaming at the mouth. Despite the administration of benzodiazepine and intubation, the patient’s movement persisted. Twenty-four
hours after extubation since the first treatment, the patient admitted to the consumption of
M. speciosa, obtained from the internet [135]. Another seizure effect after M. speciosa ingestion was reported in a case report of a 64-year-old male, followed by a period of unresponsiveness. The detected mitragynine concentration in the urine was 167 ± 15 mg/mL [136].
A 44-year-old subject bought M. speciosa leaves from the internet and consumed
them to overcome chronic abdominal pain. The patient developed a myxedematous face
and lethargy following opiate withdrawal syndrome. Severe primary hypothyroidism
occurred after consuming M. speciosa leaves for four months. However, this condition
improved after fifteen months of taking oral opiates (methadone and oxycodone) combined
with levothyroxine [137].
One case reported a 25-year-old man with jaundice and pruritus who was admitted
to the hospital after ingesting M. speciosa excessively for two weeks. Drug-induced intrahepatic cholestasis was identified after liver biopsy. Mitragynine was confirmed after both
urine and serum samples were examined [133].
In animal models, particularly in rats, Azizi et al. (2010) [138] reported lethal effects of
200 mg/kg total alkaloid extract of M. speciosa. In contrast, Janchawee et al. (2007) [139]
reported the same effect after an oral dose of 200 mg mitragynine. Spontaneous behavior, food and water consumption, absolute and relative organ weight, and hematological
parameters did not change after acute oral administration of 100, 500, and 1000 mg/kg
doses of a standardized methanolic extract of M. speciosa. However, the administration of
methanolic extract led to a substantial rise in alanine transaminase (ALT) and argininosuccinate lyase (ASL), and elevated creatinine as a sign of nephrotoxicity was also seen at the
highest (1000 mg/kg) dose [140]. The impairment of kidneys and lungs, over-inflation of
the alveoli, and increased blood urea and serum creatinine were detected in sub-chronic
high doses of M. speciosa [141].
In mice, the median lethal dose (LD50 ) for the oral administration of the methanolic
and alkaloid extracts of M. speciosa was 4.90 g/kg and 173.20 mg/kg, respectively [10],
which means that it has neither cytotoxic nor highly toxic effects. Chronic administration
of mitragynine can lead to addiction and cognitive function impairment in mice [18,33].
8. The Abuse and Addiction of the Mitragyna Species
M. speciosa is a plant from the genus Mitragyna that has been widely reported for
its abuse and addiction properties, upon consumption at high doses used (10–30 leaves
daily). As has been previously reported, consumption of the fresh leaf of M. speciosa, about
3–10 times a day depending on the sensation of their need, was intended to overcome
fatigue. In addition to fresh leaves, users or addicts may also consume the dried leaves
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after grinding [33]. Consumption of the dried leaf is usually either by a drink of warm
liquid such as warm water or hot coffee or in the form of a self-made cigarette prepared
from the dried leaves. Withdrawal symptoms that occur are similar to those of narcotic use.
This may be related to the dose and duration of use [33]. The use of M. speciosa leaves was
able to reduce pain and treat drug addiction. Several cases and studies in the United States
and Southeast Asia can be used to reference this traditional medicine.
8.1. Abuse and Adverse Effects of M. speciosa
In the United States, Tabayali et al. (2018) [39] described a kratom user who developed
a brief prodromal acute sickness, accompanied by increased liver enzymes with cholestatic
characteristics and jaundice. In this aspect, kratom use is a crucial contributor to the spread of
the opioid crisis, as therapeutic benefits are gained at the expense of potentially fatal adverse
effects [39]. He had a liver disorder characterized by yellow skin accompanied by nausea,
fatigue, joint pain, long night sweats, and high bilirubin values with detectable mitragynine
concentrations in urine. The pharmacological effects of using M. speciosa leaves and their
constituents depend on the usage dose. Low doses (1–5 g) may provide a mild stimulant
effect to help the user with fatigue. Opioid-like effects such as analgesia, constipation,
euphoria, and sedation are produced at moderate to high doses (5–15 g) [33,34].
In another case, a 64-year-old man had recurrent seizures after consuming M. speciosa
leaf tea mixed with Datura stramonium for one month due to chronic pain after postcolostomy surgery [136]. Men also experienced tonic-clonic seizures 43 years after taking
M. speciosa leaves and 100 mg of modafinil. The combination of M. speciosa with tramadol
and propylhexedrine has been reported to cause death [142]. There were 11 deaths in
the United States related to M. speciosa exposure, and all of them were among adults
aged 22–38 years. Two deaths involved single-substance M. speciosa use, and nine other
deaths involved exposure to multiple substances with agitation and tachycardia symptoms.
M. speciosa abuse has been found to be on the rise in Texas from January 2009 to the present.
Some cases are of M. speciosa alone and involve additives from the opioid and alcohol
groups. The reported effects are clinical signs of potentially toxic abuse [35,36].
8.2. Addiction Effects of M. speciosa
The consumption of M. speciosa leaves in Thailand and Malaysia has been shown to
improve quality of life, especially as part of postoperative treatment. For treating pain
after surgery, M. speciosa is an excellent substitute for narcotic analgesics. However, the
use of M. speciosa at high doses (in the form of juice or tea with doses exceeding more
than three glasses of the dried leaf of M. speciosa daily) and for a long time (its use as
nettle leaf supplements for more than five years) has the risk of causing addiction as in
narcotics [143,144]. In observations using the Clinical Opiate Withdrawal Score (COWS),
patients experienced a low-addiction reaction after withdrawal from M. Speciosa [145].
The average consumption of a high dose of M. speciosa leaves, such as three glasses per
day of M. speciosa leaf tea with mitragynine content per cup, is 79 mg/glass, which shows
an average intake of 276.5 mg daily. At the same time, the use of 350 mL of M. speciosa
leaf juice containing 83.4 mg of mitragynine is reported to be a risk for depression due
to withdrawal symptoms [146]. The risk of addiction is still lower compared to opioids,
methamphetamine, marijuana, benzodiazepines, and ketamine [147]. As confirmed by
the results of a study reported by Wilson et al. (2021) [148], administration of a combined
alkaloid extract of M. speciosa or mitragynine showed minimal symptoms and produced a
weaker dependence effect than the full agonist morphine.
8.3. Addiction Withdrawal Symptoms of Opioid Dependence
The alkaloid compounds of mitragynine and 7-hydroxymitragynine from the M. speciosa
leaf are known to stop opioid addiction based on studies reported by Matsumoto et al.
(2005) [124], Hassan et al. (2020) [149], and Harun et al. (2019) [150], using experimental animals. Matsumoto et al. (2005) [124] reported that the administration of 7-hydroxymitragynine
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(10 mg/kg, subcutaneous injection) twice daily for five days promoted lower withdrawal
signs than the morphine-dependent group of mice (10 mg/kg, subcutaneous injection).
Hassan et al. (2020) [149] found that mitragynine (5–30 mg/kg; intra peritoneal) can mitigate acute morphine dependence in rats. The withdrawal symptoms were significantly
reduced after four days of mitragynine replacement, suggesting that mitragynine, similar
to methadone and burprenorphine, can reduce morphine withdrawal symptoms. Similar
results were reported by Harun et al. (2019) [150]. The administration of mitragynine (twice
daily for 14 consecutive days at doses of 10 and 30 mg/kg) in rats could reduce the effect
of morphine dependence in a better rate than buprenorphine at doses of 0.3 and 1.0 mg/kg.
Mitragynine does not cause physiological dependence, but it does alleviate the physical
symptoms of morphine withdrawal, which are desirable characteristics of novel pharmacotherapeutic interventions for treating opioid use disorder (OUD) [145]. Several years
earlier, Vicknasingam et al. (2010) [69] reported similar results on the effect of symptom
relief in a clinical observation study using a cross-sectional survey of 136 active users in
the northern states of Kedah and Penang in Malaysia. The informal use of three glasses
of M. speciosa (approximately 250 mL per glass) a day with a daily content of 67.5–75 mg
mitragynine is significant for relieving symptoms of heroin dependence [69].
The potency of mitragynine and 7-hydroxymitragynine in M. speciosa is thought to
be due to the agonist activity against mu- and kappa-opioid receptors, which can reduce
opioid withdrawal symptoms [69,151]. Mitragynine and 7-hydroxymitragynine exhibit
opioid-mediated (naloxone sensitive) antinociceptive activity. Both components share
a similar structure to morphine, with three main functional groups binding to opioid
receptors: tertiary nitrogen, benzene, and hydroxyl phenolic. The group can bind to both
mu-receptors and kappa-receptors with an affinity for 7-hydroxymitragynine, 40 times
stronger than mitragynine and 10 times stronger than morphine [25]. This may cause the
dosage of M. speciosa to be lower than morphine to treat pain, so that withdrawal symptoms
are lessened. The use of M. speciosa extract or single mitragynine showed withdrawal
symptoms in mice that were lower in physical behavior than morphine on mu-receptor
agonists. Likewise, this substance has been used to improve symptoms of morphine
dependence [143]. The mytraginine content is lower in the Malaysian plants (12%) than
in the Thailand ones (66%), which can also be attributed to the large number of people
using the plant in Peninsular Malaysia, which has succeeded in reducing addiction due to
long-term narcotic use [69].
Overall, the traditional use of M. speciosa as well as mtragynine alkaloid derivatives in
laboratory experiments using experimental animals has shown a lower addictive effect on
withdrawal symptoms compared to narcotics and can be used as therapy to reduce addiction due to the use of these narcotics. So far, the addictive effects that have been reported
only occur in long-term users with high doses [143–146], while withdrawal symptoms occur
in short-term users also at high doses [69,124,149,150]. Reports of addiction to the use of
M. speciosa leaf can be a reference for the FDA of each country. Supervision and regulatory
arrangements can be a solution for the potential utilization of M. speciosa commodities.
9. Legal Issues of Mitragyna Plants
One member of the species of the Mitragyna genus, M. speciosa, is of concern in various
countries, especially regarding legal issues. M. speciosa is a widely available and unlisted
herbal supplement that has been used in the treatment of opioid addictions, traditional
medicine, and pain relief. M. speciosa preparations are available in pill, resin, herb, leaf
extract, and leaf powder forms [5,50]. In 2008, the European Monitoring Centre for Drugs
and Drug Addiction (EMCDDA) surveyed 27 European online sites selling “legal highs”
and found that M. speciosa was one of the most widely offered and available drugs on 44%
of the online sales sites investigated [152,153].
The wide availability of M. speciosa on the internet shows a wide public demand [153].
Since 2013, some dosage forms of the M. speciosa leaf, such as bottles of liquid preparations,
were available for purchase in US head shops; however, this unique formula was no
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longer available in 2014. This change in availability is due to distributors and businesses
implementing procedures for legal protection in response to changes in the law governing
certain chemical components found in M. speciosa. The powdered form of the dried leaf of
M. speciosa is currently the most readily available. When the powder this plant is added
into teas and beverages, they have a gritty taste. Small packs of 60 g (1.5 oz) beverages
(known as “Kratom Premix”) are available for purchase. Powder and liquid forms became
available in Dutch “smart shops” in 2014 [153].
Until recently, the legal status of M. speciosa plants, psychoactive alkaloids, and their
varying constituents worldwide was legal, illegal, and under government control [154]. In
2014, M. speciosa was legalized in several countries, including Austria, Belgium, Hungary,
the Netherlands, the United Kingdom, and 43 states in the United States. Additionally, countries that prohibit M. speciosa use and its derivative compounds are Indonesia, Malaysia,
Myanmar, Romania, Russia, and South Korea. Currently, dried M. speciosa leaves, mitragynine components, or other alkaloids from the plants are listed under the United Nations
Drug Conventions of 1961 or 1971; hence, each country, state, or territory determines
its legal position individually. The use of the mitragynine compound from M. speciosa,
7-hydroxymitragynine, is controlled in several countries, including Denmark, Finland,
Germany, Latvia, Lithuania, Poland, New Zealand, Sweden, Vietnam, Romania and several
states of the United States [29–31,73,154–156].
Governments have implemented various methods to try to control M. speciosa or its
alkaloids within their legislative framework. For example, in Thailand, M. speciosa has been
illegal since 1943 and is held under the 1979 Narcotics Act alongside cannabis and other
psychotropic mushroom species. However, this plant was taken off the list as a narcotic on
24 August 2021.
In Malaysia, mitragynine, the primary alkaloid of the M. speciosa leaf, is regulated
under the Poisons Act 1952, and individuals who violate this law can be fined a maximum
of RM 10,000 and can receive up to four years of imprisonment. In the United States,
M. speciosa is not scheduled under the Controlled Substances Act. However, drug information on M. speciosa is available on the DEA website, which states there are no legal medical
uses for M. speciosa in the United States. Therefore, M. speciosa leaf and its derivatives
(mitragynine and 7-hydroxymitragynine) in several different states, among others, are
prohibited from being legally advertised as a treatment, their ownership is prohibited, and
their sales are limited to particular population groups [154].
Australian law strictly prohibits the unauthorized sale, distribution, use, and manufacture of M. speciosa and mitragynine. According to Schedule 9 (S9) of the Standards for
the Uniform and Scheduling of Medicine and Poisons (SUSMP), M. speciosa may only be
used for research purposes. Under the 2009 Medicines Amendment Regulations in New
Zealand law, the sale of M. speciosa leaves to individuals without a doctor’s prescription is
illegal. Therefore, certain people interpret importing and owning M. speciosa leaf products
as technically illegal in New Zealand [154].
Further information on the legal status of M. speciosa, mitragynine, and their derivatives starting from 2014 can be seen in Table 3. The legal status of countries not listed in
Table 3 cannot be verified through primary sources [153,154].
Globally, Table 3 shows that the regulatory system related to the M. speciosa leaf is
divided into three groups, namely, (1) countries that do not prohibit the circulation and use
of M. speciosa leaf commodities; (2) countries that do not prohibit the circulation and only
restrict the use of this commodity; and (3) countries that prohibit its circulation and use.
According to Wahyono et al. (2019) [58], the difference in regulating the circulation and use
of this commodity is due to the lack of strong scientific evidence regarding generalizable
positive and negative impacts of its use in the health sector [58].
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Table 3. The legal status of M. speciosa in some countries in the world.
Country
Status
Austria [157]
Legal
Belgium [157]
Legal
Details
Hungary [157]
Legal
Not approved for human consumption, but available as incense in head shops
The Netherlands [157]
Legal
Available in head shops
United Kingdom [157]
Legal
Sold in head shops (smart shops)
Legal
Thailand is considering making M. speciosa legal again to find safer and healthier
stimulants to combat Thailand’s high rate of methamphetamine addictions.
This plant was formerly listed as a narcotic in Thailand; the change took effect on 24
August 2021.
United States
Varying regulation legal or
regulated in most states
Banned in the state of Indiana [160]. The state of Louisiana [161] prohibits the
distribution of products containing M. speciosa to minors (under age 18). It is controlled
and illegal to sell in the state of Tennessee [162]. In 2005, US Drug Enforcement
Agency (DEA) listed this as a drug of concern with abuse potential [163,164] starting
in 2014. M. speciosa is not a scheduled or restricted drug at the federal level
Russia [146,165]
Illegal
Mitragynine (9-methoxy-corynanthidine) and its derivatives are illegal
Malaysia [156,166]
Illegal
Controlled under narcotic law
Myanmar [157]
Illegal
Controlled under narcotic law
South Korea [156]
Illegal
Thailand [157–159]
Indonesia [167]
Illegal
M. speciosa plants and their processed products, including active chemical compounds,
are included in Narcotics Group I, and are stipulated under the Regulation of the
Minister of Health, with a maximum transition period of five years, since 2020.
M. speciosa, containing the alkaloid mitragynine at high doses, can have a sedative
effect. It is classified as a narcotic and is included in the list of ingredients that are
prohibited for use in dietary supplements and traditional medicines.
Burma [156]
Controlled
Denmark [157]
Controlled
Finland [157]
Controlled
Requires a prescription.
Shipments can be seized at the border
Germany [157]
Controlled
Controlled as an approved pharmaceutical drug.
Latvia [157]
Controlled
Lithuania [157]
Controlled
Poland [157]
Controlled
Sweden [157]
Controlled
Vietnam [156]
Controlled
Romania [156,157]
Controlled, illegal
New Zealand [156,157]
Controlled, restricted
M. speciosa and mitragynine are controlled under Schedule 1 of the Medicines
Amendment Regulations 2009 (SR 2009/212 prescription, restricted, and
pharmacy-only medicines). It is not legal to sell M. speciosa without a license, although
it is not illegal to possess it.
Australia [156,157]
Restricted
Both mitragynine, one of the active chemicals in M. speciosa, and M. speciosa were
placed in Schedule 9 of the Australian Standard for the Uniform Scheduling of Drugs
and Poisons (SUSDP) in 2005.
In Indonesia, M. speciosa leaves are prohibited as a raw material for traditional
medicines and food supplement products. However, no regulation prohibits the cultivation, distribution, and/or marketing in the form of fresh or dried leaves or extracts.
M. speciosa is also a potential crop in agriculture based on the regulation of the Minister of
Agriculture No. 104 of 2020. On the other hand, the National Narcotics Board (BNN) of the
Republic of Indonesia will continue to target the rules prohibiting the distribution and use
of M. speciosa leaves starting in 2022, even though the regulation does not yet exist. The
information from BNN has been widely discussed until now, becoming controversial and a
source of anxiety among farmers and exporters.
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10. The Prospective Potential of Mitragyna Species as a Pharmaceutical Product
In general, plants of the genus Mitragyna (especially M. speciosa) are well known
and have high economic value. The leaf part of this plant is a widely available herbal
supplement that is sold in various forms of dried leaves (powder or chopped), pure or
concentrated extracts, and liquid preparations (energy drinks) in Western countries, and
the forms are generally taken orally [168]. The trade-in M. speciosa leaf powder has existed
in Indonesia since the 2000s, but it has only flourished in the last five years, and it has even
become a prime commodity for export by farmers in several areas on the Indonesian island
of Kalimantan.
Schmidt et al. (2011) [169] investigated product prices and the availability of this plant
on 314 online sales sites under “legal highs” and reported price ranges of €6–15 (=£4.70–11.70,
$7.60–19) per 10 g (=0.35 ounce) of dry M. speciosa leaf and €7.50 (=£5.50, $9) per gram of
“kratom 15X” in the extract. According to a report from the DEA, dried M. speciosa leaf
retails for €8–31 (=£6–24, $10–40) per ounce (=38 g) in the United States. The leaf powder
form (commercial grade white Vein Thai, Green Malaysia, and Bali) sells for €4.70 (=£3.70)
and $6 per ounce (=38 g) on websites that marketed online in 2014. According to the
Maeng Da website (https://web.asu.edu/educationblog/maeng-da-kratom-origin-%E2
%80%93-types-and-benefits, accessed 12 October 2021), high-quality products are available
for €6–14 (=£511, $818) per ounce (=38 g). Based on the latest data quoted from website:
www.misterexport.com (accessed 12 October 2021), the selling price of domestic M. speciosa
leaf powder is Rp. 98,000 or the equivalent of about USD 6–7 per kg. Meanwhile, the
selling price abroad varies between USD 17–25 per kg, depending on the quality, with
several export destination countries such as South Korea, America, Canada, Singapore,
Japan, India, UAE, China, Hongkong, Saudi Arabia, and Kuwait [58,170].
M. speciosa has long been used to improve the stamina of outdoor laborers (farmers)
and for mood enhancement, pain relief, and opium addiction. Surprisingly, this plant has
been found to have a paradoxical effect in that it can provide both stimulant and sedative
effects depending on the dosage. The M. speciosa leaf contains many biologically active
alkaloids [171]. Because of the popularity of this plant, several studies have focused on its
use, especially on the interaction of mitragynine, which has an opioid-like effect. Given
the large number of cases of its abuse and the side effects caused by its use that have been
reported in Europe and America, this is in stark contrast to the cases reported under its
traditional use in Southeast Asia for centuries [172–174].
The overall physiological action of M. speciosa as a pharmacological agent is complicated since it involves intermixing stimulant and opiate-like qualities in a dose-dependent
manner due to the diversity of alkaloids contained in kratom extracts and the distinct
potential pharmacologic capabilities of each (primarily stimulant-like at low doses, with
opioid effects predominating at higher doses) [5,151]. In addition, other compounds such
as flavonoids and polyphenols [108] in methanol extract have antioxidant and antimicrobial activity, as reported by Parthasarthy et al. (2009) [21]. The same extract also has
anti-inflammatory and antinociceptive activity [6].
However, this plant has potential prospects for raw materials as a promising pharmaceutical product despite all the controversy. In line with the development of extraction
technology with a high degree of selectivity, modern approaches are essential in developing more effective, selective, and high-yielding methods for target secondary metabolites [175]. In addition, a non-conventional green solvent-based extraction method has been
developed, namely, the natural deep eutectic solvent-based microwave-assisted extraction
method [176,177] and ultrasound-assisted extraction [178]. This method is very effective
in attracting the target secondary metabolite compounds, mainly polyphenols and other
non-alkaloid compounds. The successful development of this modern extraction method
has become one of the main keys to developing pharmaceutical products [176–178].
On the other hand, the development of pharmaceutical products with active ingredients derived from natural products (mainly from plants) has also increased. The use of
herbal medicine is now in great demand, especially in developing countries, for primary
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health care, not only because it is cheap, but also because of its high level of cultural
acceptance, compatibility with the human body, and minimal side effects. However, the
use of the M. speciosa leaf as a source of raw materials for herbal medicines has recently
been highly controversial considering the many reports related to the effects caused by its
use. Therefore, to be accepted as a viable alternative to modern medicine, it is necessary
to develop valid pharmaceutical products that have been proven to be safe and effective.
The utilization of the natural deep eutectic solvent-based microwave-assisted extraction
method and non-conventional ultrasound-assisted extraction, or known as “a green extraction method approach,” with high selectivity in extracting the target compound of
secondary metabolites is hoped to respond to the controversy. Given the potential pharmacological activity described above, M. speciosa strongly correlates with empirical/traditional
use in society. With the application of selected extraction methods, the resulting product
can increase the effectiveness of pharmaceutical products with active M. speciosa leaves by
minimizing unwanted effects.
11. Conclusions
In conclusion, plants of the Mitragyna genus (mainly M. speciosa) are easy to cultivate,
traditionally have many benefits for treating various diseases, and have high economic
value. However, these plants contain several biologically active alkaloid compounds, such
as opioids, which can provide a stimulant effect and cause dependence, so there is a chance
for abuse. On the other hand, M. speciosa has future potential as a pharmaceutical product,
with dosage adjustment and use for oral consumption with various pharmacologically
proven properties. Therefore, taking into account the potential benefits and economic value
of this species, it is highly recommended for the preparation of government policies in
terms of regulating and supporting studies on the development of separation techniques for
compounds that have the potential for abuse and addiction so that its potential biological
benefits as drugs, as well as its potential for increasing economic income from cultivation
by local communities, can be optimized.
Author Contributions: Conceptualization, I.A. and A.M.; methodology, A.C.N., R.Y.P. and W.C.P.;
software, J.F., A.R. and F.P.; validation, N.M., N.I. and H.K.; formal analysis, H.H., N.M. and S.P.;
investigation, M.A., J.F. and H.K.; resources, F.P., F.N. and H.K.; data curation, M.A., W.C.P. and
A.C.N.; writing—original draft preparation, I.A. and F.N.; writing—review and editing, S.D.-a.,
L.R., G.A. and A.M.; visualization, H.H. and N.I.; supervision, S.D.-a., R.Y.P. and A.I.; project
administration, S.P.; funding acquisition, A.R. All authors have read and agreed to the published
version of the manuscript.
Funding: This research was funded by Lembaga Pengelolaan Dana Pendidikan (LPDP) Kementrian
Keuangan Republik Indonesia and the Ministry of Research and Technology/National Research and
Innovation Agency through RISPRO Mandatory, grant number of 48/LPDP/2020.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Acknowledgments: The authors are thankful to the head of the Pharmaceutical Research and Development Laboratory of FARMAKA TROPIS, the Faculty of Pharmacy, and the head of Lembaga
Penelitian dan Pengabdian kepada Masyarakat (LP2M) Universitas Mulawarman for support and
providing facilities.
Conflicts of Interest: The authors declare no conflict of interest. The funders had no role in the design
of the study, in the collection, analyses, or interpretation of data; in the writing of the manuscript, or
in the decision to publish the results.
Life 2022, 12, 193
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