Surash Ramanathan PhD

Centre For Drug Research (CDR)

Universiti Sains Malaysia

Kajian Ketum Sejak 2007 • Pencarian mengenai ‘ketum’ dalam PubMed. (1950 – 2017)

menghasilkan 172 kertas jurnal, dikategorikan di bawah disiplin

berikut:

• Kimia dan biologi - 59

• Farmakologi - 43

• Neurosains - 19

• Epidemiologi - 12

• Laporan kes – 19 (Ketum poisoning )

• Kertas ulasan - 20

• Pusat Penyelidikan Dadah dan Ubat-ubatan (USM)telah

menerbitkan sebanyak 50 kertas jurnal daripada jumlah

tersebut (172)

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• Presentation outline

• Brief info on history of ketum

• Traditional usage/ Ketum Pharmacology

• Brief Phytochemistry

• Ketum toxicity

• Current updates on ketum studies

• Addressing the Gap

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Introduction

Mitragyna speciosa (Korth.) locally known as Ketum or Biak (Malaysia) and Kratom or Krathom (Thailand).

• A psychotropic plant under Mitragyna genus, Rubiaceae (Coffee) family.

Native to Malaysia and Thailand, and widely cultivated in Southeast Asia (Indonesia).

• Possesses both stimulant- and opioid-like activities

Kratom leaves are long used as a general analgesic, substitute to opioids or a treatment for opioids withdrawal symptoms.

• Peter Willem Korthals (1807-

1892)

• Ahli botani Belanda

• Ditemui pada 1839

• Mitragyna speciosa (Korth)

PENEMUAN

Botani Asal Spesis

Afrika Barat Mitragyna inermis or M. Africana

Mitragyna ciliate

Mitragyna stipulosa

Afrika Timur Mitragyna rubrostipulate

India dan Asia Tenggara Mitragyna hirtusa

Mitragyna tubulosa

Mitragyna diversifolia (M. javanica)

Mitragyna speciosa

Mitragyna parvifolia

Mitragyna rotundifolia

M. diversifolia M. parvifolia

M. speciosa M. diversifolia dan M. parvifolia digunakan sebagai bahan

pengganti

Kurang berkesan seperti M. speciosa

Mitraginina hanya dijumpai dalam M. speciosa

Analisis molekul M. speciosa secara rDNA ITS (Internal

Transcribed Spacer)

Holmes, E.M. Some medical products

from the Straits settlements.

Pharmaceutical Journal

Vol. 54: 1095-1096 (1845)

(Beberapa produk perubatan dari Negeri-

negeri Selat)

Dictionary of the Economic Product: Isaac Henry

Burkill (Pengarah Botanic Gardens, Singapura)

(Nota mengenai rawatan candu)

Wray, L . Notes on the opium

Remedy. The Pharmaceutical

Journal Vol 2: 453 (1907)

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Kegunaan Tradisional

• Rawatan tradisonal (Pelbagai penyakit: demam, cirit-birit, batuk, sakit ,ubat cacing, kronik,tonik,tenaga batin,

• Penagih dadah mangambil untuk mengawal genjala tarikan

• (Burkill, 1935; Jansen and Prast, 1988; Hassan et al., 2013)

Malaysia

• mengawal kesakitan (68% Pain management

• Kegelisahan dan kemurungun (66%)

U.S

Penggunaan telah lama (Dekad) di kalangan masyarakat

Air Ketum (Decoction)

Pill ekstrak, serbuk ketum, dibeli melalui vendor internet. Ketulenan ???

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Ketum leaves

Consumption

• Freshly chewed

• Brewed and consumed as an herbal tea

• In the West, dried leaves are used with tea / coffee, or ingested as herbal decoction (Singh et al., 2014).

Traditional use

• Mild stimulant

• Pain relieving

• Antipyretic

• Antihypertensive

• Antidiarrheal

• Diabetic

Lacking scientific support

Produk tempatan

Red Malay Kratom $11.99

Green Malaysian

$14.99 - $179.99

Green Malay Kratom

$12.99

Red Vein Malay

Kratom Capsules

$24.99 - $89.99

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Farmakologi Ketum

Air Ketum : daun ketum di rebus

Bahan aktif ketum : Mitragynine(alkaloid)

Terdapat >40 alkaloid .

Mitragynine di katakan bahan yang bertanggungjawab untuk kebanyakan kesan farmakologi ketum

Kesan farmakologi. Antidepresi , anxiolitik, analgesik (pain relief) , teraputik yang lain

Kesan farmalokogi alkaloid yang lain masih tidak boleh di pertikaikan , kajian terperinci sedang di jalankan.

Liabiliti ketagihan (Abuse liability of ketum ) masih tidak terbukti . Kajian preclinical pada peringkat awal

Kajian klinikal (Control clinical trial still lacking )

Kebanyakkan kajian lapangan yang di lakukan berasaskan “survey” & Self reporting studies on ketum users

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Phytochemistry

More than 40 alkaloids were isolated from 1907 – 2014 (Brown et al., 2017).

Mitragynine is the most abundant pharmacologically active alkaloid -12% (Malaysia) to 66% (Thai) of the total alkaloid extract (Ponglux et al., 1994; Takayama et al., 1998)

7-hydroxymitragynine – a minor but more active alkaloid (< 2%) (Ponglux et al., 1994).

Other major alkaloids – paynantheine, speciogynine and speciociliatine (6 – 8% of alkaloid extract) (Takayama et al., 1998).

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Adakah Ketum opiat?

• Ketum bukan opiate (natural product)

• Tidak mempunya struktur seperti morphine tetapi ia boleh mengikat pada reseptor opiate (morphine)

• Oleh itu, ia memberi kesan se-akan opiate tetapi kurang kesan sampingan

• Berpotensi dijadikan ‘opiate substitute therapy’.

Mitragynine (ketum) Morphine (opiate)

morfina

Mitragynine

Penindihan Mitragynine dan morfina

1: tapak anionik , 2 : tapak fenolik

Discovery Studio

Pandangan 1

Pandangan 2

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Is Kratom an opiate?

Alkaloid class Non opiate Opiate

Targets • Opioid receptors (Mu, kappa) • Also bind to serotonin,

dopamine, adrenergic, adenosine receptors (Boyer et al.,2008; Kruegel et al., 2016)

• Mu opioid receptor (selective)

Mechanism of actions

• Partial MOR agonist • Activate MOR in a different

pathway –bias β-arrestin pathway

• Less side effects

• Full MOR agonist • Opiate induced side effects

such as respiratory depression, tolerance, dependence etc.

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0

50

100

65.66 61.92 54.22

89.52 90.21

7

58.77 64.41

Affin

ity

CNS Receptor binding data of Mitragynine

(Boyer et al., 2008;

Kruguel et al., 2016)

respiratory depression Addiction

Lain-lain titik akhir opioid

• Penekanan pernafasan: Mitragynine (18.4 mg/kg),

codeine (2.5 mg/kg) dan morphine (30 mg/kg) diberikan

secara i.p. dalam model kucing

• Kadar pernafasan menjadi perlahan disebabkan oleh

codeine and morphine

• Tiada perubahan dalam kumpulan Mitragynine

• Tiada depresi dalam pernafasan di laporkan di

kalangan pengguna ketum di Malaysia .(Darsan et al

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Ketum toxicity (Animal)

Preclinical Literature survey

In house laboratory studies

Mitragynine /ketum only toxic at higher dosages .

Mice - LD50 Mitragynine (477mg/kg)

Alkaloid extract - LD50(591mg/kg)

(Rats) :Subcronic (1,10,100 mg/kg) for 28 days (oral):

: No death recorded .

: Safety Dose dos 1-10 mg/kg

: Toxic Dose 100 mg/kg , Histopathological ( Liver

& Kidney)

Macko et al (1972): Reanmongkol et al (2007) Janchawee et al

(2007);Sabetghadam et al (2013) Harizal et al (2010) Kamal et al

(2012)

Potensi Penyalahgunaan

• Pengguna ketum secara berpanjangan (16-30 tahun) menyebabkan anoreksia, hilang berat badan, insomnia, pigmentasi kulit terutamanya di pipi, mulut kering, kencing kerap dan sembelit. (Suwanlert, 1995)

• Berbanding dengan gejala-gejala penarikan opiat, gejala-gejala penarikan ketum tidak berpanjangan & parah seperti opiat

• Pengguna ketum boleh menahan gejala penarikan ketum tanpa rawatan

• Gejala tarikan ketum biasanya berlarutan hingga 2-3 hari; hanya masalah ketidakselesaan seperti masalah susah tidur & kebimbangan berlarutan hingga 2-3 minggu.

(Singh et al., 2014)

KEBERGANTUNGAN: Pengambilan dadah secara

berterusan untuk mencegah atau mengurangkan gangguan

fizikal atau psikologi akibat sindrom tarikan

KETAGIHAN: Penggunaan dadah secara terpaksa dan tidak

terkawal walaupun kesan buruknya diketahui. Ciri-ciri

ketagihan termasuk keasyikan untuk memperolehi dadah,

penggunaan secara terpaksa, kecenderungan untuk

menagih semula, hilang kawalan dan penafian

Data sedia ada menunjukkan ketum menyebabkan

kebergantungan dan bukannya ketagihan

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Clinical Trials on Ketum- Thailand

• A study by S.Trakulsirichai in Thailand- 2015

• The study was approved by Institutional Review Board of the Faculty of Medicine, Ramathibodi Hospital, Mahidol University.

• This was the first human study on the pharmacokinetic parameters from 10 chronic Ketum users.

• Ketum tea was prepared dosed to the subjects

• Pharmacokinetic parameters • T ½ : Long half life • linear pharmacokinetics. • Kratom would be a good candidate for

opioid substitute in patients who are addicted to these substances.

• As for the clinical and safety aspects, no serious adverse effect was found during the study.

• The median duration of abuse was 1.75 years.

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Clinical Trials on Ketum- Malaysia

First controlled clinical trials

Number of participants: 26 Tested with: kratom and placebo decoctions Dosing: 1.6mg/kg

Randomized, double blind, placebo-controlled study.

PLASMA SAMPLES- blood samples for concentration of Mitragynine

Additional outcomes: • blinding procedures • CPT task unpleasantness • visual analogue scales • vital signs • objective and subjective

assessments of withdrawal symptoms

COLD PRESSOR TASK- Pain onset and tolerance

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Clinical Trials on Ketum- Malaysia

In terms of safety,

No discomfort, unusual symptoms,

No signs of withdrawal symptoms were reported or observed.

Therapeutic Effect

Pain relief (Analgesic) was observed

Generalized conclusion : Need to repeat in bigger population , Healthy volunteers, different dosage

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Ketum ubat atau mudarat

Benefit vs Risk (assessment )

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Current assessment

• As of to date Ketum abuse properties is not proven .

• Two clinical trials with chronic Ketum users have been conducted with the approval of Human ethics committee (no adverse reactions were reported )

• Animal toxicity studies indicate that ketum is not toxic at lower doses

• No death was reported in south Asia region after prolong consumption of ketum by users

• Field studies on ketum users indicated daily intake of air ketum was in the range of 1.6 to 5.5 mg/kg (Malaysian study)

• Ketum poising reported in the west : probably due to adulterated or contamination product purchased via internet vendor . The subjects have medical history of chronic disease etc

Toksikologi (Manusia)

• Kes kematian yg dikaitkan dgn pengambilan ketum

disebabkan ianya diambil bersama dengan:

• dadah opiod (oksikodon, o- desmetiltramadol)

• benzodiazepina

• alkohol

• ubat-ubatan (amitriptilina, propilheksidrina, prometazina)

(Nelson et al., 2010, Mc Whirter & Morris, 2010; Kroonstad et al., 2011;

Sheleg & Collins, 2011)

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Addressing the GAP

NIDA/FDA requirement for future preclinical &

clinical studies

• However the current publish data on ketum & Mitragynine preclinical (animal) toxicity were done empirically .

• Lacking GLP procedure

• Source of ketum ? Purity ? Stability ?

• Need the line of custody

• (Authentic source of ketum for future preclinical & clinical studies ) to establish the safety & efficacy of ketum

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Future Studies to establish

Fasa perkembangan (Drug development)

Pre-Klinikal Klinikal

• Fasa Praklinikal (Animal : two mammalian species)

• Kajian toksik • Kajian ADME

(Penyerapan,sebaran, metabolisma, penyingkiran

• Dose permulaan yang sesuai &

selamat untuk kajian klinikal • Mengenal pasti kesan kesan

toksik yang perlu di awasi semasa kajian klinikal

• Fasa klinikal

• Health Human volunteers & Patients (Fasa Klinikal )

• Fasa 1 ( Healthy Human: Safety & Tolerance)

• Fasa 2 in Patients (Efficacy)

• Fasa 3 in larger Population(efficacy)

FDA : Investigational of New Drug/ IND

“Kita jangan haramkan pengambilan dan

eksploitasi kajian untuk ketum kerana kalau

diharamkan, kita akan kerugian kerana tumbuhan

bernilai tinggi ini tidak terdapat di banyak negara”

“Ketum adalah satu daripada biodiversiti,

tumbuhan di negara kita yang tinggi nilainya serta

mudah ditanam”

Datuk Seri Wan Junaidi Tuanku Jaafar

MENTERI Sumber Asli dan Alam Sekitar

Berita Harian 1 Ogos 2017

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Thank you

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