Analysis and Identification of

New Psychoactive Substances

What is NPS?

Novel chemical substances with psychoactive properties, designed on the basis of the chemical structure of a given parent drug and synthesized specifically for sale on the illicit market and to circumvent regulations on controlled substances.

Not controlled by the 1961 UN Single Convention on Narcotic Drugs or the 1971 UN Convention on Psychotropic Substances.

(fall under the wider class of substances called new psychoactive substances, NPS).

NPS

• These new psychoactive substances (NPS)

have been known in the market by terms such

as “designer drugs”, “legal highs”, “herbal highs”,

“bath salts”, “research chemicals”, “laboratory

reagents”.

What’s in NPS?

• Actually contain substances that are in fact

illegal and extremely harmful.

• Actually do not contain the advertised active

substances.

• Often contain chemicals that have never been

used in drugs for human consumption, and so

they haven’t been tested to show how safe or

unsafe they are.

• Give no indication of the psychoactive

substances in the list of ingredients.

New Psychoactive Substances,

NPS

These synthetic drugs fall into nine broad categories:

• Synthetic cannabinoids (known as spice or incense)

• Synthetic cathinones (known commercially as bath salts)

• Piperazines

• Plant-based substances

• Tryptamines

• Phenethylamines – 4-FA, PMMA

• Phencyclidine-type substances – Methoxetamine (MXE)

• Amininoidanes – 2-AI

• Other substances – Opioids, sedative

Synthetic Cannabinoids

What are synthetic cannabinoids?

Chemicals that mimic the actions or have a similar

structure to THC

• Classical – structurally related to THC

• Non-Classical – alternative structures, but

produces the same desired effects

Molecular Structures

Structures of Synthetic

Cannabinoids

N

O

CH3

N

O

CH3

CH3

N

O

CH3

N

O

CH3

CH3

N

O

CH3

CH3

??? JWH-018 JWH-073

JWH-018 2′ napthyl-N-(2-methylbutyl) isomer JWH-018-N-(2-methylbutyl)

isomer

JWH-018-N-(3-methylbutyl) isomer

Synthetic Cannabinoids Enchanced affinities (K1) for the cannabinoid

receptors.

Two pharamacologically distincit cannabinoid

receptors (CB1 and CB2) in human body (brains

and organs).

Synthetic canniobinoids –designated as

cannabidiods agonist that target the CB1

receptor.

Herbal products are sprayed with synthetic

cannabinoids.

When smoked, produce effects similar to those

of cannabis.

Baybean Blue Lotus

Siberian Motherwort Red Clover

Synthetic Cannabinoids

•JWH-018/073 arrived early and have come and gone.

•JWH-250 arrived a little later and as also cycled out.

•JWH-081 was part of a second wave that has already

completed its cycle.

•JWH-122 was part of the same wave but has persisted in

popularity.

•AM-2201 was part of the same second wave and has gained

in popularity.

•JWH-022 and JWH-210 are showing signs of increasing

popularity.

•In 2012 adamantoyl (AM-1248) and tetramethylcyclopropyl

(XLR-11 and UR-144) indoles which are ahead of the latest

attempts to schedule these drug classes.

Recently emergent substances are AMB-FUBINACA , MDMB-

CHMICA and 5-fluoro ADB

Synthetic Cannabinoids Trend

Synthetic Cathinones

What are synthetic cathinones?

• Related to parent compound, cathinone.

• Cathinone – monoamine alkaloid found in the

leaves of khat (catha edulis).

• Analogues of a corresponding phenethylamine.

• Sold in internet as ‘bath salts’.

NH2

O

Synthetic Cathinones

• Substitution at amine: Methcathinone or βk-

methamphetamine, ephedrone or N-

methylcathinone.

• Substitution of atom at benzyl ring: the most

prevalent of which appears to be mephedrone

(4-methylmethcathinone, 4-MMC ,3-FMC.

• Ring-substituted: methylone (βk-MDMA; 3,4-

methylenedioxy-N-methylcathinone), MDPV

(3,4-methylenedioxypyrovalerone), methedrone

(βk-PMMA; 4-methoxymethcathinone,) and PPP

(α-pyrrolidinopropiophenone).

Synthetic Cathinones

Synthetic Cathinones

• Produced by synthetic method.

• Precursor substances are readily available.

• Appear in various form – powder, tablet.

• Snorted, smoked, injected or taken orally.

• Psychoactive stimulant.

Synthetic Cathinones

Common Synthetic Cathinones

• Mephedrone*

• Methylone*

• MDPV*

• Ethylcathinones

• Methcathinones

• Fluorocathinones

• MXE

• MPPP

• 5-APB

• 6-APDB

• Butylone

• Naphyrone

• Pentedrone

• Pentylone

• Alpha-PVP

• Alpha-PBP

• Alpha-PVT

• 5-IAI

• MDAI

Ketamine

• Chemical name is 2-(2-chlorophenyl)-2-

(methylamino) cyclohexanone, an aryl cycloalkylamine.

• First synthesized in 1962 by Calvin Stevens at

Parke Davis laboratories in Michigan.

• Chiral centre of the cyclohexanone ring permits

the existence of two enantiomers

Ketamine

ClO

HN

Phenethylamines

• Refer to a class of substances with documented psychoactive and stimulant effects and include amphetamine, methamphetamine and MDMA, all of which are controlled under the 1971 Convention.

• The phenethylamines also include ring substituted substances such as the ‘2C series’, ring substituted amphetamines such as the ‘D series’ (e.g.DOI, DOC), benzodifurans (e.g. Bromo-Dragonfly, 2C-B-Fly) and others (e.g. p-methoxymethamphetamine (PMMA))

NH2

O

Br

O

2C-B

HN

CH3

CH3

OH3C

PMMA

Synthetic piperazines

• The best known piperazine that has been used as a

new psychoactive substance is 1-benzylpiperazine

(BZP)

• Other compounds such as 1-(3-chlorophenyl)

piperazine (mCPP), 1-(3-trifluoromethylphenyl)

piperazine (TFMPP) and, to a lesser extent, 1-

Benzyl-4-methylpiperazine (MBZP) and 1-(4-

Fluorophenyl) piperazine (pFPP) have been

identified on the market.

NH

NN

NH

CF3

1-Benzylpiperazine 1-(3-trifluoromethyl)phenylpiperazine

Plant-based substances

• Khat

• Kratom

• Salvia divinorum

• Catha edulis (of the celastraceae family)

• Consumed by chewing

• Contains number of chemicals.

• Active compounds : Cathione and cathine (pseudoephedrine).

• Leaves mature or dry, cathione is converted to cathine.

Khat

• Mitragyna speciosa Korth (of the Rubiaceae

family)

• Consumed fresh, although dried leaves in

powder form are also available

• Active compound : Mitragynine.

Kratom

• Salvia divinorum (of the mint family Lamiaceae)

• Consumed by sucking and chewing the fresh

leaves from a cigar-like roll or alternatively the

fresh leaves are crashed to make a drinkable

infusion

• Active compound : Salvinorin A.

Salvia divinorum

Miscellaneous substances

• Aminoindanes

• Phencyclidine-type substances

• Tryptamines

• Other substances – Opoids, sedative

What Are the Effects and Risks

of NPS?

The main effects of almost all ‘psychoactive’ drugs,

can be described using three main categories:

• Stimulants or ‘Uppers’

• ‘Downers’ or Sedatives

• Psychedelics or Hallucinogens

The use of NPS have been directly linked to

emergency hospital admissions and, in some

cases, deaths.

NPS in Malaysia

• First appearance in 2012

• Till now Dept of Chemistry had received

2 big cases of synthetic cannabinoids and synthetic cathinones

More than 100 small cases of tablets and powder contain synthetic cannabinoids, synthetic cathinones, synthetic piperazines and tryptamines

JWH-250

JWH-018

AM-2201

JWH-081

XLR-11

3-FMC

4-MMC

3,4-MDPV

Methylone

5-methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT)

Methoxetamine

para-methoxy-N-methylamphetamine (PMMA)

para-methoxyamphetamine (PMA)

AMB-FUBINACA

MDMB-CHMICA

N-Ethylpentylone

5-fluoro-NPB-22

5-fluoro-ADB

NPS in Malaysia

Laboratory Approach

• Limitations in reference standards for confirmation

• Expensive reference standards

• Limited mass spectral databases

• Screening with chromatography technique

• Confirmation with spectroscopy technique

• Further confirmation with structure elucidation technique

Work Flow in analysis of NPS

General Screening (via

GC-MS)

• Method 1: General Drugs

• Method 2: Legal Highs

Confirmation from above screening

(via GC-FTIR, handheld FTIR &

Raman)

Further confirmation (via

LC-MS/MS)

Workflow in laboratory

Constantly changing market

• Rapidly changing products and chemicals.

Legal Status

• Regulation a step behind the market.

• How to ban them all ? (analogue, generic

scheduling ?).

• One drug becomes controlled, three more

appear on the market (cat and mouse game

continues).

Challenges

Analytical Testing

• How do we test for everything ?

• Reference materials are not available quickly

enough.

• Differentiation of isomers.

• Analysis of thermal labile compounds.

• Quality databases

Commercial peer-reviewed data

In-house with retention time data

Correct nomenclature

• Acquisition method capable of performing the

separation of closely related compounds.

• Skilled chemists who know the science and the

market.

Challenges

Analytical Testing (Toxicology)

• Toxicology (urine analysis) is more difficult.

• Metabolites are unknown and standards don’t

exist.

• Most products contain multiple drugs, extremely

complicated to identify metabolites.

Challenges

Substances control under

legislations • Ketamine – Dangerous Drug Act 1952

• Ketum (Mitragynine) – Poison Act 1952

• 25B-NBOMe

• 25C-NBOMe

• MT-45

• AH-7921 Dangerous Drug Act 1952

• U-47700

• 25I-NBOMe

• PMMA

• 5-fluoro-ADB

Substances control under

Malaysia legislations • N-benzylpiperazine (BZP)

• 25B-NBOME

• 25C-NBOMe

• AM-2201

• 25I-NBOMe Poison Act 1952

• Mephedrone

• MDPV

• JWH-018

• Pyrovalerone

1. SWGDRUG

2. NIST11

3. Wiley Designer drug

4. Cayman Chemical Company

5. AAFS

6. Pfleger

7. Your in-house database

8. Dr. Peter Rosner (Designer Drugs Online)

9. RTI (Research Triangle Institute) drug

database

10. Southern Association of Forensic Scientists

Reference Databases

DR.VANITHA KUNALAN

HEAD OF SYNTHETIC DRUG SECTION

NARCOTICS DIVISION,

FORENSIC SCIENCE ANALYSIS CENTRE

DEPARTMENT OF CHEMISTRY, MALAYSIA

03-79853837

vanitha@kimia.gov.my

Thank you for your attention