2015 07 22 Synthetic Drugs Webinar - final · Referred to as “designer” drugs and...

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Synthetic Drugs:

Presented by:Kim Samano, Ph.D., Postdoctoral Fellow

July 22, 2015

What You Need to Know

2 Synthetic Drugs: What You Need to Know | July 22, 2015

Today’s presenter

Kim Samano, Ph.D.Postdoctoral Fellow [email protected]

7/22/2015

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Agenda

Classification of drug types

Synthetic Cannabinoids (SCBs)

Designer Stimulants a.k.a “Bath Salts”

What Employers Need to Know

Questions

Synthetic Drugs: What You Need To Know


Classification of drug types

Natural

Found in nature (plants) or produced in body (endogenous) Morphine (poppy plant)

Semi-synthetic

Chemically altered natural compound Oxycodone

Synthetic

Developed to functionally act like natural drugs, structurally distinct

Synthesized in laboratory from precursor chemicals Fentanyl

Fentanyl

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Synthetic drugs

Act similar to other drugs or naturally occurring compounds

Intended to produce psychotropic, hallucinatory or stimulatory “highs”

Referred to as “designer” drugs and internationally as novel psychoactive substances (NPS)

Marketed to adults and juveniles as “legal highs”

Popular as they go mostly undetected in routine drug screens based on chemical structure(s); and are largely unregulated


Where synthetic drugs are being made

Clandestine labs primarily in Europe and China

Syntheses published in scientific literature

In 2014, the European Early Warning System was alerted to 101 previously unreported psychoactive substances

European Monitoring Centre for Drugs and Drug Addiction (EMCDDA)

Source: http://www.emcdda.europa.eu/publications/edr/trends-developments/2015

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Regulation of synthetic drugs

“Controlled Substance” is defined as a drug, other substance, or immediate precursor included in Schedules I, II, III, IV, V of the Controlled Substance Act (CSA) – alcohol and tobacco are explicitly excluded

Schedules are based on Potential for abuse

Currently accepted medical use International treaties

Changes initiated by DEA or HHS (or public petition/interest)

Temporary scheduling bypasses normal review process (e.g. MDMA, “K2”)

CSA regulates manufacturing, importation, distribution and possession


Regulation of synthetic drugs

Federal Analogue Act (21 U.S.C. §813) must meet following criteria:

Chemical structure must be substantially similar to Schedule I or II substance

Pharmacological effect substantially similar to Schedule I or II substance OR

Represented by the seller to have a pharmacological effect substantially similar to Schedule I or II substance

Synthetic Drug Abuse Prevention Act (S. 3190) signed into law July 9, 2012, adding as schedule I controlled substances:

Any material, compound, mixture, or preparation which contains specified cannabimimetic agents

Specified additional hallucinogenic substances (or the salts, isomers, or salts of isomers thereof)

Includes 5 classes and 15 specific synthetic cannabinoids

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Synthetic Cannabinoids (SCBs)


Synthetic cannabinoids

What are they?

THC-like drug (bind at CB-receptors)

Also referred to as “K2” and “Spice”

How are they used?

Smoked (pipe, bowl, paper or electronic cigarette)

Snorted

Inhalation

Orally

Examples of drugs identified

JWH-018 and JWH-073

XLR-11 and UR-144

AB-PINACA and AB-FUBINACA

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Abuse of synthetic cannabinoids

Man-made chemicals applied (often sprayed) onto plant material and marketed as a “legal” high

Available in powder form, allows for “homemade” recipes

Commonly called:

“K2”, “Spice”, “Incense”, “Potpourri”, “Synthetic Pot” and “Herbal Incense”

Brand names include:

“K2”, “Spice”, “Scooby Snacks”, “Yucatan Fire” and “Wicked X”

Photo: posted by LSDude, slashcannabis.com


“K2/Spice” herbal incense products

Product components are variable from one to another, despite same appearance

Labeled as, “Not for Human Consumption” to evade FDA-requirements

Available online, head shops and local retailers

Cost is $30-50 per packet (3-5 grams)

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SCBs were created as scientific tools

1930-1970s

THC structure elucidated by R.S. Cahn; Synthesis by R. Adams (Pertwee, 2006)

Structure of THC first published (Gaoni and Mechoulam, 1964) Lipid membrane theory for cannabinoid effects (Lawrence and Gill, 1975)

1980s-1990s

Identification and characterization of a cannabinoid receptor (Devane et al. 1988)

Cannabinoid receptor (CB1) sequenced in human tissue (Gerard et al. 1991)

Researchers explored how alterations in the THC structure could be used to understand the endocannabinoid system and as treatment for pain

Relationship between chemical/3D structure of a molecule and its biological activity led to the development of 100’s of synthetic cannabinoids

Some of which are still currently used in research


Development of synthetic cannabinoids

THC analogs (1960s)

“Classical”

Hebrew University (HU)

Cyclohexylphenols (1970s)

“Non-classical”

Pfizer

Aminoalkylindole (1990s)

Winthrop-Sterling

John W. Huffman (Clemson)

CP47,497

THC

WIN55,212-2

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Endogenous cannabinoid system

Receptors (“lock”)

CB1 CNS (i.e. brain)

CB2 Immune cells

Ligands (“key”)

Plant-derived THC, cannabidiol

Endogenous 2-arachidonoylglycerol (2-AG)

Anadamide (AEA)

Synthetic “K2” and “Spice”

Source: www.caymanchemical.com


Anandamide(Endocannabinoid)

2-arachidonylglycerol(Endocannabinoid)

∆-9-THC HU-210 CP-47,497

JWH-018RCS-4 XLR-11

AKB-48 5F-AB-PINACA

Synthetic compared to naturally occurring cannabinoids

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Anandamide(Endocannabinoid)

2-arachidonylglycerol(Endocannabinoid)

∆-9-THC HU-210 CP-47,497

JWH-018RCS-4 XLR-11

AKB-48 5F-AB-PINACA

Synthetic compared to naturally occurring cannabinoids


Str

uct

ura

l Co

mp

lexi

ty

Identification of new compounds in response to legislative bans

Evolution of SCB drugs

1st Generation (2010)

Prior to Ban JWH-018

JWH-073

JWH-250

2nd Generation (2011)

After Temp Scheduling AM-2201

JWH-210

RCS-4

3rd Generation (2012)

After Syn Drug Abuse Prev Act XLR-11

UR-144

AKB-48

4th Generation (2013)

Additional Temp Scheduling AB-PINACA

AB-FUBINACA

PB-22 (QUIPIC)

Scope of Compounds

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Synthetic cannabinoid compounds

JWH-018

JWH-073

JWH-250

AM-2201

JWH-081

RCS-4

RCS-8

UR-144

XLR-11

AM-2233

PB-22

F-PB-22

MAM-2201

AKB-48

AB-PINACA

AB-FUBINACA

ADB-PINACA

THJ-2201

THJ-018


ABCs of SCB nomenclature

AB-PINACA

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Amino

AB-PINACA



Amino

Oxobutane

AB-PINACA

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Amino

Oxobutane

Pentyl

AB-PINACA



Amino

Oxobutane

Pentyl

Indazole

AB-PINACA

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Amino

Oxobutane

Pentyl

Indazole

CarboxAmide

AB-PINACA



Amino

Dimethyl

Oxobutane

Pentyl

Indazole

CarboxAmide

ADB-PINACA

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Pharmacology of synthetic cannabinoids

Calm and euphoric effect almost immediate

Onset of action is seconds to minutes

Duration of effects can last 30 minutes-1 hour

Tolerance and dependence develop

More drug needed for same “high”

Full and potent agonists at CB1 receptors

Markedly greater affinity (3-10X) at CB1 receptors than THC

As compared to THC, synthetic cannabinoids produce much more intense responses with smaller amounts of drug.


AAPCC – synthetic cannabinoids

6,968

5,230

2,668

3,682

4,377

0

1,000

2,000

3,000

4,000

5,000

6,000

7,000

8,000

2011 2012 2013 2014 2015*

Number of casesIn 2015, through July 6, poison centers received reports of 4,377 exposures to synthetic marijuana.

*2015 data through July 6

Source: American Association of Poison Control Centers

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Adverse effects of SCBs

Source: Antoniou and Juurlink, Five Things to Know About Synthetic Cannabinoids, CMAJ , Feb 18;186(3)2014.


Severe adverse effects of SCBs

22 patients were treated for associated SCB use 16–57 years (median: 25 years)

82 percent (18/22) male

Reported symptoms included: hyperglycemia (13 [59%])

tachycardia (13 [59%])

hypokalemia (nine [41%])

acidosis (seven [32%])

nausea/vomiting (eight [36%])

confusion/disorientation (seven [32%])

aggression (seven [32%])

somnolence/unresponsiveness (seven [32%])

seizures (three [14%]).

Five tested positive for ADB-PINACA

Implicated product, “Crazy Clown,” shown to contain ADBPINACA

Georgia Department of Public Health (2013)

Source: Morbidity and Mortality Weekly Report Weekly / Vol. 62 / No. 46 November 22, 2013

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Why people continue to use SCBs

Compounds mimic effect of THC

Not included in routine drug test panels

Evolution of chemicals, stay one step ahead of laboratories

Users report using SCBs to combat positive drug tests and return to marijuana between drug tests

CesarFAX, 22(27); July 8, 2013

Easy access (adolescents)

Perception of safety

Experimentation

Photo: Huffington Post


Synthetic cannabinoids detection in toxicology tests

Metabolism is still not well understood Few human studies suggest extensive metabolic profiles, projected overlap between parent compounds

Research published with HLM and in silico modeling corroborate PK data

Initial testing kits are not readily available Rapid (“on-site”) tests designed to detect 1st generation compounds

ELISA (lab-based testing) available, but limited drugs detected

No FDA-cleared immunoassay tests available

Comprehensive screening requires more complex methods (LC-MS(MS) or GC-MS(MS))

Illicit manufacturers stay ahead of legislation, more banned, more SCBs of a different kind are available Currently experiencing the 4th/5th generation of SCBs

Limited number of laboratories with SCB panels Vary in scope, metabolites tested, and limit of detection

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Designer Stimulant Drugs-“Bath Salts”


Designer stimulants

What are they?

Amphetamine-like stimulants drugs (e.g. cathinone family)

Also referred to as “legal cocaine” and “legal ecstasy”

How are they used?

Snorting

Inhalation

Injection

Orally/ingestion (powders, crystals, liquids)

Examples of drugs identified

MDPV

Mephedrone

Methedrone

Methylone and other “cathinones”

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Designer stimulant product information

Like SCBs, the term “bath salt” refers to many different compounds

Product components are variable from one to another, despite same appearance

Labeled “Not for Human Consumption” to evade FDA-requirements

Available online, “head shops” and local retailers

Cost is $20-50 per packet (250 mg, 500 mg and 1 gram)

Commonly called:

“Bath Salts,” “Plant Food,” “Gravel” and “Flakka”

Brand names include:

“Ivory Wave,” “Purple Wave,” “Vanilla Sky,” “White Rush,” “White Girl,” “White China,” “Dynamite,” “Bliss”, “White Lightening,” “Red Dove,” “Cloud-9” and “White Dove”


Synthetic cathinones or “bath salts”

Man-made chemicals related to the stimulant amphetamine-like compound found in the Khat plant

Methylenedioxypyrovalerone (MDPV), mephedrone, and methylone

Khat (Catha edulis)

Flowering evergreen shrub, indigenous to Africa and Arabian Peninsula Retained in cheek, intermittently chewed, similar to tobacco

Active ingredients are cathinone (Schedule I) and cathine (Schedule IV)

Acts similar to cocaine and amphetamine(s) stimulant drugs Increased BP and HR

Delusions/Hallucinations

Paranoia

Hyperactivity

CathinoneAmphetamine

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Synthetic cathinones or “bath salts”

Man-made chemicals related to the stimulant amphetamine-like compound found in the Khat plant

Methylenedioxypyrovalerone (MDPV), mephedrone, and methylone

Khat (Catha edulis)

Flowering evergreen shrub, indigenous to Africa and Arabian Peninsula Retained in cheek, intermittently chewed, similar to tobacco

Active ingredients are cathinone (Schedule I) and cathine (Schedule IV)

Acts similar to cocaine and amphetamine(s) stimulant drugs Increased BP and HR

Delusions/Hallucinations

Paranoia

Hyperactivity

CathinoneAmphetamine


How stimulant drugs work

Source: drugabuse.gov

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Pharmacology of designer stimulants

Affects release of “feel-good” chemicals in brain (e.g. dopamine)

Elicits extreme cravings and drug-seeking behavior

Onset of action is 15-30 minutes

Drug duration is 2-7 hours

Desirable effects: alertness, euphoria, increased sociability and sex drive

Adverse effects: paranoia, agitation and hallucinatory delirium

Psychotic and violent behavior, characterized by erratic body movements


Amphetamine

Cathinone Methcathinone

MDPV (Methylenedioxypyrovalerone)Mephedrone

Methamphetamine Alpha-PVP

Methylone

4-methcathinone Ethylone

How similar are synthetic cathinones to amphetamine?

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Synthetic cathinone compounds

Alpha-PVP

Methylone

MDPV

4-MEC

Pentedrone

Mephedrone (4-MMC)

Butylone

Fluoromethcathinone

Pentylone

4-MePPP

Alpha-PBP

Ethylone

Buphedrone

Methcathinone

Naphyrone

MDPBP

MPHP

Ethylcathinone


Str

uct

ura

l Co

mp

lexi

ty

Identification of new compounds in response to legislative bans

Evolution of designer stimulants

1st Generation (2011)

Prior to Ban MDPV

Mephedrone

Methylone

2nd Generation (2012)

After Syn Drug Abuse Prev Act Αlpha-PVP

Pentylone

Pentedrone

3rd Generation (2013) 4-MEC

Butylone

BZP

4th Generation (2014) Ethylone

TFMPP

Mityragnine (kratom)*

Scope of Compounds

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Designer stimulant hierarchy


“Flakka”

Spanish meaning beautiful, thin, woman who charms all she meets

Notoriously thought to contain α-PVP

Identified in “Bath Salt” products since 2012

Banned by DEA in 2014

On July 9, 2015- Miami-Dade, Florida crime laboratory identified drug-laced gummy bears

Not α-PVP, but thought to contain ethylone (3,4-methylenedioxy-N-ethylcathinone)

Cathinone

α -PVP

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Novel hallucinogens - NBOMe derivatives

Substituted phenylethylamines

Active hallucinogen, entactogen

Encountered as liquids and powders applied to blotter paper

Taken similarly to LSD

Examples

2C-I, DOB, or 25I-NBOMe, etc.

A. Shulgin coined the term “2C” for 2 carbon atoms between the benzene ring and the amino group

25I-NBOMe2C-I

Source: www.undoc.org


Adverse effects of designer stimulants

Tachycardia

Dehydration

Increased blood pressure

Chest pain

Hyperthermia

Nauseous/vomiting

Seizures

Psychomotor impairment

Paranoia/violent behavior

Hallucinations

Violent behavior

Delusions

Panic attacks

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AAPCC – “Bath Salts”

6,137

2,691

995582

267

0

1,000

2,000

3,000

4,000

5,000

6,000

7,000

2011 2012 2013 2014 2015*

Number of cases In 2015, through June 30, poison centers received reports of 267 exposures to “Bath Salts”

Popular with individuals aged 20-29

Exposure reported from < 6 to 59 years old

*2015 data through June 30

Source: A Fatal Case of Pentedrone and α-Pyrrolidinovalerophenone Poisoning Sykutera et. al. Journal of Analytical Toxicology (2015)


Why people continue to use designer stimulants

Compounds mimic amphetamine, cocaine, LSD stimulant drugs

Not included in routine drug test panels

Evolution of chemicals, stay one step ahead of laboratories

Easy access (adolescents)

Perception of safety (i.e. “legal high”)

Experimentation

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Bath salts detection in toxicology tests

Metabolism is still not well understood Few human studies suggest extensive metabolic profiles, projected overlap between parent compounds

Research published with HLM and in silico modeling corroborate PK data

Initial testing kits are not readily available ELISA available, but limited in configurations, 1st generation drugs

Requires more complex screening methods (LC-MS(MS) or GC-MS(MS))

Illicit manufacturers stay ahead of legislation, compounds become available Currently experiencing the 4th generation of synthetic stimulant compounds

Limited number of laboratories with “Bath Salt” panels Vary in scope, metabolites tested, and limit of detection

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What Employers Need to Know

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Challenges of synthetic or designer drug testing

As another designer drug is identified, multiple others are being synthesized and marketed

Hundreds of distinct drugs are available

Testing field lags behind clandestine laboratories

Driven by legislation

Lack of immunoassay capable of detecting scope of designer-type drugs

Resource-intensive for MS-based screening methodology

Decision to monitor designer stimulants in workplace drug testing should take into account user demographics, benefits and limitations

Source: www.policechiefmagazine.org


Technical issues in testing products marketed as “legal highs”

Test for metabolites, not parent compound

Need documented, peer-reviewed studies for maximum legal defensibility

Limited or no effective rapid screening tests

Point of collection testing (POCT) device for synthetic cannabinoids Not FDA-cleared

Tests for parent and not metabolite(s)

Generally, requires slower throughput, more expensive instrumentation (e.g. LC/MS/MS) for screen and confirmation

Recent ELISA at a few labs for screening synthetic cannabinoids, targeted at 1st generation compounds

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Usage and patterns vary by demographic and region

Community Drug Early Warning System (CDEWS)1

SCB metabolites vary by geographical region Tampa (UR-144 metabolite) vs. Washington, D.C. (10+ metabolites)

Legal status

Only a limited number of substances are listed on CSA “Analogue Act” provisions may impact some substances

Differences in state laws Impacts multi-state employers (with more recent legislation,

less of an issue)

Impacts how policies are written

1 Adapted from Wish, E.D., Billing, A.S., and Artigiani, E.E., Community Early Warning System: The CDEWS-2 Replication Study, Office of National Drug Control Policy (ONDCP), 2015


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State legislation - NFLIS report

National Forensic Laboratory Information System (NFLIS)

Differences in state laws Impacts multi-state employers

(with more recent Federal legislation, less of an issue)

Massachusetts and New Hampshire have legislation pending as of April 9, 2014

Additional resources

National Conference of State Legislatures, www.ncsl.org

Special Report: Synthetic Cannabinoids and Synthetic Cathinones Reported in NFLIS, 2010-2013


Legislative changes

All 50 states have banned synthetic cannabinoids and cathinones to some degree since 2011

At first, specific chemicals were banned

Modifications (minor and major) to chemical structure lead to new (albeit similar) drug which was NOT covered by law

Moving forward, laws are more general in scope and target entire drug classes

Some state recently passed laws that restrict marketing, display and labeling

Legal status

Only a limited number of substances are listed on CSA “Analogue Act” provisions may impact some substances

Impacts how policies are written

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Thank you

2015 07 22 Synthetic Drugs Webinar - final · Referred to as “designer” drugs and...

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