Precursor Chemicals Trends: U.S. Perspectives

Liqun L. Wong Unit Chief Drug & Chemical Evaluation Section Diversion Control Division United States Drug Enforcement Administration

U.S. Drug Enforcement Administration 1 Opioid Health Crisis in U.S.

Total Number of Overdose Deaths, 1999 ‐ 2018

120,000

100,000 Psychostimulants with abuse potential Benzodiazepines Methadone 12,801 80,000 Synthetic Opioids Natural and Semisynthetic Opioids 3,040 Cocaine 60,000 Heroin 31,473

40,000 Total Number of Deaths 12,588

20,000 14,762

15,073 0

‐‐ ‐‐ ‐‐ 2018 Provisional data (12‐Month Period Ending on December 2018) No provisional data for benzodiazepine drug class U.S. Drug Enforcement Administration 2 Number of NPS Encounters in U.S.

140,000 Total Number of NPS Drug Reports by Drug Category and Year 96,212 87,094 120,000

Synthetic Cannabinoids 100,000 Synthetic Cathinones 45,882 80,000 Synthetic Opioids 17,968

865 5,769 60,000 1,298 14,998 14,527 15,715 40,000 16,215

Total Number of Drug Reports of Drug Total Number 744 9,461 10,938 7,209 11,535 43,197 20,000 39,812 35,980 34,628 29,526 678 23,699 26,350 20,233 636 743 29 3,291 0 23 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018*

Source: National Forensic Laboratory Information System (NFLIS), DEA, Queried as of June 12, 2019. * NFLIS reporting still pending.

U.S. Drug Enforcement Administration 3 Number of NPS in U.S.

250 Number of Drugs by Category 2009 ‐ 2018*

200 Synthetic Cannabinoids 29 45 Synthetic Cathinones 54 15 150 Synthetic Opioids 9 80 75 8 56 55 69 100 8 43

Number of NPS Drugs 39 5 50 23 86 93 94 88 81 4 62 67 2 12 44 19 0 2 6 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018* * NFLIS reporting still pending. Source: National Forensic Laboratory Information System (NFLIS), DOE/DC/DEA, Queried as of June 12, 2019 U.S. Drug Enforcement Administration 4 Fentanyl Clandestine Laboratory -2006

• April 2005 ‐ March 2007: Spike in fentanyl seizures • Over 1013 documented non‐pharmaceutical (NPF) overdose deaths • Primary synthetic route identified as Siegfried method

Fentanyl Fatal Overdose Epidemic, 2005-2007 • N‐phenethyl‐4‐ piperdidone (NPP) added as a List 1 chemical in 2007 • 4‐anilino‐N‐ phenethyl‐4‐ piperidine (ANPP) added as a Schedule II immediate precursor in 2010 CDC. Nonpharmaceutical fentanyl‐related deaths—multiple states, April 2005–March 2007. MMWR 2008; 57: 793–6.

U.S. Drug Enforcement Administration 5 Fentanyl Clandestine Laboratory - 2016

ANPP/4‐ ANPP

Seattle, Washington 2016 U.S. Drug Enforcement Administration 6 Clandestine Pill Press Operation

U.S. Drug Enforcement Administration 7 Fentanyl Synthesis - Siegfried Route

U.S. Drug Enforcement Administration 8 Synthetic Opioids in Counterfeit Tablets

U.S. Drug Enforcement Administration 9 Control of Precursor Chemicals

internationally controlled (CND, 2017)

U.S. Drug Enforcement Administration 11 Variety of Delivery Methods

cyclopropyl fentanyl spray

aerosolized acetyl carfentanil on blotter paper fentanyl

deceased tested positive for acetyl fentanyl

U.S. Drug Enforcement Administration 12 U.S. Fentanyl Signature and Profiling Program

U.S. Drug Enforcement Administration 14 Analysis of Fentanyl Synthesis

Janssen

O O O N H NH N N N N N N H

O O N HN N H O N N N N N N H NPP ANPP

fentanyl

Diversion Control Division U.S. Drug Enforcement AdministrationSiegfried U.S. Drug Enforcement Administration 15 Fentanyl Synthesis - Other Methods

Br

HN

H2N N H 4-anilinopiperidine (4-AP) Br O

O O HN N O

H2N Cl N N N N H 4-piperidone

NPP ANPP fentanyl

U.S. Drug Enforcement Administration 16 Fentanyl Synthesis – New Precursors

• New method utilizes a substance called 4-AP instead of NPP • INCB reported 32 notifications (late 2018 - early 2019) representing 30 kg of 4-AP • Origins: China, Hong Kong, Netherlands, Singapore, India • Destination: Mexico

30 kg of 4-AP can produce 57 kg of fentanyl!

falsely declared as “foodstuffs or consumables”, “gifts”, “unspecified goods”, “glass bottles” and “protein” U.S. Drug Enforcement Administration 17 Fentanyl Precursor - Packaging

U.S. Drug Enforcement Administration 18 Suppliers Help to Evade Customs Detection

“discreet package :the packing suits you best would be chosen to cross customs safely. or if you have your own ideal way, it could be also taken into consideration .”

“safety guarantee (we do this business long time ,we know how to disguise let the product through customs)”

“our company promise to deliver clients' package to his hands safely, or we'll cover the total loss and reship in time”

U.S. Drug Enforcement Administration 19 Precursor Chemical Names

From a January 2019 International Alert Salt form CAS number Base 23056-29-3 Hydrochloride (1:1) 1193388-65-6 Hydrobromide (1:1) 24775-80-2 Hydrobromide (1:2) 24998-99-0 4-methylbenzenesulfonate (1:?) 918535-64-5 Hydrochloride (1:2) 99918-43-1

U.S. Drug Enforcement Administration 20 Precursor Chemical – CAS Numbers

Salt form CAS number Base 23056-29-3 Hydrochloride (1:1) 1193388-65-6 Hydrobromide (1:1) 24775-80-2 Hydrobromide (1:2) 24998-99-0 4-methylbenzenesulfonate (1:?) 918535-64-5 Hydrochloride (1:2) 99918-43-1

U.S. Drug Enforcement Administration 21 Internet Sales - Precursor Chemicals

Diversion Control Division U.S. Drug Enforcement Administration U.S. Drug Enforcement Administration 22 22 Heibei Guanlang Biotechnology (Crovellbio)

• All products have a connection to drug trade • Designer precursors • Cutting agents • Non-controlled solvents • Product offerings evolve re: chemical controls • Pervasive online presence • Marking materials reference a “Mexico Branch” • Only one of many of examples…

U.S. Drug Enforcement Administration 23 Designer Precursor Chemicals

CAS number: 125541‐22‐2 U.S. Drug Enforcement Administration 24 Designer Precursor Chemicals

U.S. Drug Enforcement Administration 25 Methamphetamine Designer Precursor Chemicals

N O NH2 MAPA O O methyl 3-oxo-2-phenylbutanoate methyl alpha-acetylphenylacetate 3-oxo-2-phenylbutanamide 3-oxo-2-phenylbutanenitrile CAS 16648-44-5 APAA APAAN 4433-77-6 4468-48-8

O O

O O

methyl 3-oxo-2-phenylbutanoate 1-phenylpropan-2-one MAPA BMK / P-2-P 16648-44-5 103-79-7 O OH

O O

O

O 3-oxo-2-phenylbutanoic acid ethyl 3-oxo-4-phenylbutanoate 4433-88-9 718-08-1

U.S. Drug Enforcement Administration 26 INCB on “Designer” Precursor Chemicals

“designer” precursor: A close chemical relative of a controlled precursor that is purpose-made to circumvent controls and usually does not have any recognized legitimate use.

 Established in 2013, in response to the proliferation of “designer” precursors  The list currently contains 53 individual substances  Expanded the list in a generic manner  ISSL and definitions cover:  esters and other simple derivatives  Stable chemical intermediates,  Purpose-made chemical intermediates  Masked derivatives of controlled precursors  others

U.S. Drug Enforcement Administration 27 Contact Information

Liqun L. Wong [email protected] +1-202-307-7183 U.S. Drug Enforcement Administration www.deadiversion.usdoj.gov

U.S. Drug Enforcement Administration 28