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Home , Alexander Shulgin, Coca, Federal Analogue Act

New of Abuse – The Other Market

Jack DeRuiter, Professor Harrison School of Pharmacy Auburn University June, 2019 US Drug Prescription Use

Use (16-18% total HC Cost): >Prescription drugs per capita and > Cost/drug Rate of deaths in the US: Assessment of Positive versus Negative Outcomes Prescription Drug Abuse/Misuse - CDC Prescription Drug Abuse (CDC)

Five most commonly abused prescription drug classes: • • • Benzodiazepines • Barbiturates • Sleep medications Growth in and Use: Growth and Diversity in the Clandestine Market Prescription Drugs – Relative ADR Danger and link between Prescription versus “Illicit Drugs” DEA Scheduling: Drug’s Principle of Relativity and the “Harm Index” Prescription Drug Flow Use and Abuse: The Secondary Pharmaceutical Market Drug of Abuse Profile in US and Abroad (2016) Abuse and Ethical Pharmaceuticals

• Long history of use/abuse • Coca- invented in 1885 by John Pemberton, an Atlanta pharmacist, and contained small amounts cocaine. Marketed as a “” for headache, fatigue and upset stomach • Cocaine removed from “Coke” in 1929 (Prohibition) and beverage offered for broader consumption • Local in US (occasional ENT use) • Template for design of modern day safer local DEA: New York City issues Health Advisory about overdoses from fentanyl added to cocaine • June, 2017: The NYC Health Department warned that cocaine samples contained the potent opioid fentanyl and these samples were implicated in a growing number of cocaine-involved overdose deaths. • In recent years fentanyl has been most commonly present in -related deaths, but fentanyl is increasingly being identified in overdose deaths involving other drugs. • In 2016, 37% of overdose deaths involved cocaine and fentanyl without heroin, up from 11% in 2015. The Status of Marijuana… 40+ States by 2025? Use and Concerns

Expanded use? Health care concerns? Liability Issues? THC and Cannabidiol (CBD)

In 2018 the FDA approves Epidiolex (cannabidiol) [CBD] oral solution for the treatment of seizures associated with two rare and severe forms of epilepsy, Lennox- Gastaut syndrome and Dravet syndrome, in patients two years of age and older.

**Cannabinoid hyperemesis syndrome (CHS) is a condition that leads to repeated and severe bouts of vomiting. It is rare and only occurs in daily long-term users of marijuana (Reflexive action and GI tract) Stimulant and Natural Products: Expansion of Decriminalization? DEA or FDA? Kratom (Biak, Ketum, Kakuam, Ithang, Thom)

• The of the kratom tree () found in SE Asia, used as a remedy for diarrhea, fatigue and pain. • Popular in North America and Europe as a -based NPS. • Sold as a green powder in packets labeled "not for human consumption" or as an extract, gum. • Mitragynine also interacts with other receptor systems in the CNS to produce stimulant effects when kratom is taken in small amounts. • Interact with opioid receptors to produce sedation, pleasure, and decreased pain, especially when used in large amounts. • Not currently controlled in US (failed attempt in 2016) Select Kratom Products Recalled Due to Potential Contamination with Salmonella

• The U.S. Food and Drug Administration posted Sunstone Organics’ recall announcement on March 1, 2019.

• These two lots include Sunstone Organics White Vein Kratom Lot 119 and Sunstone Organics Maeng Da Kratom Lot 124A in both capsules and powder form and in all sizes.

• Products potentially contaminated with Salmonella. Symptoms of Salmonella can include: illness, vomiting, and in some cases, even death. Question 1

Which prescription drug class is most commonly abused in the US today?

A. Opioids B. Stimulants ( salts, Ritalin) C. Benzodiazepines D. Barbiturates E. Sleep medications The “Other” Global Drug Market: The Novel Psychoactive Substances (NPSs) The Other Pharmaceutical Industry

• Most prepared abroad • Marketed via the internet or shipped in bulk to processors Federal Analogue Act and NPS “Marketing”

• The Federal Analogue Act (21 U.S.C. 813) is a section of the United States Controlled Substances Act passed in 1986 which allowed any chemical "substantially similar" to a controlled substance listed in Schedule I or II to be treated as if it were also listed in those schedules, but only if intended for human consumption. These similar substances are often called “designer drugs” or “novel psychoactive substances (NPSs)”.

Testing the limits of US Control: Is a new psychoactive substance “illegal” if it is marketed as a “research chemical, not for human consumption”? Synthetic cannabinoids: From Basic Research to Drugs of Abuse

“Structure–activity relationships for 1-alkyl-3-(1-naphthoyl)indoles at the cannabinoid CB1 and CB2 receptors: steric and electronic effects of naphthoyl substituents”. John W. Huffman et al., Bioorganic & Medicinal 13 (2005) 89–112.

Cannabinoids of potential therapeutic use? Synthetic Cannabinoids “Spice” on the Clandestine Market • On December 15, 2008 JWH-018 was found in forensic samples in Germany as one of the active components in the grey market drug “Spice”, sold as an incense in a number of countries around the world. • Sale and distribution banned in Germany in January 2009 • An analysis of samples acquired four weeks after the German ban of JWH-018 revealed the presence of the N-butyl analogue to circumvent the ban Spice and The Emergence of Designer Analogs

Zombie” Outbreak Caused by the Synthetic Cannabinoid AMB-FUBINACA in New York, N Engl J Med 2017; 376:235-242, Axel J. Adams et. al.

• More potent than THC; significantly higher mortality • ADEs: Ataxia, N/V, Anxiety, seizures, psychosis, stroke Opioids and The Emergence of Designer Analogs • The third US epidemic? • Diversion and “pill mills” (inappropriate prescribing) • “Counterfeit street products” (oxycontin) • “Contaminated” products (fentanyls) • State and Federal Initiatives to address the current epidemic (PDMP) • Increased opioid-related criminal and civil litigation: • 1,900 cases pending vs manufacturers, distributors, providers “Drug wholesalers shipped 9 million pain pills over two years to a single West Virginia pharmacy” (NYT)

• McKesson, Cardinal Health, and AmerisourceBergen sold 423 million opioid drug doses ($17 billion) in West Virginia between 2007-2012. • Six of the 55 counties in West Virginia have the highest death tolls resulting from opioid addiction in the country. Over six years, almost 2,000 patients died from overdoses on hydrocodone and oxycontin in those counties. • Kermit, West Virginia (392 residents): a single pharmacy dispensed 9 million doses over two years. US Arrests Medical Professionals in Illegal Distribution of Opioids

April 18, 2019 Designer Analogs: Street Name: “Krokodil,” “Crocodil”

• Developed by Roche in 1922; potency 10X • Marketed as Permonid in Switzerland; short duration, less nausea • Illicitly produced in Eastern Europe since 2002 • Contaminated “krokodil” product injection associated with serious damage to the skin, blood vessels, bone and muscle sometimes requiring limb amputation. • Schedule I in the US Fentanyl and the Clandestine Drug Market Most produced in foreign clandestine labs DEA Nationwide Warning on Carfentanil Sudden surge in overdoses related to street drugs sold as yellow opioid pain medication

• The GBI in June identified two new fentanyl analogues, acrylfentanyl and tetrahydrofuran fentanyl, warning that both can be absorbed through the skin and are considered highly dangerous. Neither is approved for human or animal use. • Multiple reports in other states indicate that the opioid reversal drug naloxone, may not be effective if someone overdoses after ingesting acrylfentanyl. History of Fentanyl and its Derivatives

• Produced in clandestine labs (Asia) • Sold via the internet (“research chemicals” • Inexpensive: Carfentanil 50 grams for $361 (web) • Designer modification relatively easy • Potency >> morphine, heroin Fentanyl Analogues Detected Across the Globe The Clandestine Chemist and the Literature: Opioid U-47700 emerges from History

Street names: “Pink”, “ Pinky” Gulf Coast HIDTA and the Georgia Bureau of Investigation Issue Synthetic Opioids Alert

• The Gulf Coast High Intensity Drug Trafficking Area has issued an alert for a substance with the street name “Grey Death.” • Contains several potent opioids with potency much higher than heroin and is reportedly administered via injection, ingestion, insufflation, and smoking. • Analysis of each grey death sample revealed the presence of three opioids: U-47700, heroin, and fentanyl; though the amount of each drug within grey death varied from sample to sample. The New Clandestine Market: Online Availability of U-47700 (Dark Net)

Pick your favorite drug and find its source online! Is there one you can’t find? Future Designer Opioids: A rationale approach to better opioids – The “Utopioids”

• AH-7921 synthesized by Allen and Hanburys Ltd (UK) in 1970s • In October 2015, two horses (Bossmon and Literata) tested positive for AH-7921 at Belmont Park racetrack • Available online (“doxylam”); potency = morphine Tramadol Abuse Rising

• Many countries in West and Central Africa and North Africa (mostly Egypt) have reported large quantities of tramadol on the illicit market. • Tramadol tablets available in the illicit market in some parts of Africa contain dosages higher than that normally prescribed for medical purposes (225 mg and higher tablets) Question 2:

Most designer opioids including the fentanyl, U-4700 and AH-7921 are:

A. Produced in clandestine labs in the US B. Produced in clandestine labs abroad C. Are obtained by diversion of prescription drugs

Question 3: Most designer opioids including the fentanyl, U-4700 and AH-7921 are:

A. More potent than morphine B. Less potent than morphine The Story: “Precursor Chemical Control” and “Outsourcing” Precursor Chemical Control in the US: Unintended Consequences - “Breaking Bad” Methamphetamine Synthesis in the US: Gains and Losses

Shifting Markets: • Enforcement and Precursor () control: > 50% reduction in US production • >100% increase in Worldwide production; most in , C. America and Asia and Drug Testing – the “isomer and analog problem”

Gas chromatographic-mass spectral (GC-MS) Analysis Adderall and Pharmaceutical Stimulant Abuse 3,4-Methylenedioxymethamphetamine (MDMA, Ecstasy, XTC, E, X, Beans, Adams)

• MDMA synthesized in 1912 by Merck as an intermediate for coagulant drug synthesis • Alexander Shulgin and Leo Zeff discover MDMA’s “entactogenic” (empathy and closeness) effects, popularize the drug as an adjunct for in late 1970s (TAAR actions on NE, DA, 5-HT) • 1980s: Appeared as a street drug, commonly associated with dance parties (); still very popular across the globe • Often sold mixed with other substances such as , amphetamine, methamphetamine. Other drugs often sold as MDMA (Legal X) • In 2016, about 21 million people between the ages of 15-64 used ecstasy; in the US about 7% of the population has used MDMA at some point in their life MDMA Designer Drugs: 20 years of clandestine research!

2017: FDA Grants Breakthrough Therapy Designation for MDMA-Assisted Psychotherapy for PTSD, Agrees on Special Protocol Assessment for Phase 3 Trials Clandestine Syntheses of MDMA

• Mostly in central and eastern Europe • Piperonal and PMK are controlled precursors • Safrole and isosafrole are natural products! The Aminoindanes (“AIs”)

• “Structural variation and (+)-amphetamine-like discriminative stimulus properties”, R. Oberlender and David Nichols”, and Behavior (1991): 38: 581-586

• Synthetic aminoindanes were originally developed as potential antiparkinson drugs (derivatives of ) and a potential tool for psychotherapy.

• 2-AI is not scheduled at the federal level in the US, but may be considered an analog of amphetamine, in which case purchase, sale, or possession could be prosecuted under the Federal Analog Act. Aminoindanes as Designer MDMAs

• 1995: 300 grams of a tan powder containing ascorbic acid as a diluent. Identified as 5-iodo-2-aminoindan, commonly referred to as “5-IAI,” ordered via the Internet. • Since 2000: Many derivatives sold as “” and substituted for MDMA The Drugs of Abuse -“Design” 1-[3-(Trifluoro-methyl)-phenyl]piperazine (Street Names: “TFMPP” or “Molly”)

• Often found in combination with BZP: “A2”, “Legal E” or “Legal X”) • DEA temporarily controlled TFMPP in 2002 as a Schedule I hallucinogen under the Controlled Substances Act (CSA) • 2011-2012, federal, state and local forensic laboratories identified 2,188 and 2,461 substances as TFMPP. Use waning in recent years • No longer federally controlled per recommendations by NIDA but many states have controls • Some abusers describe TFMPP as a mild hallucinogen and report feeling mild, pleasant and mellow after ingesting TFMPP. In addition, some abusers stated that BZP enhances the effects of TFMPP. Piperazine Designer Analogs

Simple synthesis from “uncontrolled” Question 4

Based on their pharmacologic action, MDMA and its derivatives are classified as:

A. Stimulants B. C. Analgesics D. Entactogens () and “Bath Salt” Development

• Khat or qat (Catha edulis): plant native to the Horn of Africa and Arabian Penisula. Contain the stimulant cathonine (effects similar to methamphetamine) • Among communities from the areas where the plant is native, khat chewing has a history as a social custom dating back thousands of years (similar to coca leaves in SA). • Cathinone schedule I in US in 1993 • Khat seized by DEA: MDPV and Bath Salt “Drug Development”

• 1969: Boehringer-Ingelheim files a patent application for MDPV for treatment of chronic fatigue and potential antidepressant. • Actions: NET >> DAT >>>SERT • CNS stimulant and CV adverse effects prevented further development

• synthesized and approved in 1985 as an antidepressant. DAT > NET

• A significant incidence of seizures at the originally recommended dosage caused the withdrawal of the drug in 1986.

• Subsequently, the risk of seizures was found to be highly dose-dependent, and bupropion was re-introduced to the market in 1989 with a lower maximum recommended daily dose MDPV and the “Bath Salts”

• 2005: MDPV appears as a recreational drug; first mention on Drugs-Forum. • 2007: First seizure of MDPV as a recreational drug, by customs officials in the Germany where it had been shipped from China. • 2008: First seizure of MDPV in the US. • 2009-2010: MDPV illegal in Denmark and a controlled drug in the UK and Sweden. • 2010: First reports of the widespread retail marketing of MDPV "bath salts" in the US, sold at gas stations, convenience stores. • October 21, 2011, MDPV and derivatives temporarily controlled in Schedule I of the Controlled Substances Act. Designer Bath Salts Increasing Annually

Sold as: Bloom Cloud Nine Cosmic Blast Flakka Ivory Wave Lunar Wave Scarface Vanilla Sky Bupropion Abuse PMC (“Poor man's crack”)

“Pharmacies in the Tri-State area (WV, OH & KY) have reported fraudulent scripts being called in under physicians who have never seen these patients” April 2018

The effects of bupropion on and levels in the brain overlap with illicit stimulants such as cocaine and bath salts

Routes of abuse: • Most common: crushing and snorting (overcome slow release) • Injection of dissolved drugs • Multiple oral doses Emergence of Synthetic Cannabinoids and “Bath Salts”: New Global Economies Question 5:

The pharmacologic effects of the “bath salt” class of drugs are most similar to the:

A. MDMA class of drugs B. Amphetamine stimulants C. Opioids D. The synthetic cannabinoids

Question 6: Structurally the “bath salt” drugs are most closely related to the:

A. and bupropion B. MDMA drugs C. Fentanyl opioid drugs D. Synthetic cannabinoids The Designer Hallucinogens: From LSD to “NBOMes”

• Origin: Academic research published by Nichols (Purdue) and Glennon (MCV) and published in the Journal of in 1970-80s • Also Shulgin synthesis and experimentation (books) The Designer Hallucinogens Popularized

Alexander Shulgin: • Dow Scientist, invented “Zectran” • DEA licensed lab in 1970-80s • DEA raids the lab and shuts it down PIHKAL and -B: The early synthetic hallucinogens

• 5-HT2A/2C partial agonist and increases dopamine – hallucinogen

• 2C-B popularized in the US as a substituted for MDMA (1985).

• Since 2013, 2C-B emerged as the drug of choice for users in South America

• Street prices range between $10-30 per tablet (15-25 mg doses)

• Wholesale purchases of 2C-B range from $100-$300/gram – 40-70 doses “NBOMes” from basic research….

11C-25I-NBOMe imaging tool to map 5-HT2 receptors in the CNS The NBOMes “N-Bomb", "Solaris", "Smiles" or "Wizard"

• 25I-NBOMe, 25C-NBOMe, and 25B-NBOMe are three synthetic substances encountered across the globe on the market. These substances are sold online and through illicit channels, purported to be illicit hallucinogens such as LSD. • They target the same 5-HT2A receptor as many other hallucinogens, including Schedule I hallucinogens like LSD, 2C-I, 2C-C, and 2C-B. • These substances have been encountered as powders, liquid solutions, laced on edible items, and soaked onto blotter papers (Schedule 1, 2013). NBOMe Intoxications – Multiple Reports

“Four males between the ages of 18 and 19 simultaneously presented to the emergency department after recreational exposure to 25I-NBOMe. They purchased the drug from a dealer who obtained it through the internet. The substance was either snorted or ingested orally. Upon arrival, all patients were tachycardic and displayed varying levels of psychomotor agitation. None were capable of providing a clear history. Three patients experienced prolonged seizure activity which required pharmacologic therapy, intubation, and mechanical ventilation. One patient developed rhabdomyolysis and renal failure requiring hemodialysis” – Kelly et al.

“Mobile, AL: The drug found in the University of South Alabama student who was fatally shot by a police officer in October, 2013, is a research drug similar, but stronger, than LSD” – AL.com

Kelly A, Eisenga B, Riley B, Judge B (2012). Case series of 25I-NBOMe exposures with laboratory confirmation. Clinical Toxicology 50: 702 NBOMes….Just a few known “Designer Analogs” Question 7:

The “NBOMe” drugs produce their pharmacologic effects and have very specific affinity for:

A. Dopamine and norepinephrine reuptake transporters B. Cannabinoid receptors C. Opioid mu receptors D. Serotonin 5-HT2 receptors and and PCP

Ketamine (US in 1970) • Veterinary anesthetic • in children: sole anesthetic for minor procedures or as an induction agent • Sedative for physically painful procedures in EDs • Supplement spinal or epidural anesthesia • Emergency surgery in field conditions in war zones (Vietnam War) • Drug of Abuse and date rape drug (“etheogenic”)

Esketamine (Spravato): Nasal spray, in conjunction with an oral antidepressant, for the treatment of resistant depression. • Because of the risk of serious adverse outcomes (sedation and dissociation) and the potential for abuse and misuse of the drug, it is only available through a restricted distribution system (REMS) PCP/Ketamine “Designer Analogs”: The accomplishment of a single individual! Ketamine and PCP Anabolic Steroids and Testosterone: Three Market Impacts: Pharmaceutical, Abuse and “Supplements”

Expanding pharmaceutical market GHB/GBL and Rohypnol: “Auburn University lab tech charged with selling date rape drug” Inhalants: From Reddi-Whip to “If it’s volatile someone will inhale it” Thank you!

Questions?