New Drugs of Abuse – The Other Drug 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 drug overdose 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: • Opioids • Stimulants • Benzodiazepines • Barbiturates • Sleep medications Growth in Stimulant and Opioid 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) Cocaine Abuse and Ethical Pharmaceuticals • Long history of use/abuse • Coca-Cola invented in 1885 by John Pemberton, an Atlanta pharmacist, and contained small amounts cocaine. Marketed as a “patent medicine” for headache, fatigue and upset stomach • Cocaine removed from “Coke” in 1929 (Prohibition) and beverage offered for broader consumption • Local anesthetic in US (occasional ENT use) • Template for design of modern day safer local anesthetics 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 heroin-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 Decriminalization by 2025? Cannabis 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 Hallucinogen Natural Products: Expansion of Decriminalization? DEA or FDA? Kratom (Biak, Ketum, Kakuam, Ithang, Thom) • The leaves of the kratom tree (Mitragyna speciosa) found in SE Asia, used as a remedy for diarrhea, fatigue and pain. • Popular in North America and Europe as a plant-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 (Amphetamine 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 Chemistry 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: Desomorphine Street Name: “Krokodil,” “Crocodil” • Developed by Roche in 1922; potency 10X morphine • 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