48Th Annual Meeting

7/19/2014

48th Annual Meeting

Why is this even a concern? Synthetic Drugs of Abuse

Dawn R. Sollee, Pharm.D., DABAT Assistant Director Florida/USVI Poison Information Center- Jacksonville

Navigating the Oceans of Opportunity

Disclosure Monitoring the Future Study

 I do not have a vested interest in or affiliation with any corporate organization offering financial support or grant monies for this continuing education activity, or any affiliation with an organization whose philosophy could potentially bias my presentation Percentage

MDMA = 3,4-methylenedioxy methamphetamine LSD = lysergic acid diethylamide http://www.monitoringthefuture.org

Objectives DEA News: Huge Synthetic Drug Takedown

By the end of the presentation, the audience will be  Project Synergy Phase II continues attack on drug able to: networks, sources of supply, global money flow

 Describe complications associated with the  29 states involved

utilization of synthetic drugs of abuse  More than 150 individuals arrested

 Identify commonly used synthetic drugs of abuse in  More than $20 million in cash and assets seized adult and in pediatric patients  Targeted synthetic cannabinoids and cathinones  Discuss key principles in the management of patients intoxicated with synthetic drugs of abuse

Drug Enforcement Administration, May 7, 2014 http://www.justice.gov/dea/divisions/hq/2014/hq050714.shtml

1 7/19/2014

Discussion Topics Synthetic Cannabinoids

 Cannabinoid receptor homologs Pharmaceutical Federal  Synthetic cathinones and research Legislation companies in • November 10,  Molly search of Emerging 2010 agonists use in USA • May 2013 • 1960’s • 2010 • January 2014  Kratom

Recognized State drug of abuse Legislation in Europe • March 18, • Early 2000’s 2010

Synthetic Cannabinoids Background

 Agents work at cannabinoid receptors

 Chemicals placed into a solvent

 Sprayed onto plants/herbal blends

 Can be smoked or ingested

 Still able to be purchased

Photo: FPIC/Jax

FPIC Network Data In the Media

Synthetic Cannabinoid Exposures 90

60 50 Largest Synthetic Marijuana K2 Bust in Marion 40 County To Date - Ocala Post, Sept 17, 2013

0 Jan Feb Mar April May June July Aug Sept Oct Nov Dec 800 Packages of Synthetic Marijuana 2011 2012 2013 2014 Confiscated in Seminole County Raids – WFTV.com, Jan 14, 2014 FPICN Query Builder

2 7/19/2014

Major Structural Groups Mechanism of Action

JWH-018, JWH-073 Naphthoylindoles  Cannabinoid receptor agonists

Adamantoylindoles Naphthylmethylindoles  CB1 – brain, the spinal cord, and PNS  CB2 – peripheral tissues (spleen and immune cells)

Tetramethylcyclopropylindoles Cyclohexylphenols

Naphythoylpyrroles Benzoylindoles

Naphthylmethylindenes Phenylacetylindoles

Classical

Presley BC, et al. Forensic Sci Rev 2013. Thornton MD, Baum CR. Pediatr Emer Care 2014.

Newer Products Presentation

 APINACA, AB-FUBINACA, ADB-FUBINACA, AB- PINACA, ADB-PINACA Seizures Agitation Paranoia Tachycardia  Newer products  QUPIC and QUCHCI Chest Pain Hypertension Nausea Vomiting  No pharmacological data

Acute Kidney Myocardial Mydriasis Hyperthermia  UR-144, XLR-11, APINACA, QUPIC, 5F-PB-22, AB- Injury Infarction FUBINACA, ADB-PINACA  Scheduled in 2013, 2014

Monte AA et al. NEJM 2014;370:389-90 Fed Register. 2013: 28735-9 Harris CR, Brown A. J EM 2013. Fed Register. 2014: 1776-1780

Properties Withdrawal

 Lipid soluble  Nightmares

 Quicker onset  Sweating

 Variable duration of action  Tremor

 Active metabolites  Headache

 Potency is 4 to 100 X that of delta-9-THC  Hypertension

 Tachycardia

Nelson ME, et al. Emerg Med Clin N Am 2014. Zimmerman et al. Dtsch Arztebl Int 2009

3 7/19/2014

Synthetic Cathinones Synthetic Cathinones

First synthetic Schedule I Mephedrone cathinone substance in USA market (methcathinone) •Cathinone •1928 1993 •2009

Outbreaks Mephedrone Federal in USA in use in Legislation Europe Australia and • September •1990’s Europe 2011 •2007 • March 2014

Photo: FPIC/Jax Thornton MD, Baum CR. Pediatr Emer Care. 2014

FPIC Network Data 10 Synthetics Into Schedule I

Synthetic Cathinone Exposures 50

45 4-methyl-N-ethylcathinone (4-MEC) 4-methyl-alpha-

40 pyrrolidinopropiophenone (4-MePPP)

35 Alpha-pyrrolidinopentiophenone (alpha- 1-(1,3-benzodioxol-5-yl)-2- PVP) (methylamino)butan-1-one (butylone) 30

25 2-(methylamino)-1-phenylpentan-1-one 1-(1,3-benzodioxol-5-yl)-2- (pentedrone) (methylamino)pentan-1-one (pentylone) 20 4-fluoro-N-methylcathinone (4-FMC) 3-fluoro-N-methylcathinone (3-FMC) 15

10 1-(naphthalene-2-yl)-2-(pyrrolidin-1- Alpha-pyrrolidinobutiophenone (alpha- yl)pentan-1-one (naphyrone) PBP) 5

0 Jan Feb Mar April May June July Aug Sept Oct Nov Dec 2011 2012 2013 2014

Fed Regist. 2014 FPICN Query Builder

In the Media

 “To be able to start a beautiful organic garden you must need to commit to it, and the best way to do this is by using plant fertilizers. Plant fertilizers, such as 4mec, which you can easily Man sentenced to prison for drugs after buy online, are a key to achieve a garden that everyone several overdosed on bath salts – Orlando envies.… Spreading 4mec helps maintain a neutral PH, which Sentinel, Feb 19, 2014 means it helps to hold on to more nutrients for the plant to feed on and be able to grow.” http://www.slyplants.com/

 “Plant Feed Shop is a leading plant feed supplier offering wide range of plant food products including Mephedrone, 4- methylmethcathinone, 4-MMC, MCAT, Bubbles and many such products” http://www.plantfeedshop.com/

4 7/19/2014

Background Presentation

 Chewing the khat plant (Catha edulis)

 Routes of exposure Hypertension Tachycardia Hyperthermia Agitation  Snorting, orally  IV, IM, rectal Headache Chest Pain Tremors Bruxism

 Sold as bath salts, plant food, stain remover powders, glass cleaner, pipe cleaner, lady bug Insomnia Paranoia Delusions Mydriasis attractant, shoe deodorizer Acute Renal Diaphoresis Rhabdomyolysis Nausea Failure

German CL et al. Life Sciences. 2014

Mechanism of Action Molly

 Inhibit reuptake of dopamine, serotonin, and  Used to be a pure form of MDMA

norepinephrine  Versions have contained  Increase presynaptic release  1-(3-trifluoromethyphenyl) piperazine (TFMPP)  Sympathomimetic  4-methylmethcathinone (4-MMC)  4-methyl-n-ethylcathinone (4-MEC)  MDPV  Methylone

http://www.ner.cap.gov/ddr/molly.htm http://www.syracuse.com/news/index.ssf/2011/08/post_466.html http://www.cnn.com/2013/11/22/health/9-things-molly-drug/index.html http://www.miamiherald.com/2013/03/12/3281778/police-expect-club-drug-molly.html

Pharmacokinetics Kratom

 Methylone, mephedrone  100-200 mg orally has onset of 30-45 min and duration of 2-5 hours  Metabolism by phase I pathways

 MDPV  10-15 mg orally has onset of15-30 min and duration of 2-7 hours Kratominformation.blogspot.com www.kratomgalaxy.com  CYPs (1A2, 2D6, 2C19) involved in demethylation

Rosenbaum CD et al. J. Med Toxicol. 2012. Nelson ME, et al. Emerg Med Clin N Am 2014.

5 7/19/2014

In the Media Need a Pick-Me-Up?

Is Kratom quickly becoming a legal addiction? DEA, FDLE investigating new drug popular with  Ingredients teens - Click Orlando, Feb 7, 2013  L-tryptophan  Kratom  Caffeine

http://buzzgum.com/

Background 4X100

 Available in multiple forms  Components  Chewed, pills, tea, cocktails  Kratom

 Mitragyna speciosa contains 25 alkaloids  Caffeinated soft drink  Mitragynine is the main focus  Cough syrup  Codeine or diphenhydramine  On the DEA’s list of Drugs and Chemicals of Concern  Ice  Antidepressant or analgesic

Hassan Z, et al. Neuroscience and Behavioral Reviews. 2013 Hassan Z, et al. Neuroscience and Behavioral Reviews. 2013

Krypton Mechanism of Action

 Contains kratom leaves infused  Stimulant effects at low doses

with o-desmethyltramadol  Opiate effects at high doses  Still available on the internet  Has high affinity at mu opioid receptors  More than 10X the potency of morphine

2+  Blocks neuronal Ca channels

http://the-tripreport.com/site/news/acmd- advise-o-desmethyltramadol-ban/

Rosenbaum CD et al. J. Med Toxicol. 2012. Hassan Z, et al. Neuroscience and Behavioral Reviews. 2013 Arndt et al. Forensic Science International. 2011.

6 7/19/2014

Pharmacokinetics Management

 Onset of 5 minutes  ABC’s

 Duration of 1 hour  Supportive care

 Inhibits the activity of 3 CYP450’s  Agitation, seizures, tachycardia, hypertension  2C9, 2D6, 3A4  Benzodiazepines  Persistent hypertension  Vasodilators  Hyperthermia  Cooling measures

 Naloxone may be an option for Kratom exposures

Presentation Monitoring

 Vital signs, including temperature Low Dose  Electrocardiogram and cardiac monitoring Tremors Euphoria Giddiness Talkativeness  Potential laboratory evaluation  Cardiac enzymes  Renal function tests High Dose  Sedation Nausea Vomiting Dizziness Electrolytes  Creatinine kinase

Nelson ME, et al. Emerg Med Clin N Am. 2014

Withdrawal Take Home Message

 Hostility  These products are readily available

 Aggression  Lack of product information and testing

 Excessive tearing  We’re playing catch up

 Aching muscles/bones  No specific antidote

 Jerky limb movements  Talk to your adolescents about the dangers!

 Anxiety

 Tremor

 Sweating

Rosenbaum CD et al. J. Med Toxicol. 2012 Singh et al. Drug and Alcohol Dependence. 2014

7 7/19/2014

Any Questions?

Arndt T, Claussen U, Gussregen B, et al. Kratom alokaloids and O-desmethyltramadol in urine of a “Kryton” herbal mixture consumer. Forensic Science International. 2011;208:47-52. CDC. Notes from the field: Severe illness associated with reported use of synthetic marijuana- Colorado, August-September 2013. MMWR Weekly. 2013;62:1016-7. DEA. Schedule of controlled substances: Temporary placement of 10 synthetic cathinones into Schedule I. Final order. Fed Regist. 2014;79:12938-43. DEA. Schedules of controlled substances: Temporary placement of four synthetic cannabinoids into Schedule 1. Fed Regist. 2014;79:1776-1780. DEA. Schedules of controlled substances: Temporary placement of three synthetic cannabinoids into Schedule 1. Fed Regist. 2013;78:28735-9. Editorial Staff: THC Homologs (Management/Treatment Protocol). In: Klasco RK (Ed): POISINDEX System. Truven Health Analytics, Greenwood Village, Colorado (Edition expires 6/2014). Editorial Staff: Synthetic Cathinone Derivatives (Management/Treatment Protocol). In: Klasco RK (Ed): POISINDEX System. Truven Health Analytics, Greenwood Village, Colorado (Edition expires 6/2014). ElSohly MA, Gul W, Wanas AS, et al. Synthetic cannabinoids: analysis and metabolites. Life Sciences. 2014;97:78-90. German CL, Fleckenstein AE, Hanson GR. Bath salts and synthetic cathinones: An emerging designer drug phenomenon. Life Sciences. 2014;97:2-8.

Gunderson EW, Kirkpatrick MG, Willing LM, et al. Substituted cathinone products: A new trend in “bath salts and other designer stimulant drug use. J Addict Med. 2013;7:153-162.

Harris CR and Brown A. Synthetic cannabinoid intoxication: A case series and review. JEM. 2013; 44:360-6.

Hassan Z, Muzaimi M, Navaratnam V, et al. From Kratom to mitragynine and its derivatives: Physiological and behavioural effects related to use, abuse, and addiction. Neuroscience and Behavioral Reviews. 2013;37:138-151.

Hill SL and Thomas SHL. Clinical toxicology of newer recreational drugs. Clinical Toxicology. 2011;29:705-19.

Johnston, L. D., O'Malley, P. M., Bachman, J. G., & Schulenberg, J. E. (December 18, 2013). "American teens more cautious about using synthetic drugs." University of Michigan News Service: Ann Arbor, MI. Retrieved 04/04/2014 from http://www.monitoringthefuture.org

Levin M, Levitan R, Skolnik A. Compartment syndrome after bath salts use: A case series. Ann Emerg Med. 2013;61:480-3.

Lewin AH, Seltzman HH, Carroll FI, et al. Emergence and properties of spice and bath salts: A medicinal chemistry perspective. Life Sciences. 2014;97:9-19.

Nelson ME, Bryant SM, Aks SE. Emerging drugs of abuse. Emerg Med Clin N Am. 2014;32:1-28.

Presley BC, Jansen-Varnum SA, Logan BK. Analysis of synthetic cannabinoids in botanical material: A review of analytical methods and findings. Forensic Science Review. 2013;25:27-46,

Prosser JM and Nelson LS. The toxicology of bath salts: A review of synthetic cathinones. J. Med Toxicol. 2012;8:33-42.

Rosenbaum CD, Carreiro SP, Babu KM. Here today, gone tomorrow…and back again? A review of herbal marijuana alternatives, synthetic cathinones, salvia divinorum, methoxetamine, and piperazines. J. Med. Tox. 2012;8:15-32

Singh D, Muller CP, Vicknasingam BK. Kratom dependence, withdrawal symptoms and craving in regular users. Dug and Alcohol Dependence. 2014;139:132-7.

Thornton MD and Baum CR. Bath salts and other emerging toxins. Pediatr Emer Care. 2014;30:47-55.

Wiley JL, Marusich JA, Huffman JW. Moving around the molecule: Relationship between chemical structure and in vivo activity of synthetic cannabinoids. Life Sciences. 2014;97:55-63.

Zimmermann US, Winkelmann PR, Pilhatsch M, et al: Withdrawal phenomena and dependence syndrome after the consumption of "spice gold". Dtsch Arztebl Int. 2009; 106:464-467.