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Home , Bufotenin, Dextrorphan, Levomethorphan

What are the kids using? , CCCs, and other

Kirk Moberg, MD, PhD, FASAM Medical Director, Illinois Institute for Recovery Clinical Professor, Departments of Internal Medicine and Psychiatry and Behavioral Medicine University of Illinois College of Medicine Illinois and other Abuse Professional Certification Association, Inc. March 17, 2016 Agenda

• Statistics • Inhalants • • Hallucinogens • Cold remedies • Miscellaneous • Synthetic STATISTICS Let’s start with some statistics

Monitoring the Future Study University of Michigan 44,892 students 382 public and private schools Funding Source: National Institute on Drug Abuse Prevalence among past year drug use among 12th graders

Drug Prevalence Alcohol 58.2 Marijuana/ 34.9 Hookah 19.8 Small cigars 15.9 * 7.7 Adderall* 7.5 Snus 5.8 o/t * 5.4 5.2 Tranquilizers* 4.7 Cough Medicine* 4.6 Vicodin* 4.4 Hallucinogens 4.2 OxyContin* 3.7 Sedatives* 3.6 MDMA (Ecstasy) 3.6 LSD 2.9 Hall other than LSD 2.9 (any form) 2.5 Ritalin* 2.0 Inhalants 1.9 Salvia 1.9 * Nonmedical use Categories not mutually exclusive e-cigarette risk e-cigarette substance Tobacco vs. Cannabis Cannabis Cannabis Risk Synthetic Cannabinoids Prescription Prescription Opioids Heroin INHALANTS Inhalants Inhalants

• Volatile hydrocarbons – – Adhesives – Paint removers – Etc. • • Three classifications

Gas phase

Volatile hydrocarbons Aerosol Volatile hydrocarbons

Adhesives and thinners

Diflouroethane

Ether Alkyl nitrites

Uses: vasodilator ( disease); cyanide ; (especially with cocaine and MDMA); enhance sexual experience Chloroethane ?

• GABA-A • NMDA • Acetyl DISSOCIATIVES NMDA antagonists The trail to dextromethorphan

Antitussive Dissociative

Dextromethorphan (DXM)

Racemethorphan

Levomethorphan (DXO)

Dextromethorphan Dextrophan

Levorphanol DXO pharmacology

• N-Methyl-D-Aspartate • m, k receptor Nitrous oxide Schedule II

Oral Intravenous Inhalation Intranasal Clinical Presentation

• Rage • Erythema • Dilated Pupils

• Delusions • Amnesia • Nystagmus • Excitation • Skin Dryness Receptors

• NMDA receptor antagonist • -2 receptor partial agonist HALLUCINOGENS Hallucinogens

MDMA

Dimethyltryptamine (DMT)

Salvia divinorum

Psylocybin receptors 3, 4, 5-trimethoxyphenethylamine

Peyote Lophophora williamsii Results

• Altered thinking • Altered sense of time and self awareness • Color brilliance and intensity • Distortions and kaleidoscope forms • Flattening of three dimensional objects Psylocybin More

• 200 species • Psylocybin • Human usage dates back thousands of years • Serotonin agonist Effects

• Euphoria • Visual • Distorted sense of time • Changes in perception Dimethyltryptamine

50 4 animals Hallucinogenic toads

5-methoxy-N, N-dimethyltryptamine (N, N,-dimethylserotonin) Lysergic Acid Diethylamide Methylenedioxymethamphetamine (MDMA)

• Ecstasy • XTC • Adam • Clarity • Lover’s speed • Molly Two sterioisomers

• (l) – hallucinogenic – indirect agent • (d) isomer – – indirect sympathomimetic agent Molly, Mandy or Ecstasy?

• Mandy = Molly (Mandy is a UK term) • Molly can be defined in two ways – MDMA that is “pure” – : a synthetic synthesized in 1996 for use as an (b, k MDMA)

Methylone Structural comparison

MDMA Methylone (b, k MDMA) Pleasurable effects

• Energetic • Peaceful • Empathetic • “Gooey” • “A six hour orgasm” NBOMe compounds Schedule I

Phenylethylamine The base compound 1st generation

2C-C -B 2C-I

1-(4-chloro-2,5-dimethoxyphenyl)-2-aminoethane 2nd generation

25C-NBOMe 2-(4-chloro-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine

25B-NBOMe 25I-NBOMe High affinity, high potency Kyriakou et al., 2015.

Effects 5-H2A receptor agonist • Paranoia • Dystonia and clonus • Confusion • Seizures • Syncope • Shaking • Vasoconstriction • Scrambled • Nausea communication • Yawning • Tunnel vision • Insomnia • Time dilation • Tachycardia • Dilated pupils DEATH… with as little as one drop Overdose or Trauma

Expert Committee on Drug Dependence, WHO, 2014. DEA, Drug and Chemical Diversion Section, 2013.

k opioid agonist partial D2 agonist Salvia divinorum—pharmacology

• Ingested by – Chewing – Drinking juice – – Inhaling vapor • Effects – Hallucinations – Psychosis • Duration – Few minutes Salvia divinorum—legal status

• Federal— act doesn’t apply • Illegal in many states—Illinois, Minnesota • Wisconsin—illegal to grow and sell but legal to possess COLD REMEDIES Lots to choose from

Dextromethorphan; chlorpheniramine Acetaminophen; dextromethorphan;

Acetaminophen; chlorpheniramine; Dextromethorphan; dextromethorphan Acetaminophen; chlorpheniramine Ingredients

• Acetaminophen—analgesic—not mind altering • Chlorpheniramine——sedative • Doxylamine—antihistamine—sedative • Dextromethorphan—antitussive—dissociative • Guaifenesin—expectorant—sedative The key? The key?

Guaifenesin causes nausea Lots to choose from

Dextromethorphan; chlorpheniramine Acetaminophen; dextromethorphan; doxylamine

Acetaminophen; chlorpheniramine; Dextromethorphan; guaifenesin dextromethorphan Acetaminophen; chlorpheniramine MISCELLANEOUS and

• Children who are CYP2D6 rapid metabolizersoverdose • Codeine + promethazine + soda pop and/or Jolly Rancher = “Sizzurp,” “,” “Purple Drank,” “Syrup.” • Promethazine in opioid addicts • Mepergan = meperidine + promethazine Alcohol sanitizer

• Best ethyl alcohol on the market is 70% • A few comparisons – —4-5% – —12-14% – Vodka, whiskey, gin—45% But if you want you want to drink it

Add salt SYNTHETIC CANNABINOIDS Synthetic cannabinoids 100-800x more potent Anti-emetic; analgesic

No psychoactive effects Pfizer

CB reverse agonist CB reverse agonist

Weak metabolite of THC Prototype of JWH Full agonist

Partial agonist Raphael Mechoulam—1960s Professor of Medicinal Chemistry The Hebrew University Pfizer—1979 John W. Huffman—1984 Professor Emeritus, Organic Chemistry Clemson University

Washington Post August 9,2015 Alexandros Makriyannis—2001 Director of Center for Drug Discovery, Northeastern University Classes

• HU series—Raphael Mechoulam at Hebrew University • CP series—Charles Pfizer • JWH series—John W. Huffman • AM series—Alexandros Makriyannis

Debruyne & Le Boisselier, 2015 ananda=joy (Sanskrit)

Activates m opioid and GABA receptors which increase dopamine and serotonin

Acetaminophen metabolized to AM404 which is a potent agonist at TRPV1 receptor (analgesia); also may act as for anandamide. JWH-018

Full agonist Potency: 5x THC 2002: circulated as “spice” 2008: banned in Germany after discovering the presence of the compound JWH-073

Partial agonist Discovered in circulation 4 weeks after JWH-018 ban HU-210 Hebrew University

Difficult to synthesize 100-800x as potent as THC Seely et al., 2012 XLR-11 Cannabis vs. cannabinoids

• Most symptoms similar to cannabis intoxication – Tachycardia – Reddened eyes – – Mild sedation – Hallucinations, acute psychosis – Memory deficits • Symptoms not typically seen after cannabis intoxication—clenbuterol – Seizures – Hypokalemia – Metabolic acidosis – Hypertension (?) – Nausea/vomiting – Coma – Agitation/violent behavior

Seely et al., 2011 Effects increasing in frequency

• Tachycardia followed by bradycardia • Seizures • • Cardiac • Altered mental status Three demographic groups

• Marijuana smokers • Occasional drug users seeking to avoid legal consequences • Drug naïve, curious experimenters

Seely et al., 2012 Black Mamba University of Colorado, 2014 Questions?

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