"Technological Approaches in the Synthesis of Designer Drugs, and Creative Prosecution of the What is a “Designer Drug”? Non-Scheduled, Illicit, Analogue Drug"  Designer drug is an informal term for psychoactive drugs that are related, by structure and/or activity, to existing psychoactive drugs frequently used for “recreational” use.

 In many instances, designer drugs have been David M. Benjamin, Ph.D. Clinical Pharmacologist & Toxicologist synthesized by small chemical modifications Adjunct Associate Professor, Dept. of Pharmaceutical Sciences, of known active drugs, and Northeastern University, Boston, MA Fellow, American Academy of Forensic Sciences (Toxicology)  Resemble the “parent” drug as: structural Fellow, American Society for Healthcare Risk Management Fellow, American College of Clinical Pharmacology analogues, stereoisomers and derivatives of Fellow, American College of Legal Medicine those drugs. Member, Society of Forensic Toxicologists [email protected]

Federal Analog Act Substantially Similar  Substantially similar means that the chemical  Controlled Substance Analogue Enforcement Act of 1986 structures are very similar  Substantially similar does not mean exactly the same;  Effective October 27, 1986 some level of difference is acceptable and all experts  Federal Analog Act, 21 U.S.C. § 813, is a section of do not agree the United States Controlled Substances Act which allowed any chemical "substantially similar" to a  Substantially similar can be: (1) a readily cognizable controlled substance listed in Schedule I or II to be (chemical) similarity between the alleged analog treated as if it were also listed in those schedules, but and the controlled substance prior to ingestion, (2) only if intended for human consumption. These has a CNS effect equal to or greater than the similar substances are often called designer drugs.* substance scheduled in C-I or C-II, or (3) is metabolized to the alleged the controlled substance  *Wikipedia, accessed January 11,2014. analog after ingestion, e.g., 1, 4 – butanediol -> GHB

Classification of Synthetic Drug Abuse Prevention Act of 2012 – Chemical Classes Designer Drugs by Chemistry  Naphthoxylindoles  Legislation  Control by classes  Naphthylmethylindoles  Analogs (Chemical groups) Compounds:  Naphthoylpyrroles e.g., Spice, K-2 Designer stimulants, e.g.  Naphthylmethylindenes Cathinones, bath salts Synthetic cannabinoids,  Phenylacetylindoles Benzylpiperazines Phenethylamines  Cyclohexylphenols Tryptamines  Pyrrolidinophenones  Benzoylindoles My thanks to Heather L. Harris, MFS, JD, D-ABC for permission to use her slides.  Adamantoylindoles

1 Chemical Structure of THC vs. Synthetic Mechanism of Action of the Cannabinoids – Substantially Similar? Cannabinoids 5 Cannabinoid Therapy

1 Neurotransmitter (NT) from presynaptic neuron activates the postsynaptic neuron. Inhibition of Neurotransmitter Release CB1 Receptor 4 2 Activated postsynaptic neuron Presynaptic releases endocannabinoids. THC; Tetrahydrocannabinol Neuron 3 Endogenous CB1 ligand diffuses 9 (−)-trans-Δ - tetrahydrocannabinol, 1 back to and binds to the a dibenopyran. Endogenous presynaptic CB1 receptor. 3 Cannabinoid 2 Retrograde Signaling CP-47,497 has been identified 4 CB1 receptor activates a G- in Spice. Neurotransmitter protein, leading to inhibition of Receptor NT release. Modified from: Synthetic Cannabinoids The Challenges of Testing for Designer Drugs Postsynaptic 5 Synthetic Cannabinoids are By Bridgit O. Crews, PhD Neuron thought to activate CB1

receptors directly, mimicking the February 2013 Clinical Laboratory effects of endocannabinoids. News: Volume 39, Number 2 Endogenous and Exogenous Accessed online: Jan. 4,2014 Cannabinoids Reduce Neuronal Signaling

Effects of Cannabinoid Receptors Cathinones in “Bath Salts” in Pain Neuromodulation CB1 CB2 Mephedrone (Miaow CB1 Effects High-affinity nerve growth factor Miaow)  CGRP  NGF (4-methylmethcathinone, 4-  Plasma extravasation MMC)  Hyperalgesia  Edema Methylone

CB2 Effects (βk-MDMA, 3,4-  Mast cell degranulation methylenedioxy-N-  Histamine  5-HT methylcathinone)  NGF sensitization  Neutrophil migration  NO production by macrophages MDPV (3,4- methylenedioxypyrovalerone) CGRP=calcitonin gene-related peptide 5-HT=5-hydroxytryptamine NGF=nerve growth factor NO=nitric oxide

Adapted from Lynch M. Pain Res Manage. 2005;10(suppl A):7A-14A. Gwen DeCelles, MFA, Medical Illustrator.

Cathinones Cathinone ADRs Kesha,K., Boggs, CL, Allan, CH, et al., MDPV (“Bath Salts”) Related Death: Case Report and Review of the Lit., JFS 2013;58:(6)1654-1680.

Mephedrone (Miaow Miaow) (4-methylmethcathinone, 4- MMC) Methylone (βk-MDMA, 3,4- methylenedioxy-N- methylcathinone)

MDPV (3,4- methylenedioxypyrovalerone)

2 Grazie, Drs. Papanti, Schifano & Spice drugs and Botteon for this great paper! psychopathological ADRs -1  Situational anxiety, agitation  From: “Spiceophrenia”: a systematic overview of “Spice”-related  *Recurrent psychotic episodes triggered psychopathological issues and a case report. by cannabis Duccio Papanti, Fabrizio Schifano, Giulia  “Spice” Anxiety, psychotic symptoms; Botteon, et al. Hum. Psychopharmacol Clin hallucinations Exp 2013; 28: 379–389.  16 year old “Spice” Altered mental status  Visual hallucinations, agitation, restlessness and anxiety  *Long-lasting psychotic episodes

Spice drugs and Spice drugs and psychopathological ADRs -2 psychopathological ADRs -3

 “Spice” Severe anxiety and paranoia,  *Long-lasting psychotic episodes and auditory and visual hallucinations, halted substance-induced psychosis (auditory and speech visual hallucinations, paranoid delusions,  Anxiety, anger, euphoria/sadness, irritability, flat affect, thought blocking, disorganized restlessness, memory changes, auditory/visual speech, alogia, psychomotor retardation, perceptual changes, paranoid thoughts. agitation, suicidal ideation, anxiety, dysthymia) Subjects had no psychiatric history before using Synthetic Cannabinoids.

Spice drugs and Spice drugs and psychopathological ADRs - 4 psychopathological ADRs - 5

 Nonsensical speech, paranoia, delusions,  Sedation, confusion, disorientation, agitation disorganization  Unresponsiveness, agitation, paranoia,  Tremulousness, anxiety, confusion delusions  Anxiety, disorientation, tremulousness,  Hx PTSD, brief substance-induced psychotic  “feeling psychotic” episode; *2 of 3 positive for THC  Motor retardation, auditory and visual  “Spice”- Persistent psychosis after SC intake, hallucinations disorganized speech, poverty of thought,  Delusions, aggressiveness, inappropriate  Loosening of associations, paranoia, affect suicidality

3 Spice drugs and (A) CT angiogram showing a proximal left MCA clot (arrow). (B) MRI diffusion- weighted imaging sequence showing large area of infarct in the left MCA psychopathological ADRs - 6 distribution. MCA 5 middle cerebral artery  “Capgras delusions” a disorder in which a person holds a delusion that a friend, spouse, parent, or other close family member has been replaced by an identical-looking impostor. (Invasion of the Body Snatchers; Day of the Triffids)  From: “Spiceophrenia”: a systematic overview of “Spice”-related psychopathological issues and a case report. Duccio Papanti, Fabrizio Schifano, Giulia Botteon, et al. Hum. Ischemic stroke after use of the synthetic marijuana 'spice'‘ Psychopharmacol Clin Exp 2013; 28: 379–389. Melissa J. Freeman, David Z. Rose, Martin A. Myers, et al. Neurology published online November 8, 2013, p. 3., Figure 2.

Don’t Take Pharmacology from Strangers

Thanks to Richard S. Blum, MD for permission to use his slides

© Richard S. Blum, 2000

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