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"Technological Approaches in the Synthesis of

Designer Drugs, and Creative Prosecution of the

Non-Scheduled, Illicit, Analogue Drug"

David M. Benjamin, Ph.D.

Clinical Pharmacologist & Toxicologist

Adjunct Associate Professor, Dept. of Pharmaceutical Sciences,

Northeastern University, Boston, MA

Fellow, American Academy of Forensic Sciences (Toxicology)

Fellow, American Society for Healthcare Risk Management

Fellow, American College of Clinical Pharmacology

Fellow, American College of Legal Medicine

Member, Society of Forensic Toxicologists

medlaw@doctorbenjamin.com

What is a “Designer 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

synthesized by small chemical modifications

of known active drugs, and

Resemble the “parent” drug as: structural

analogues, stereoisomers and derivatives of

those drugs.

Federal Analog Act

Controlled Substance Analogue Enforcement Act of

1986

Effective October 27, 1986

Federal Analog Act, 21 U.S.C. § 813, is a section of

the United States Controlled Substances Act 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.*

*Wikipedia, accessed January 11,2014.

Substantially Similar

Substantially similar means that the chemical

structures are very similar

Substantially similar does not mean exactly the same;

some level of difference is acceptable and all experts

do not agree

Substantially similar can be: (1) a readily cognizable

(chemical) similarity between the alleged analog

and the controlled substance prior to ingestion, (2)

has a CNS effect equal to or greater than the

substance scheduled in C-I or C-II, or (3) is

metabolized to the alleged the controlled substance

analog after ingestion, e.g., 1, 4 – butanediol -> GHB

Classification of

Designer Drugs by Chemistry Legislation

Control by classes

Analogs (Chemical groups)

Compounds:

e.g., Spice, K-2

Designer stimulants, e.g.

Cathinones, bath salts

Synthetic cannabinoids,

Benzylpiperazines

Phenethylamines

Tryptamines

Pyrrolidinophenones

My thanks to Heather L. Harris, MFS, JD, D-ABC for permission to use

her slides.

Synthetic Drug Abuse Prevention

Act of 2012 – Chemical Classes Naphthoxylindoles

Naphthylmethylindoles

Naphthoylpyrroles

Naphthylmethylindenes

Phenylacetylindoles

Cyclohexylphenols

Benzoylindoles

Adamantoylindoles

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Chemical Structure of THC vs. Synthetic

Cannabinoids – Substantially Similar?

THC; Tetrahydrocannabinol (−)-trans-Δ9- tetrahydrocannabinol,

a dibenopyran.

CP-47,497 has been identified

in Spice.

Modified from: Synthetic Cannabinoids

The Challenges of Testing for Designer Drugs

By Bridgit O. Crews, PhD

February 2013 Clinical Laboratory

News: Volume 39, Number 2 Accessed online: Jan. 4,2014

Mechanism of Action of the

Cannabinoids

Neurotransmitter (NT) from

presynaptic neuron activates the

postsynaptic neuron.

1

2

3

4

5

Endogenous and Exogenous

Cannabinoids Reduce Neuronal Signaling

Postsynaptic

Neuron

Neurotransmitter

Receptor

Endogenous

Cannabinoid

Retrograde Signaling

CB1 Receptor

Presynaptic

Neuron

Inhibition of

Neurotransmitter

Release

Cannabinoid Therapy

Activated postsynaptic neuron

releases endocannabinoids.

Endogenous CB1 ligand diffuses

back to and binds to the

presynaptic CB1 receptor.

CB1 receptor activates a G-

protein, leading to inhibition of

NT release.

Synthetic Cannabinoids are

thought to activate CB1

receptors directly, mimicking the

effects of endocannabinoids.

1

2

3

4

5

CB1

CB2

High-affinity nerve growth factor

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.

CB1 Effects

CGRP

NGF

Plasma extravasation

Hyperalgesia

Edema

CB2 Effects

Mast cell degranulation

Histamine

5-HT

NGF sensitization

Neutrophil migration

NO production by

macrophages

Effects of Cannabinoid Receptors

in Pain Neuromodulation

Cathinones in “Bath Salts”

Mephedrone (Miaow

Miaow)

(4-methylmethcathinone, 4-

MMC)

Methylone

(βk-MDMA, 3,4-

methylenedioxy-N-

methylcathinone)

MDPV (3,4-

methylenedioxypyrovalerone)

Cathinones

Mephedrone (Miaow

Miaow)

(4-methylmethcathinone, 4-

MMC)

Methylone

(βk-MDMA, 3,4-

methylenedioxy-N-

methylcathinone)

MDPV (3,4-

methylenedioxypyrovalerone)

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.

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Grazie, Drs. Papanti, Schifano &

Botteon for this great paper!

From: “Spiceophrenia”: a systematic

overview of “Spice”-related

psychopathological issues and a case report.

Duccio Papanti, Fabrizio Schifano, Giulia

Botteon, et al. Hum. Psychopharmacol Clin

Exp 2013; 28: 379–389.

Spice drugs and

psychopathological ADRs -1

Situational anxiety, agitation

*Recurrent psychotic episodes triggered

by cannabis

“Spice” Anxiety, psychotic symptoms;

hallucinations

16 year old “Spice” Altered mental status

Visual hallucinations, agitation, restlessness

and anxiety

*Long-lasting psychotic episodes

Spice drugs and

psychopathological ADRs -2

“Spice” Severe anxiety and paranoia,

auditory and visual hallucinations, halted

speech

Anxiety, anger, euphoria/sadness, irritability,

restlessness, memory changes, auditory/visual

perceptual changes, paranoid thoughts.

Subjects had no psychiatric history before

using Synthetic Cannabinoids.

Spice drugs and

psychopathological ADRs -3

*Long-lasting psychotic episodes and

substance-induced psychosis (auditory and

visual hallucinations, paranoid delusions,

flat affect, thought blocking, disorganized

speech, alogia, psychomotor retardation,

agitation, suicidal ideation, anxiety,

dysthymia)

Spice drugs and

psychopathological ADRs - 4 Nonsensical speech, paranoia, delusions,

disorganization

Tremulousness, anxiety, confusion

Anxiety, disorientation, tremulousness,

“feeling psychotic”

Motor retardation, auditory and visual

hallucinations

Delusions, aggressiveness, inappropriate

affect

Spice drugs and

psychopathological ADRs - 5

Sedation, confusion, disorientation, agitation

Unresponsiveness, agitation, paranoia,

delusions

Hx PTSD, brief substance-induced psychotic

episode; *2 of 3 positive for THC

“Spice”- Persistent psychosis after SC intake,

disorganized speech, poverty of thought,

Loosening of associations, paranoia,

suicidality

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Spice drugs and

psychopathological ADRs - 6

“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.

Psychopharmacol Clin Exp 2013; 28: 379–389.

(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

distribution. MCA 5 middle cerebral artery

Ischemic stroke after use of the synthetic marijuana 'spice'‘

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

© Richard S. Blum, 2000

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