Chapter 88 Novel Drugs of Abuse: Cannabinoids, Stimulants, and Hallucinogens Evan S. Herrmann, Patrick S. Johnson, Matthew W. Johnson, Ryan Vandrey Behavioral Pharmacology Research Unit, Department of Psychiatry and Behavioral Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA Abbreviations pFPP para-Fluorophenylpiperazine SCBs Synthetic cannabinoids 25B-NBOMe 2-(4-Bromo-2,5-dimethoxyphenyl)-N-[(2-methoxy- TFMPP 3-Trifluoromethylphenylpiperazine phenyl)methyl]ethanamine THC Δ9-Tetrahydrocannabinol 25C-NBOMe 2-(4-Chloro-2,5-dimethoxyphenyl)-N-[(2-methoxy- α-PVP alpha-Pyrrolidinovalerophenone phenyl)methyl]ethanamine 25I-NBOMe 2-(4-Iodo-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl) INTRODUCTION methyl]ethanamine 2C-B 4-Bromo-2,5-dimethoxyphenethylamine From 2009 to 2012, 164 unique and previously undetected 2C-B-BZP 4-Bromo-2,5-dimethoxy-1-benzylpiperazine psychoactive compounds were observed following analyses 2C-E 2,5-Dimethoxy-4-ethylphenethylamine of illicit drugs confiscated and tested in Europe (European 2C-I 2,5-Dimethoxy-4-iodophenethylamine Monitoring Centre for Drugs and Drug Addiction, 2012). This 2C-T-7 2,5-Dimethoxy-4-propylthiophenethylamine trend is a sharp contrast to most of the 20th century, when a 4-AcO-DMT O-Acetylpsilocin comparatively small number of psychoactive recreational 4-MEC 4-Methyl-N-ethylcathinone drugs were available on illicit drug markets. Although many 4-MePPP 4-Methyl-α-pyrrolidinopropiophenone new compounds continue to be identified annually, most of 5-HT 5-Hydroxytryptamine those that have emerged as popular drugs of abuse since the 5-MeO-AMT 5-Methoxy-α-methyltryptamine late 1990s can generally be classified into one of six categories 5-MeO-DALT N,N-Diallyl-5-methoxytryptamine based on similarities in both molecular structure and in 5-MeO-DiPT 5-Methoxy-diisopropyltryptamine physiological, subjective, and behavioral effects: synthetic Bromo-DragonFLY 1-(4-Bromofuro[2,3-f][1]benzofuran-8-yl)- cannabinoids (SCBs); synthetic cathinones; phenethylamines; propan-2-amine piperazines; tryptamines; and Salvia divinorum. Some of these BZP Benzylpiperazine compounds (e.g., newer “second-generation” synthetic cathi- CB1 Cannabinoid receptor type 1 nones) were first synthesized shortly before they emerged as CB2 Cannabinoid receptor type 2 recreational drugs, while others (e.g., S. divinorum) have had DMT N,N-Dimethyltryptamine known psychoactive properties for hundreds of years, but have DOB 2,5-Dimethoxy-4-bromoamphetamine just recently become popular as drugs of abuse. DOC 2,5-Dimethoxy-4-chloroamphetamine This chapter focuses on providing a review of the basic DOI 2,5-Dimethoxy-4-iodoamphetamine pharmacology, history, current trends of use, and psychological, DOM 2,5-Dimethoxy-4-methylamphetamine subjective, and behavioral effects of representative substances DSM-IV Diagnostic and Statistical Manual for Metal Disorders, in each of the aforementioned drug classes. Because this is a 4th Edition relatively new and rapidly emerging area of study on an unstable DEA Drug Enforcement Administration drug market, the inclusiveness of drugs and related scientific LSD Lysergic acid diethylamide data described in this chapter are somewhat limited. However, MDMA 3,4-Methylenedioxy-methamphetamine the data available are sufficient to provide a general overview MDPV 3,4-Methylenedioxypyrovalerone of these novel classes of substances, supplemented by providing MeOPP para-Methoxyphenylpiperazine examples of specific compounds that are representative of each Mephedrone 4-Methylmethcathinone drug class. When possible, we provide references to published Methylone 3,4-Methylenedioxymethcathinone work that provides more in-depth information on individual Naphyrone Naphthylpyrovalerone compounds. Neuropathology of Drug Addictions and Substance Misuse, Volume 3. 893 894 PART | VII Emerging Addictions and Drugs of Abuse SYNTHETIC CANNABINOIDS these substances via regulatory mechanisms typically used for con- trolling drugs of abuse. However, clandestine chemists’ response As a broad classification, SCBs can include any synthetically to this was to drastically increase the number of compounds, with derived compounds that have a binding affinity for and pharmaco- similar pharmacology, but distinct chemical structures, used to adul- logically modulate (e.g., have agonist, antagonist, inverse agonist, terate the plant material in commercially available SCB products neutral antagonist effects) endogenous cannabinoid receptors (e.g., (Seely et al., 2013). Indeed, the number of new SCBs on the illicit cannabinoid receptor types 1 and 2; CB1 and CB2). The develop- drug market increased rapidly from two new compounds in 2009 to ment of SCBs began when the structure and function of the CB1 51 new compounds in 2012 (Randolph, 2014). Hundreds of brands receptor was discovered and characterized in the late 1980s (e.g., emerged and the availability and use of these products increased Devane, Dysarz, Johnson, Melvin, & Howlett, 1988). Following rapidly from 2009 to 2011 as media reports and Internet content the discovery of the endogenous cannabinoid receptor system, a expanded awareness of their existence and availability. number of SCBs were formulated and evaluated by academic sci- Due to the relatively recent availability of SCBs on the drug entists as pharmacologic tools for understanding endocannabinoid market, few data are available on SCB use from large represen- pharmacology and neurobiology, or by pharmaceutical companies tative drug use surveys. Perhaps the best available epidemiologi- as candidate medications for the treatment of various health condi- cal data is from the US Monitoring the Future survey. Outcomes tions (Gurney, Scott, Kacinko, Presley, & Logan, 2014). from that study suggest that the prevalence of SCB use peaked Beginning around the year 2004, retail products sold primar- among US high-school seniors (grade 12) in 2011, when 11.4% ily under the brand name “Spice” began to surface in Europe of students surveyed indicated that they had used an SCB product (Psychonaut Web Mapping Research Group, 2009). Spice products in the past year (Johnston, O’Malley, Bachman, Schulenberg, & consisted of inert dried plant material that later was discovered to Miech, 2014). Data from more recent Monitoring the Future sur- have been adulterated with one or more SCBs (Auwärter et al., veys suggest the prevalence of use among surveyed students has 2009). The general consensus is that chemists in clandestine declined annually, with past year use being reported by only 6% in laboratories were mining the published work of scientists such as 2014 (Johnston et al., 2014). More detailed analyses of Monitor- John Huffman and Alex Makriyannis to find potent CB1 receptor ing the Future survey data indicated that use of alcohol, tobacco, agonists that were not explicitly regulated chemicals under drug or other drugs was robustly associated with increased odds of SCB laws at the time (Table 1 displays common synthetic cannabinoid use, with intensity of use of natural cannabis being the most robust products grouped according to scientific origin). These products predictor of SCB use (e.g., only 0.5% of those who had never used were, and continue to be, sold as “herbal blends,” “incense,” or cannabis reported use of SCBs in the past year, whereas 39.8% of “potpourri” in retail stores (e.g., tobacco shops, “head” shops, gas those who had used cannabis 40 or more times in their lifetime stations) or from Internet-based vendors and labeled as “not for reported SCB use in the past year) (Palamar & Acosta, 2015). human consumption.” This type of labeling is used by distributors Another proxy for the prevalence of use is data tracking by as a means of selling psychoactive substances without overtly vio- emergency health providers. In the United States, calls to poison lating drug control laws, though the legality of this remains a point control centers reported only 13 cases related to SCB administra- of contention (e.g., Vandrey, Dunn, Fry, & Girling, 2012). tion in 2009. The number of SCB-associated cases then increased Forensic analysis of products began in earnest to identify and annually from 2906 in 2010 to a peak of 6959 calls in 2011. SCB- characterize the SCBs used in Spice and similar products. Initial test- related calls to poison control centers declined in 2012 and 2013 ing identified JWH-018, JWH-073, JWH-250, JWH-398, HU-210, (5200 and 2668, respectively), but increased again in 2014 to a and CP-47,497 as the predominant compounds used. This resulted total of 3680 in 2014 (American Association of Poison Control in relatively fast action by governing authorities to effectively ban Centers, 2015). Controlled studies evaluating the effects of SCBs have been rare and limited to preclinical experiments. These studies indicate that the SCBs commonly found in commercial products intended TABLE 1 Synthetic Cannabinoids for illicit drug use typically have the following characteristics: (1) Specific Compounds they have high affinity for the CB1 receptor; (2) they are full ago- Commonly Found in nists at the CB1 receptor; (3) they are highly potent; (4) they share Origin (First Synthetic Cannabis discriminative stimulus properties with Δ9-tetrahydrocannabinol Family Synthesized) Products (THC), the primary psychoactive compound in cannabis; and (5) the potent psychoactive metabolites have been observed for some CP Pfizer CP 47,497 compounds (e.g., Fantegrossi, Moran, Radominska-Pandya, & HU Raphael Mechoulam, HU-210