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Cannabinoids, Stimulants, and Hallucinogens

Cannabinoids, Stimulants, and Hallucinogens

Chapter 88

Novel of Abuse: , , and

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 25B-NBOMe 2-(4-Bromo-2,5-dimethoxyphenyl)-N-[(2-methoxy­ TFMPP 3-Trifluoromethylphenylpiperazine phenyl)methyl]ethanamine THC Δ9- 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 -B 4-Bromo-2,5-dimethoxyphenethylamine From 2009 to 2012, 164 unique and previously undetected 2C-B-BZP 4-Bromo-2,5-dimethoxy-1- 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 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- physiological, subjective, and behavioral effects: synthetic Bromo-DragonFLY 1-(4-Bromofuro[2,3-f][1]benzofuran-8-yl)­ ­cannabinoids (SCBs); synthetic ; ; propan-2- ; ; and Salvia divinorum. Some of these BZP Benzylpiperazine compounds (e.g., newer “second-generation” synthetic cathi- CB1 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- 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 4-Methylmethcathinone drug class. When possible, we provide references to published 3,4-Methylenedioxymethcathinone work that provides more in-depth information on individual 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 , antagonist, , 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 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 , tobacco, 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 Prather, 2014; Gatch & Forster, 2014; Ginsburg, Schulze, Hruba, Hebrew University & McMahon, 2012; Marshell et al., 2014; Wiley, Marusich, & Huffman, 2014). In comparative studies, SCBs tend to be several JWH John W. Huffman, JWH-018, JWH-073, times more potent than THC (Fantegrossi et al., 2014; Gatch & Clemson University JWH-081, JWH-210, Forster, 2014; Ginsburg et al., 2012). JWH-250 Though no controlled studies of SCBs have been conducted AM Alexandros AM-694, AM-2201 in humans, several case reports and survey studies have been ­Makriyannis, North- ­published to help understand the human behavioral pharma- eastern University cology of these substances. As suggested by the preclinical drug discrimination studies, reports in humans suggest that the Novel Drugs of Abuse Chapter | 88 895

physiological, subjective, and behavioral effects of SCBs are sold at “head” shops and over the Internet under such brand names generally similar to the effects of cannabis. The most common as “Ivory Wave,” “Bliss,” and “White Lightning,” synthetic cathi- route of administration is smoking, though vaporization, oral, nones are intentionally mismarketed as “bath salts,” “plant food,” or and rectal routes of administration have also been endorsed “glass cleaner,” and therefore “not for human consumption,” in an (Vandrey et al., 2012). Users report subjective effects includ- effort to avert regulatory control by government agencies (e.g., the ing feeling a “pleasant high,” with effects that are characteristic US Food and Drug Administration). Synthetic cathinones, like many of cannabis intoxication (e.g., increased appetite, laughter, dry of the illicit drugs for which they are meant to serve as “legal high” mouth, etc.) (e.g., Vandrey et al., 2012). However, because most alternatives (e.g., , , MDMA), typically appear of the compounds found in SCB products are full agonists at in the form of a white powder that is insufflated (snorted) or smoked, the CB1 receptor (THC is only a ), use of these but can also be swallowed, injected, or taken rectally. products can produce more intense effects and even unique Synthetic use, and in particular use of 4-methyl­ effects compared with traditional cannabis. Potentially dramatic (mephedrone), appears to have originated in increases in heart rate and blood pressure can occur from SCB the UK dance music scene in 2009. Mephedrone (also known use (Heath, Burroughs, Thompson, & Tecklenburg, 2012), and as “meow meow” or “M-CAT”) increased rapidly in popularity­ may be associated with an increased risk of cardiac events (Mir, (commonly detected compounds, common/street names, and Obafemi, Young, & Kane, 2011). SCBs may also produce more products detected in are displayed in Table 2). Indeed, a cross- severe anxiety than cannabis, and users are more likely to expe- sectional online survey conducted at this time found that 41% rience hallucinations with SCBs than with traditional cannabis of participants recruited from a UK-based dance music website (e.g., Vandrey et al., 2012). Case reports have linked use of SCBs reported having used the drug (Winstock et al., 2011). ­Regulations to acute psychotic episodes (e.g., Hurst, Loeffler, & McLay, banning mephedrone were enacted shortly thereafter (April 2010) 2011) and to exacerbation of preexisting (Müller et al., in the United Kingdom and European Union (December 2010). A 2010). In some instances, more severe health conditions such as similar pattern of synthetic cathinone use occurred in the United convulsions and seizures, stroke, brain hemorrhage, and even States in 2010, resulting in a dramatic increase in the volume of death have been attributed to SCB exposure (e.g., Takematsu calls to local poison control centers concerning “bath salt” intoxi- et al., 2014), although these reactions are rare. cation (Bronstein et al., 2011). Concerns regarding synthetic Use of SCBs may in some cases lead to symptoms of abuse/ cathinone use culminated in emergency scheduling by the Drug dependence that are similar to symptoms of cannabis dependence. Enforcement Administration (DEA) of mephedrone and two other SCBs like JHW-018 have been shown to cause desensitization cathinone derivatives, 3,4-methylenedioxymethcathinone (methy- of CB1 receptors in the same manner as natural cannabis, which lone) and 3,4-methylenedioxypyrovalerone (MDPV). Although could lead to tolerance and withdrawal symptoms if regular use these first-generation synthetic cathinones have since been per- is abruptly discontinued (Atwood, Huffman, Straiker, & Mackie, manently scheduled by the DEA, a number of second-generation 2010). A ­subset of users who completed an online survey on SCB cathinone analogs have appeared including naphthylpyrovalerone use met the American Psychiatric Association’s Diagnostic and (naphyrone), 4-methyl-N-ethylcathinone (4-MEC), and 4-methyl- Statistical Manual for Metal Disorders, Fourth Edition criteria for α-pyrrolidinopropiophenone (4-MePPP), and alpha-pyrrolidi- abuse (37%) and dependence (12%) on SCBs (Vandrey et al., 2012). novalerophenone (α-PVP). Using SCBs in a hazardous situation (e.g., while driving a car) was Synthetic cathinones exert their effects through a variety of the most commonly endorsed abuse criteria (27%). Being unable neurobiological mechanisms. Some synthetic cathinones, such as to cut down or stop SCB use (38%), experiencing symptoms of mephedrone and methylone, have mechanisms of action s­imilar tolerance (36%), using for longer periods than originally intended to MDMA, increasing the release of , norepineph- (22%), and having­ interference with other activities (18%) were rine, and . MDPV’s is similar to the most commonly reported dependence criteria. Despite endors- that of cocaine, blocking of dopamine and norepineph- ing problems related to SCB use, no respondent had ever sought rine with limited effect on serotonin reuptake (Baumann et al., or received treatment. Reported withdrawal symptoms following 2013). Actions of second-generation cathinone derivatives can be cessation of SCB use were less common and most prevalent among more complex, with 4-MEC acting as a serotonin releaser and a more frequent users. The most commonly reported withdrawal dopamine reuptake inhibitor and 4-MePPP acting as a reuptake effects were headaches­ (15%), anxiety/nervousness (15%), coughing inhibitor of both serotonin and dopamine, but primarily dopamine (15%), insomnia/sleep disturbance (14%), anger/irritability (13%), (Saha et al., 2014). Studies have examined the effects of a vari- impatience (11%), difficulty concentrating (9%), restlessness (9%), ety of synthetic cathinones on behavior using laboratory rodents, nausea (7%), and depression (6%) (Vandrey et al., 2012). Although demonstrating that they increase heart rate, blood pressure, and ­similarities between the abuse/dependence of SCBs and natural locomotor activity in a manner similar to cocaine and amphet- cannabis are apparent from these survey data, controlled laboratory (Marusich, Grant, Blough, & Wiley, 2012). However, dif- studies are needed to confirm these findings. ferent synthetic cathinone compounds appear to have differences in efficacy, , and pharmacokinetics, suggesting this class SYNTHETIC CATHINONES of compounds has some heterogeneity (Baumann et al., 2013; ­Marusich et al., 2012). Researchers have also confirmed that labo- Synthetic cathinones are derivatives of cathinone, a monoamine alka- ratory rodents will readily self-administer synthetic cathinones, loid found in the plant (Catha edulis), and as such elicit a variety suggesting they have significant abuse potential (e.g., Watterson of amphetamine-like and/or 3,4-methylenedioxy-methamphetamine & Olive, 2014). These findings are supported by anecdotal reports (MDMA)-like physiological, subjective, and behavioral effects. Often from users of these compounds. 896 PART | VII Emerging Addictions and Drugs of Abuse

TABLE 2 Synthetic Cathinones

Compound Common Namesa Product(s) Found inb Methylone (bk-MDMA) M1 Euphoria, Cotton cloud, White dove, Dynamite, Snow day Mephedrone (4-MMC) Meph, drone, M-CAT, meow meow White lightning, Cotton cloud, Bayou ivory flower, NRG-1, Coco cherry Methylenedioxypyrovalerone (MDPV) Ivory wave, White lightning, Zoom, Vanilla sky, Cloud 10, Dynamite plus, White China, Snow day, Bolivian bath salts, NRG-1 Naphyrone (O-2482) NRG-1, Energy-1, Rave

4-Methyl-N-ethylcathinone (4-MEC) NRG-2, Coco, Coco cherry

4′-Methyl-α-pyrrolidinopropiophenone NRG-3 (4-MeOPP)

alpha-Pyrrolidinovalerophenone (α-PVP) Flakka, gravel “Bath salts,” “research chemicals,” brands unknown at this time

aSeveral of the common names have been obtained from the websites www.erowid.org and www.bluelight.org. bInformation on product content taken from a variety of sources.

In contrast to the expanding body of preclinical data on syn- “bath salt” intoxication is primarily supportive and similar to thetic cathinones, there have been no controlled studies of the management of toxicity in general, often involving effects of experimentally administered synthetic cathinones in treatment with benzodiazepines. humans. Given the paucity of human laboratory studies, self- reports of synthetic cathinone use collected via online surveys OTHER NOVEL PHENETHYLAMINES may help to better understand their effects and patterns of use in uncontrolled settings. A survey has found that “bath salt” admin- There are several novel noncathinone phenethylamines that have istration produced rapid onset of drug effects, which lasted several recently become more popular as recreational drugs of abuse. hours, although the approximate duration was dependent on the These drugs are chemically unique from synthetic cathinones, and route of administration (Johnson & Johnson, 2014). The effects have not commonly been sold as “bath salts” (see Table 3 for a most ­frequently endorsed by survey respondents as occurring list on commonly sold phenethylamines). These drugs may act as every time “bath salts” were used included feeling stimulated/ stimulants, psychedelics, or entactogens. These phenethylamines energetic, having a decreased appetite, feeling more talkative than fall into three general groups: DOx compounds, 2C-x compounds, usual, feeling one’s heart racing, feeling euphoric, feeling a pleas- and 25x-NBOMe compounds. ant high, having a dry mouth, feeling more focused than usual, and having an increased sex drive. Collectively, these data suggest that DOx Compounds synthetic cathinones sold as “bath salts” exhibit powerful psycho- active effects consistent with other stimulant drugs of abuse like DOx compounds are long-acting psychedelic drugs that act as cocaine and . highly selective 5-HT2A, 5-HT2B, and 5-HT2C receptor partial Unsurprisingly, synthetic cathinones can also produce agonists. 2,5-Dimethoxy-4-methylamphetamine (DOM) was negative effects similar to those of other stimulants, especially first synthesized by in 1964; other ana- at higher doses. This is particularly true with compounds that logs such as 2,5-dimethoxy-4-bromoamphetamine (DOB), act primarily on dopamine and , either as reup- 2,5-dimethoxy-4-chloroamphetamine (DOC), 2,5-dimethoxy- take inhibitors or transporter substrates (e.g., MDPV). Com- 4-iodoamphetamine (DOI), and 1-(4-bromofuro[2,3-f][1]ben- mon negative effects are consistent with a sympathomimetic zofuran-8-yl)propan-2-amine (Bromo-DragonFLY) followed. and include tachycardia, hypertension, abdominal Various DOx compounds have been available on the illicit drug pain, hyperthermia, dizziness, tremors, , hallucina- market for several decades, but none sustained popularity in the tions, paranoia, rhabdomyolysis, and kidney damage ­(Coppola 20th century. DOM was prevalent on the black market in the & Mondola, 2012). Synthetic cathinones were associated with 1960s, while recreational use of other compounds like DOC and nearly 23,000 emergency department visits in the United States Bromo-DragonFLY has occurred relatively recently (Corazza in 2011 (U.S. Department of Health and Human ­Services, et al., 2011; Ovaska et al., 2008). DOx compounds have sub- 2013), and have been implicated in multiple deaths (e.g., jective effects similar to those of classic hallucinogens (e.g., Maskell, De Paoli, Seneviratne, & Pounder, 2011). Clinical lysergic acid diethylamide (LSD), ), and since most care of individuals presenting with symptoms consistent with of these compounds are quite potent (psychoactive in doses of Novel Drugs of Abuse Chapter | 88 897

rodents suggests that DOx compounds have effects unique from TABLE 3 Other Phenethylamines other amphetamines, but somewhat similar to classic hallucino- gens like LSD and mescaline (Glennon, Young, Jacyno, Slusher, Common Name(s) & Rosecrans, 1983; Silverman & Ho, 1980). Survey data col- a Compound of Drugs lected from Bromo-DragonFLY users suggests the drug has DOx Compounds unique pharmacokinetics/dynamics. Users report that the onset of effects can be delayed up to 6 h after ingestion, and that effects 2,5-Dimethoxy-4-methylamphetamine STP may last 2–3 days after consumption of a single dose (Corazza (DOM) et al., 2011). 2,5-Dimethoxy-4-bromoamphetamine Use of DOx compounds has been associated with negative (DOB) health outcomes. High doses of these drugs may cause cardio- 2,5-Dimethoxy-4-chloroamphetamine vascular complications (e.g., Bowen, Davis, Kearney, & Bardin, (DOC) 1983). Use of Bromo-DragonFLY has been associated with toxic reactions, including symptoms of severe agitation and tonic–clonic 2,5-Dimethoxy-4-iodoamphetamine seizures, and at least two deaths (e.g., Andreasen, Telving, Birkler, (DOI) Schumacher, & Johannsen, 2009). These negative outcomes may 1-(4-Bromofuro[2,3-f][1]benzofuran-8-yl) be due to both the misrepresentation of these compounds as LSD propan-2-amine (Bromo-DragonFLY) and the relatively narrow therapeutic index of these drugs. Since 2C-x Compounds the time to onset of DOx drugs like Bromo-DragonFLY is quite long, users may repeatedly redose under the assumption that their 4-Bromo-2,5-dimethoxyphenethyl- Nexus, bees, venus initial dose was too low and accidently ingest dangerous amounts amine (2C-B) of these substances. 2,5-Dimethoxy-4-iodophenethylamine Smiles (2C-I) 2C-x Compounds 2,5-Dimethoxy-4-ethylphenethylamine Europa Most of the currently known 2C-x compounds were first synthe- (2C-E) sized by Alexander Shulgin in the 1970s–1980s. These compounds 2,5-Dimethoxy-4-propylthiophenethyl- Blue mystic, T7, 7th emerged as recreational drugs in Europe, the United States, and amine (2C-T-7) heaven Asia in the late 1990s–early 2000s (de Boer & Bosman, 2004). 25x-NBOMe Compounds Some of these compounds were already illegal in several countries by the time their popularity as recreational drugs emerged (e.g., 2-(4-Iodo-2,5-dimethoxyphenyl)-N- 25-I, N bomb 4-bromo-2,5-dimethoxyphenethylamine (2C-B) was placed on [(2-methoxyphenyl)methyl]ethanamine Schedule I in 1995), while others were not scheduled until more (25I-NBOMe) recently (e.g., 2,5-dimethoxy-4-iodophenethylamine (2C-I) was 2-(4-Bromo-2,5-dimethoxyphenyl)-N- N bomb placed on Schedule I in 2012). As 2C-x analogs were scheduled, [(2-methoxyphenyl)methyl]ethanamine others became available from suppliers as legal alternatives. These (25B-NBOMe) drugs are found in both powdered and pill form, and are generally 2-(4-Chloro-2,5-dimethoxyphenyl)-N- N bomb administered orally or nasally. [(2-methoxyphenyl)methyl]ethanamine 2C-x compounds initially became popular in Europe among (25C-NBOMe) patrons of the club/electronic music scene. Data indicate the avail- ability and use of 2C-B in Spain increased significantly from 2006 aCommon names obtained from websites (e.g., www.erowid.org, to 2009 (Caudevilla-Gálligo et al., 2012). Data from the Global www.bluelight.org). Drug Survey, an annual, online, and anonymous survey of drug use behavior from a large, international self-selected sample, ­provide data on the prevalence of 2C-x compound use. Participants a few milligrams or less) DOx drugs have been misrepresented/ (n = 22,289) who completed the survey in 2013 had, in general, sold as LSD (Drug Enforcement Administration, 2009). DOx much higher rates of use than the general population analogs are illegal in most countries, with some exceptions. For (e.g., 39% reported lifetime use of LSD, 43% reported lifetime instance, DOC and Bromo-DragonFLY are unscheduled in the use of mushrooms) with 11.3% of participants indicat- United States at the federal level, although they could be con- ing use of at least one 2C-x drug in their lifetime (Lawn, Barratt, sidered analogs of DOM/DOB, so possession or sale could be ­Williams, Horne, & Winstock, 2014). A survey of 42 high-risk prosecuted under the Federal Analog Act. youth who inject indicated that 29% had used 2C-B, 26% DOx compounds are derivatives had used 2C-I, and 21% had used 2,5-dimethoxy-4-ethylphenethyl- that are believed to elicit their behavioral effects via agonism amine (2C-E) in their lifetime, with use of other 2C-x compounds of 5-HT2A receptors (Arvanov, Liang, Russo, & Wang, 1999), being rare ­(Sanders, Lankenau, Bloom, & Hathazi, 2008). To our although some DOx compounds have very high affinity for other knowledge, there are no published data on prevalence of 2C-x com- 5-HT receptor subtypes (Shannon, Battaglia, Glennon, & Titeler, pound use among the general population, but it is doubtful that it 1984). There have been relatively few experimental studies of the would even approach the prevalence among the samples that com- behavioral effects DOx compounds. Research with laboratory pleted the surveys summarized above, suggesting that use of 2C-x 898 PART | VII Emerging Addictions and Drugs of Abuse

compounds seems to be most prevalent among those who are expe- compounds such as 3-trifluoromethylphenylpiperazine (TFMPP), rienced polydrug users, specifically those who use “club drugs” 4-bromo-2,5-dimethoxy-1-benzylpiperazine (2C-B-BZP), para- such as hallucinogens­ or ketamine. methoxyphenylpiperazine (MeOPP), and para-fluorophenylpiper- 2C-x compounds can act as either agonists or antagonists of azine (pFPP) have been sold as “dietary supplements” or “legal 5-HT2A and alpha adrenergic receptors. There are no known clini- highs” under names such as “A2,” “Jet,” “Charge,” “Party Pills,” cal studies characterizing 2C-x drugs in humans; however, anec- and “Legal X” and are used recreationally for their stimulant and dotal reports suggest the effects of 2C-x compounds are similar entactogenic effects similar to amphetamines and MDMA (Table 4 to a combination of classical hallucinogen and MDMA. Potency displays names of commonly encountered piperazines and some varies considerably between different 2C-x analogs. At lower of the commercial products in which they are often found). doses, 2C-x drugs tend to have stimulating effects and to increase Recreational use of BZP and other piperazines became popu- the intensity of sensory perception. At higher doses, users may lar around 1999 in many countries, but these compounds became experience unpleasant hallucinations and sympathomimetic signs especially popular in New Zealand. Many preparations available such as tachycardia, hypertension, hyperthermia, and seizures, and on the market contain both BZP and TMFPP, and users claim use of 2C-x drugs has been linked to multiple hospitalizations and that this combination mimics the subjective effects of MDMA at least seven deaths (Dean, Stellpflug, Burnett, & Engebretsen,­ (Lin et al., 2011). BZP was placed under Schedule I in the United 2013). These patients often present in a state of “excited delir- States in 2002, scheduled in all Australian states in 2006, and clas- ium,” with causes of death being attributed to hyperthermia, sified along with related piperazines as Class C drugs in the United ­cardiopulmonary arrest, etc. (Dean et al., 2013). Anecdotal reports Kingdom in 2009. on Internet message boards suggest that 2C-x drugs have a narrow The neurobiological mechanisms of drugs are therapeutic index, with as little as 2–3 times a normal recreational not universally understood. Data from animal studies indicate dose causing significant negative side effects. that BZP stimulates parallel releases of dopamine and 5-HT, although at lower levels than released by MDMA, while TFMPP acts as a nonselective 5-HT receptor agonist that also stimulates 25x-NBOMe Compounds the release of 5-HT from neurons (Auerbach, Rutter, & Juliano, 25x-NBOMe compounds were first synthesized in the early 2000s 1991; Schoeffter & Hoyer, 1989). Human laboratory studies of and became available for purchase for recreational use from Inter- BZP and TFMPP demonstrate that both drugs administered alone net distributors around 2010. These compounds were first men- have amphetamine-like physiological and subjective effects (e.g., tioned in the scientific literature in 2011 (Ettrup et al., 2011) and increases in heart rate, blood pressure, alertness, elevated mood, this literature remains scant. Data from the 2013 Global Drug Sur- etc.), with the exception of TFMPP, which produces more dyspho- vey indicated that 2.6% of respondents had knowingly taken at ria than amphetamine or BZP (e.g., Jan et al., 2010). Interestingly, least one 25x-NBOMe compound at least once in their lifetime when TFMPP and BZP are coadministered they appear to have (Lawn et al., 2014). 25x-NBOMe users average 21.5 years of age, a synergistic effect on dopamine and 5-HT release that mimics and almost all were male (99.7%). Most (81.2%) reported taking the pharmacological effects of MDMA (Baumann et al., 2004). the drug orally or nasally. A human laboratory study of coadministered BZP and TFMPP 25x-NBOMe compounds are chemically similar to 2C-x com- did not observe MDMA-like subjective drug effects, but the doses of BZP and TFMPP administered were lower than those found in pounds and are potent 5-HT2A receptor agonists, are psychoac- tive in submilligram doses (Zuba, Sekuła, & Buczek, 2013), and many commercially available “party pills” (Lin et al., 2011). have subjective effects similar to those of classical hallucinogens Data collected from a sample of piperazine users in New Zea- (e.g., LSD, psilocybin mushrooms). 25x-NBOMe compounds land suggest that negative effects are common (approximately have stronger sympathomimetic effects than LSD. As a result, 50% of sample report experiencing at least one), and are generally they appear to have a less desirable safety profile relative to clas- sic hallucinogens, and use of these compounds has been associ- ated with negative effects, hospitalizations, and death (e.g., Hill TABLE 4 Piperazines et al., 2013). Individuals hospitalized for acute 25x-NBOMe tox- a icity have symptoms consistent with stimulant and serotoninergic Compound Product(s) Found in ­toxicity, including tachycardia, hypertension, seizures, agitation, Benzylpiperazine (BZP) Bolts, Charge, Jet, confusion, elevated creatine kinase, and symptoms of kidney dam- SunRise, Majik age (Hill et al., 2013). Like many of the compounds mentioned 3-Trifluoromethylphenylpiperazine Bent, d-Lite, SunRise, here, these negative outcomes may be related to the potency and (TFMPP) Majik narrow therapeutic index of 25x-NBOMe compounds and misrep- resentation of these drugs as LSD. 4-Bromo-2,5-dimethoxy-1-­ benzylpiperazine (2C-B-BZP)

para-Methoxyphenylpiperazine Extreme bean PIPERAZINES (MeOPP) Piperazines are a broad class of compounds with diverse phar- para-Fluorophenylpiperazine (pFPP) Extreme bean macological actions, and are thus used for a variety of purposes, aProduct names obtained from websites (e.g., www.erowid.org, including as , , , and www.bluelight.org). as recreational drugs. Benzylpiperazine (BZP) and other related Novel Drugs of Abuse Chapter | 88 899

similar to those experienced after use of stimulants or MDMA primary psychoactive constituent of the plant and is a kappa opi- (e.g., insomnia, sweating, stomach pains, headaches, tremors, oid agonist (Roth et al., 2002). Unlike many compounds with hal- etc.) (Wilkins, Girling, & Sweetsur, 2007). Although less com- lucinogenic properties, shows no action at the 5-HT2A mon, toxic side effects have been reported (Schep, Slaughter, Vale, receptor. Although S. divinorum is not scheduled under federal law, Beasley, & Gee, 2011). There have been a few fatalities involving over half of the states and several municipalities within the United BZP/TFMPP, but all of these involved other drugs (e.g., MDMA) States have passed laws making it illegal to possess. Many countries and other extenuating circumstances, making the exact cause of have no law against the plant, and it is therefore readily available death unknown. for purchase­ in “head” shops and through Internet-based vendors. When administered by the smoked or vaporized route (the most common routes), the effects of salvinorin A have quick NOVEL TRYPTAMINES onset (≤1 min), peak within 2 min, and dissipate within 15–20 min Several novel compounds have appeared on the drug (Johnson, MacLean, Reissig, Prisinzano, & Griffiths, 2011). Users market in the last several decades, including 5-methoxy-diisopro- describe the effects as being only somewhat similar to classic pyltryptamine (5-MeO-DiPT), N,N-diallyl-5-methoxytryptamine ­hallucinogens, unique, and at high doses more intense than clas- (5-MeO-DALT), 5-methoxy-α-methyltryptamine (5-MeO-AMT), sic hallucinogens (e.g., MacLean, Johnson, Reissig, Prisinzano, & and O-acetylpsilocin (4-AcO-DMT). Some commonly available Griffiths, 2013), with the addition of sedative effects associated with tryptamines and their common “street” names are displayed in Table 5. other kappa agonists (e.g., Johnson et al., 2011). Johnson These compounds are structurally similar to well-characterized et al. found that even at higher doses (e.g., 21 μg/kg, vaporized) tryptamines that have a long history of human use (e.g., N,N-dimeth- no changes in heart rate or blood pressure were observed, despite yltryptamine (DMT), 5-MeO-DMT, psilocybin). Novel tryptamine the presence of strong hallucinogenic effects. This general lack of compounds began to appear on the drug marketplace in the late somatic effects suggests that S. divinorum is physiologically safe. 1990s, and were available for purchase from Internet vendors. Data Case reports have described persisting psychotic-type episodes on law enforcement seizures reported by the DEA suggested that use associated with S. divinorum use (e.g., Singh, 2007), although these of these drugs increased during the early 2000s (Drug Enforcement cases have been complex (e.g., involving use of multiple substances), Administration ­Intelligence ­Division, 2002). leaving the causal role of S. divinorum unknown. Like classic hallu- Case reports on patients presenting to emergency depart- cinogens, the possibility exists that use of S. divinorum may trigger ments after ingesting the synthetic tryptamines 5-MeO-DiPT and lasting psychiatric reactions in individuals with a predisposition for 5-MeO-DALT indicate that these compounds can produce symp- psychotic disorders (e.g., Johnson, Richards, & Griffiths, 2008). It toms of sympathomimetic drug toxicity (Alatrash, Majhail, & seems clear at this point, however, that the most likely potential dan- Pile, 2006). At least one fatal overdose of 5-MeO-DiPT has been gers of S. divinorum are related to very strong subjective effects and reported (Tanaka, Kamata, Katagi, Tsuchihashi, & Honda, 2006). motor impairing effects during its relatively brief effects. Although there are no clinical toxicology data on 4-AcO-DMT, its chemical similarity to psilocybin suggests it may share its phar- macological mechanisms, and thus its generally favorable safety DISCUSSION profile. The growth in the number and variety of psychoactive com- pounds available for use that occurred between the 1990s and Salvia divinorum 2015 is unprecedented. Most of these compounds are analogs of previously known and established cannabinoids, cathinones, S. divinorum is a member of the mint family native to mountainous ­phenethylamines, piperazines, and tryptamines. These drugs regions of southwestern Mexico. Shamans of the Mazatec people are synthesized in clandestine laboratories and are marketed as of Oaxaca, Mexico have used S. divinorum for centuries as part “research chemicals,” “natural highs,” and “dietary supplements” of traditional religious and medical practices. Salvinorin A is the in an attempt to circumvent national and international drug laws. As these compounds are scheduled and legal distribution becomes impossible, manufacturers synthesize and distribute new ana- TABLE 5 Tryptamines logs of these compounds. This cyclical pattern combined with an unknown number of potential psychoactive compounds amenable Compound Common Name(s)a to recreational use suggests that regulation alone is likely insuf- ficient to eliminate the availability of these compounds. 5-Methoxy-diisopropyltryptamine Foxy, foxy methoxy (5-MeO-DiPT) N,N-Diallyl-5-methoxytryptamine APPLICATIONS TO OTHER ADDICTIONS (5-MeO-DALT) AND SUBSTANCE MISUSE 5-Methoxy-α-methyltryptamine Alpha-O Many of the novel drugs of abuse reviewed in this chapter fall (5-MeO-AMT) into respective drug classes that contain some more long-standing O-Acetylpsilocin (4-AcO-DMT) Psilacetin and well-known psychoactive compounds. Many of these com- pounds are often misrepresented as more established drugs of aCommon names obtained from websites (e.g., www.erowid.org, www.bluelight.org). abuse (e.g., 25x-NBOMe compounds as LSD), and users of tradi- tional drugs in respective drug classes may be much more likely 900 PART | VII Emerging Addictions and Drugs of Abuse

to use novel drugs from that class (e.g., cannabis users are much l As synthetic cathinone compounds come under regulatory more likely than noncannabis users to use SCBs). Concurrent use control, they are often replaced on the drug market with newer of these novel compounds should be examined among individu- compounds. als who enter medical care or treatment primarily for use of more l Use of synthetic cathinones has been associated with sympa- ­traditional substances of abuse. thomimetic toxidrome.

DEFINITION OF TERMS SUMMARY POINTS Synthetic cannabinoids Synthetically derived compounds that have a l The number of psychoactive compounds on the market has binding affinity for and pharmacologically modulate endogenous dramatically increased recently. cannabinoid receptors, and often elicit physiological, subjective, l The number and type of novel drugs on the illicit market is and behavioral effects similar to those of natural cannabis. constantly changing. Synthetic cathinones Derivatives of cathinone, a monoamine alka- l These compounds are mostly cannabinoids, stimulants, and loid found in the khat plant, which is often referred to colloqui- hallucinogens. ally as “bath salts,” and elicit a variety of amphetamine-like and/or l The safety profile of these compounds is unknown and adverse MDMA-like physiological, subjective, and behavioral effects. side effects have occurred. Novel phenethylamines Noncathinone phenethylamines that have l Some of these compounds may be more dangerous than the recently become more popular as recreational drugs of abuse (e.g., established drugs they mimic. DOx compounds, 2C-x, compounds, 25x-NBOMe compounds), which are chemically unique from synthetic cathinones, and have not commonly been sold as “bath salts.” The may have stimulant, entactogenic, and/or hallucinogenic effects. REFERENCES Piperazines A broad class of compounds with diverse pharmacologi- cal actions, and are thus used for a variety of purposes. Those used Alatrash, G., Majhail, N. S., & Pile, J. C. (2006). Rhabdomyolysis after as recreational drugs typically have stimulant effects similar to ingestion of “foxy,” a hallucinogenic tryptamine derivative. Mayo amphetamines. Clinic Proceedings, 81, 550–551. Novel tryptamines Recently emergent compounds that have chemical American Association of Poison Control Centers. (2015). Synthetic mari- structures and behavioral effects that are similar to more the well- juana data. Retrieved from https://aapcc.s3.amazonaws.com/files/ characterized tryptamines that have a long history of human use library/Syn_Marijuana_Web_Data_through_5.3.2015.pdf. (e.g., DMT, 5-MeO-DMT, psilocybin). Andreasen, M. F., Telving, R., Birkler, R. I. D., Schumacher, B., & Salvia divinorum A member of the mint family that contains the Johannsen, M. (2009). A fatal poisoning involving Bromo-Dragonfly. ­psychoactive compounds salvinorin A, a kappa opioid agonist that Forensic Science International, 183, 91–96. has short-acting hallucinogenic effects. Arvanov, V. L., Liang, X., Russo, A., & Wang, R. Y. (1999). LSD and DOB: interaction with 5‐HT2A receptors to inhibit NMDA receptor‐ mediated transmission in the rat prefrontal cortex. European Journal KEY FACTS of Neuroscience, 11, 3064–3072. Atwood, B. K., Huffman, J., Straiker, A., & Mackie, K. (2010). JWH018, Key Facts on Synthetic Cannabinoids a common constituent of ‘Spice’herbal blends, is a potent and effica-

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