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Veterans’ Use of Designer and

Gerald Scott Winder, MD; Bradley Stilger, MD; Colleen Ehrnstrom, PhD; and Avinash Hosanagar, MD

Although not a new phenomenon, the use of designer by veterans is rising, and health care providers need to understand their impact and how to diagnose their use.

lthough the elevated risks end up on the street, often prom- Drugs and Crime documents its and rates of veterans’ sub- ising a novel mind-altering expe- growing concern about the “new stance abuse patterns are rience as a “legal high.”14-18 The psychoactive substances” category Awell documented, little has Designer Enforcement Act of of illicit recreational substances been written about veterans’ use of 1986 was an initial attempt in the (in which designer drugs.1-6 In recent months U.S. to define and control the early and cathinones are included) that throughout Europe and the U.S., rise of copycat drugs that appeared has increased by 50% since 2009.24 there has been a flurry of media at- on the streets and mimicked the Alone, this category now outnum- tention for 2 classes of designer effects of other illicit substances. bers the total number of substances drugs: synthetic cathinones and More recent legislation enacted in controlled by international drug synthetic cannabinoids.7,8 In the the U.S. has imposed Schedule I conventions. U.S., the popularity of these drugs controls on the manufacture, dis- The novelty and variability of de- has surged, and a disproportionate tribution, possession, importation, signer drugs causes difficulties with amount of use of these 2 drug classes and exportation of these types of detection and regulation. Innovative is coming from locations near mili- drugs, including both synthetic chemists can legally manufacture tary instillations.9,10 cathinones and synthetic cannabi- new versions of known molecules The purpose of this article is noids. State laws are perennially in intended for illicit use with a ra- to raise awareness regarding these flux trying to keep up with the lat- pidity that outpaces bureaucratic 2 burgeoning classes est drug trends.19-21 control. Local law enforcement of- and their impact on veterans. De- Similar efforts have been made ficials may be unaware of the latest signer drugs affecting vulner- by the European Union to control designer drug trends, stifling efforts able populations are not a new , a synthetic , at public education or restriction. phenomenon, yet many provid- citing multiple fatalities, seizures, Designer drugs are often decep- ers are unfamiliar with the effects related crime, lack of medical use, tively packaged and are available of these unique drugs of abuse on and risk of dependence.22 Although in convenience stores, out- their veteran populations.11-13 uniform levels of control do not lets, gas stations, pawnshops, tat- Many designer drugs begin their exist in Europe for synthetic canna- too parlors, and truck stops.25-28 The existence as variations of other ad- binoids, many countries have inde- Internet may be the singular reason, dictive or psychoactive drugs. pendently acted to limit their use.23 however, that designer drugs con- Others begin in laboratories as in- In its recent World Drug Report tinue to be widely available to vet- vestigative research compounds that 2013, the United Nations Office on erans.11,18 Innumerable websites discuss, Dr. Winder is a psychosomatic medicine fellow, and Dr. Stilger is a psychiatry resident, and Dr. Hosanagar is promote, and sell designer drugs or on the faculty and a psychiatrist all at the University of Michigan Department of Psychiatry in Ann Arbor, Michi- deceitfully market them as safe, le- gan. Dr. Hosanagar is a psychiatrist and Dr. Ehrnstrom was a clinical psychologist at the VA Ann Arbor Health Care System and at the University of Michigan Department of Psychiatry and now is a clinical psychologist at gitimate household products (“not the Eastern Colorado Health Care System in Aurora, Colorado. for human consumption”), which

22 • FEDERAL PRACTITIONER • NOVEMBER 2014 www.fedprac.com can be ordered online and shipped Table 1. Common Street Names by commercial carriers.12 Little ac- curate information is known about Synthetic Blue Silk, Charge+, Ivory Snow, Ivory Wave, Ocean their effects or about the specific cathinones Burst, Pure Ivory, Purple Wave, Snow Leopard, Star- compounds they contain. When the dust, Vanilla Sky, White Knight, and White Lightening recreational nature of the drugs is actually acknowledged, information Synthetic Spice, Yucatan Fire, Smoke, Sence, ChillX, Highdi’s on how the buyer can evade pros- cannabinoids Almdröhner, Earth Impact, Gorillaz, Skunk, Genie, ecution is often provided in tan- Galaxy Gold, Space Truckin, Solar Flare, Moon dem. The suppliers’ inventory of the Rocks, Blue Lotus, Aroma, Scope, Spice Diamond, drugs has been shown to be variable XXX, K2, K2-Blond, Black Box, and Smoke ‘n’ Skulls and inconsistent, and the product ingredients can be similarly unpre- are evolving and seemingly limit- water and loading it through a cotton dictable despite comparatively more less in their variability, and there filter in a syringe). The patient admit- stable naming and labeling.14,29 is often a paucity of pure reference ted to finding the drug significantly In the clinical setting, a reliable materials. As such, it is impossible more addictive than any others he had patient drug history may not be to guarantee reliable test results. used, and his use resulted in leaving his available. This ensures that the di- The following profiles of each of job and abandoning his family. agnosis of designer drug use will be these drug classes will be accompa- Severe cravings and depression an exclusionary process involving nied by clinical cases depicting the were present between episodes of use. routine laboratory work, physical drugs’ effects and how an affected He spent $40,000 over 6 months of examination, and at times electro- veteran might present clinically. The use. Insomnia lasted for several days, encephalogram and/or neuroim- severe effects of these novel agents his appearance changed dramatically aging. Psychiatric consultation is illustrate the value in maintaining (including persistent skin infections), often useful in this setting. Routine a functional knowledge base about and he became paranoid, believing immunoassay tests do not detect emerging drug trends. The accuracy that everyone around him was an un- either synthetic cathinones or syn- of diagnosis as well as the outcome dercover police officer. He remained thetic cannabinoids.30 of a veteran’s treatment may depend on medications for persistent anxiety. Both cannabinoids and cathi- on the provider’s ability to identify His daily drug cravings continued, nones can be identified using gas the presence of a drug and manage although he remained uncertain about chromatography-mass spectroscopy its effects. the actual ingredients of . (GC-MS) or liquid chromatogra- Cathinone is a naturally occur- phy-mass spectroscopy (LC-MS). SYNTHETIC CATHINONES ring from the plant However, this technology is lim- Mr. H is a 28-year-old Iraq War vet- (Catha edulis), which grows indige- ited to specialized laboratories.31,32 eran with a history of posttraumatic nously in Egypt and on the Arabian The laboratory results often are not stress disorder (PTSD), abuse, Peninsula. The recreational and reli- immediately available, potentially and dependence who presented gious use of this plant has occurred limiting the tests’ use in emergency for inpatient psychiatric admission for thousands of years, though it is or inpatient settings, as the patient after making suicidal statements to not without risk: The chewing of may have left the hospital by the his wife in the context of 2 weeks of the leaves containing natural cathi- time the results are available. Ad- “bath salts” use. A family member ini- nones has been associated with ditionally, these drugs’ prevalence of tially introduced him to the drug. His esophagitis, gastritis, oral keratosis, use, while increasing, often does not first drug purchase had been 1 gram myocardial infarction, dilated car- justify the cost of these tests. ($30) at a local movie rental store. diomyopathy, hypertension, cere- The inability to routinely detect After discharge from the hospital, bral ischemia, thromboembolism, metabolites in urine may increase Mr. H began purchasing increasing diabetes, sexual dysfunction, duo- the enticement of these drugs given amounts online with a credit card. Al- denal ulcer, and hepatitis.33,34 the likelihood that active-duty per- though he initially had been insufflat- The known collo- sonnel could use them surrepti- ing and inhaling the substance, he later quially as bath salts are synthetic tiously. Further, these compounds began injecting it (dissolving it in tap cathinones, which have become

www.fedprac.com NOVEMBER 2014 • FEDERAL PRACTITIONER • 23 Designer Cathinones and Cannabinoids

Table 2. Intoxication and Withdrawal Symptoms

Intoxication Symptoms Withdrawal Symptoms

Synthetic Energy increase, mood elevation, empathy, Intense cravings, dysphoria, cathinones openness, increased libido, diaphoresis, headache, depression, anxiety, fatigue, nausea and vomiting, muscle twitching, dizziness, paranoia, restlessness, irritability, vertigo, short-term memory difficulty, anxiety, insomnia, poor concentration hallucinations, delusions, insomnia, nightmares, tremor, tachycardia, paranoia

Synthetic Disorientation, anxiety, tremulousness, Irritability, anxiety, tremor, cannabinoids palpitations, tachycardia, agitation, injected palpitations, diaphoresis, insomnia, conjunctivae, hyperrefflexia, nausea, vomiting, headache, diarrhea, nausea, vomiting nystagmus, myoclonus more widely available within the the drugs for many of the same rea- of these drugs, a specific request past 10 years: first in the Middle sons that other recreational stimu- should be given to the technicians East, then Europe, and now in the lants have appeal: , energy, to look for signals of MDPV (most U.S.5,9,10,14,19,25,35-41,44 Although the empathy, heightened sexuality, so- common metabolite is dimethyle- current rise in use has occurred in ciability, and an overall intensifica- nyl-methyl-MDPV), mephedrone the past few years, the first docu- tion of senses. Synthetic cathinones (4-methylmethcathinone), 3-bro- mented abuse of synthetic cathi- have become preferred to momethcathinone (3-BMC), nones in the U.S. dates to the early for some users.43 or 3-fluoromethcathinone (flu- 1990s in Michigan.42 The drugs can be used via oral phedrone).45-48 The study testing Bath salts is the most common and anal routes. Using methods (both in VA and civilian settings) of the many names used to denote known as “bombing” or “keystering,” for Mr. H was done by a commer- synthetic cathinones. The com- users deliver boluses of the powder cial laboratory several states away pounds have no utility when used wrapped in cigarette paper, which where patented techniques can as such but often are marketed as they swallow or insert into the rec- screen for more than 30 compounds research chemicals, plant fertilizer, tum. Insufflation and IV injection are via LC-MS. The laboratory offered or shoe polish. It is this deliberate also common methods of adminis- bath salts panels for urine, serum/ counterfeit of household product tration with a quicker onset of action plasma, and blood samples. names that allows many distributors expected.40 The prices of the drugs Synthetic cathinones are danger- to avoid classifying the compounds range from $25 to $50 per 500-mg ous, and as the body of medical lit- according to the true, intended packet (though the cost is increasing erature continues to expand, reports use. More appealing brand names with more regulation). Users typically of significant morbidity and death may also be used to entice the user use 500 mg to 2 g in one session. related to their use are appearing. (Table 1).25 The 2 most commonly abused The harmful effects of recreational Synthetic cathinones owe their synthetic cathinones are me- synthetic cathinone use has been popularity to similarities with co- phedrone and MDPV (methylene- documented across the globe in the caine and . They dioxypyrovalerone). There is some form of serotonin syndrome, in- are sympathomimetic with synaptic regional variability about which toxication delirium, hyperthermia increases of monoamines after use: ingredient is present; mephedrone and multi-organ failure, myocar- Surges in and do- tends to be more prevalent in Eu- ditis, hypo-osmotic hyponatremia pamine account for the stimulant rope, whereas MDPV is noted to be with encephalopathy, agitation, psy- qualities, and serotonergic changes more common in the U.S.10,44 chosis, and death after cardiac ar- mediate distinct psychoactive effects When ordering a laboratory rest.5,12,38,39,49-53 Published treatment (Table 2).40 Users are interested in test to evaluate for the presence methods are largely supportive with

24 • FEDERAL PRACTITIONER • NOVEMBER 2014 www.fedprac.com Designer Cathinones and Cannabinoids

the available literature, suggesting (THC), an ac- the benzoylindoles, such as AM- that , antipsychot- tive ingredient in marijuana.28,54 The 964 and RCS-4, which also bind ics (both typical and atypical), re- availability of these drugs online strongly to CB1 and CB2.60,62 straints to maintain safety, and IV and in specialty shops has been doc- Constitutional symptoms of fluids may be indicated.5,9,50 umented since the mid-2000s.27,28,32 synthetic intoxica- Their packaging often describes tion include disorientation, anxi- SYNTHETIC CANNABINOIDS the contents as incense or herbal ety, tremulousness, palpitations, Mr. W is a 58-year-old veteran with blends, using various names. Spice tachycardia, agitation, injected a history of alcohol dependence and is a common name, but these prod- conjunctivae, hyperreflexia, nau- PTSD who reported use of the syn- ucts are also known by a myriad of sea, vomiting, lateral gaze nystag- thetic cannabinoid “Spice” during other designations (Table 1).28 A mus, and myoclonic jerks, which intake assessment for treatment of al- single packet usually contains sev- have been mistaken for seizure ac- cohol dependence. He reported using eral grams of the drug and costs tivity.27,30,55 Pupils are often normal Spice about 4 times over a 2-month about $30.55 sized.55 Withdrawal phenomena are period. He purchased a small jar of To the user, who may already be similar to those of with- the substance from a party store for familiar with marijuana, the contents drawal: irritability, anxiety, tremor, $15 per gram and understood its con- intentionally appear similar to the palpitations, diaphoresis, insomnia, tents to be synthetic marijuana, which dried buds of cannabis.30,56 In real- headache, diarrhea, nausea, and he appreciated for its low cost and as- ity, the drug has just been sprayed vomiting.59 sumed legality. He denied having any onto inert plant material.57 The drug Given the established link be- understanding of the package’s con- is smoked, and the psychoactive tween cannabis use and psycho- tents beyond “synthetic marijuana.” dose can be as little as 1 mg.30 Users sis, synthetic cannabinoids may The patient ingested the drug by describe potent drug effects (Table stand as a precipitant of psychotic and inhaling from a pipe. 2). There is a rapid onset of action, symptoms, which may include vi- For the first 3 times that he used and duration of effects last 1 to sual hallucinations, auditory hal- the substance, Mr. W reported feel- 2 hours.58 lucinations, disorganized speech, ing a pleasant sensation that started The compounds’ mechanism of paranoia, grandiose delusions, quickly and lasted about 30 minutes. action and appeal are derived from disorganization, or bizarre behav- The fourth time that he used synthetic their high affinity for the cannabi- ior.58,63-66 These symptoms may cannabis he felt nauseated and vom- noid receptors. The CB1 receptor represent a relapse of a primary ited several times, had auditory hal- is located primarily in the central thought disorder or, for some unfor- lucinations, and increased anxiety; he nervous system and is responsible tunate individuals, a de novo psy- also reported a hangover effect after for the psychoactive component of chotic illness.58,65,66 Symptoms can this use. He identified that the effects the drugs’ actions.27,30,58,59 Two par- linger for months after drug use.65 may have been different the fourth ticular synthetic cannabinoids, can- A key risk in the use of synthetic time “because the brands were chang- nibicyclohexanol and JWH-018, are cannabinoid moieties may involve ing.” potent cannabinoid CB1 agonists the absence of cannabidiol. Can- Mr. W also reported that his with affinity exceeding their natural nabidiol naturally occurs in many neighbor—a daily user of synthetic counterparts.27,30, 32,56,58,59 strains of cannabis and is thought to cannabinoids for several months— Chemically, these drugs are var- have antipsychotic, neuroprotective became paranoid, suspicious, and ied. The largest structural family of properties.67 The absence of this mol- developed incomprehensible speech. these compounds is the JWH group, ecule in synthetic cannabinoids may His neighbor’s symptoms and his own which includes JWH-018.60 Also at least partially explain their severe unpleasant experiences prompted a common are CP 47,497 and other psychoactive effects. Treatment for discontinuation of use. CP compounds.58 HU compounds, synthetic cannabinoid intoxication Synthetic cannabinoids are a di- such as HU-210, have also been and related psychosis is largely sup- verse group of agents numbering in identified and have been shown to portive and may include the use of excess of 100 artificial compounds be 100 to 800 times more potent antipsychotic medication.66 that act as agonists at cannabinoid at the CB1 and CB2 receptors than Detection of synthetic cannabi- receptors, mimicking the effects of is THC.60,61 A final group includes noids in urine is difficult, yet many

www.fedprac.com NOVEMBER 2014 • FEDERAL PRACTITIONER • 25 Designer Cathinones and Cannabinoids

compounds can be detected via is difficult, and new versions of the 1999;156(12):1924-1930. 4. Sirratt D, Ozanian A, Traenkner B. Epidemiology GC-MS or LC-MS. Molecules of sig- molecules may evade even cutting- and prevention of substance use disorders in the nificance include JWH-018, JWH- edge techniques. military. Mil Med. 2012;177(suppl 8):21-28. 5. Winder GS, Stern N, Hosanagar A. Are “bath salts” 073, JWH-015, JWH-250, CP-47 Due to the high cost of detecting the next generation of stimulant abuse? J Subst 497, HU-210, cannabicyclohexanol, synthetic cathinones and synthetic Abuse Treat. 2013;44(1):42-45. 6. Bobes J, Sáiz PA, González MP, et al. Use of MDMA and oleamide; however, these com- cannabinoids in body fluids, screen- and other illicit drugs by young adult males in pounds are rarely excreted in urine in ing should be considered only in northern Spain. A five-year study. Eur Addict Res. their pure form. The many hydrox- settings where severe symptoms are 2002;8(3):147-154. 7. D.E.A. Cracks Down on Designer Drug Operations. ylated or dealkylated metabolites of accompanied by reasonable clini- The New York Times Website. http://www.nytimes these compounds, mostly unnamed, cal suspicion of use and an other- .com/2013/06/27/us/dea-cracks-down-on-designer -drug-operations.html. Published June 26, 2013. are more consistently detected in wise negative toxicologic workup. Accessed October 6, 2014. urine.68,69 One author has noted that As more designer drugs inevitably 8. Travis A. Mushrooming legal highs leave drug con- trol system floundering, UN warns. The Guardian the pentanoic acid metabolite of emerge, research will be needed on Website. http://www.guardian.co.uk/world/2013 JWH-018 seems to appear most reli- their , toxidromes, and /jun/26/legal-highs-drug-control. Published June 26, 68 2013. Accessed October 6, 2014. ably in urine specimens. detection. Military and civilian prac- 9.  Jerry J, Collins G, Streem D. Synthetic legal in- Many synthetic cannabinoid titioners must remain abreast of the toxicating drugs: The emerging ‘incense’ and ‘bath salt’ phenomenon. Cleve Clin J Med. herbal mixes also contain a detectable dynamic trends in designer drugs to 2012;79(4):258-264. compound called tocopherol, seem- ensure that their patients receive the 10. Murphy CM, Dulaney AR, Beuhler MC, Kacinko S. 69,70 ● “Bath salts” and “plant food” products: The experi- ingly added as an antioxidant. highest level of medical care. ence of one regional US poison center. J Med Toxicol. Synthetic cannabinoids are an evolv- 2013;9(1):42-48. 11. Wax PM. Just a click away: Recreational drug web ing drug class, and reliable detection Author disclosures sites on the Internet. Pediatrics. 2002;109(6):e96. will require that laboratories stay up- The authors report no actual or poten- 12. Vardakou I, Pistos C, Spiliopoulou C. Drugs for youth via Internet and the example of mephedrone. to-date in their detection methods. As tial conflicts of interest with regard to Toxicol Lett. 2011;201(3):191-195. stated earlier, a commercial laboratory this article. 13. Winickoff JP, Houck CS, Rothman EL, Bauchner H. Verve and jolt: Deadly new Internet drugs. Pediat- in the region accepted the civilian and rics. 2000;106(4):829-830. veteran patient samples for these case Disclaimer 14. Camilleri A, Johnston MR, Brennan M, Davis S, Caldicott DG. Chemical analysis of four capsules studies. The synthetic cannabinoid The opinions expressed herein are containing the analogues panels offered evaluation of the drug those of the authors and do not nec- 4-methylmethcathinone, 2-fluoromethamphet- amine, alpha- and itself (GC-MS), an oral fluid screen essarily reflect those of Federal N-ethylcathinone. Forensic Sci Int. 2010;197(1- (LC-MS), and isolation of metabolites Practitioner, Frontline Medical Com- 3):59-66. 15. Carroll FI, Lewin AH, Mascarella SW, Seltzman HH, in urine (enzyme-linked immunosor- munications Inc., the U.S. Govern- Reddy PA. Designer drugs: A medicinal chemistry bent assay). ment, or any of its agencies. This perspective. Ann N Y Acad Sci. 2012;1248:18-38. 16. Christophersen AS. designer article may discuss unlabeled or in- drugs—An overview and epidemiology. Toxicol Lett. CONCLUSION vestigational use of certain drugs. 2000;112-113:127-131. 17. Buchanan JF, Brown CR. ‘Designer drugs.’ A prob- Designer drugs will remain a chal- Please review complete prescribing in- lem in clinical . Med Toxicol Adverse Drug lenge for providers caring for vet- formation for specific drugs or drug Exp. 1988;3(1):1-17. 18. Griffiths P, Sedefov R, Gallegos A, Lopez D. How erans for several key reasons: (1) combinations—including indications, globalization and market innovation challenge how Veterans are a vulnerable population contraindications, warnings, and ad- we think about and respond to drug use: ‘Spice’ a case study. . 2010;105(6):951-953. who abuse substances at higher rates verse effects—before administering 19. Drug Enforcement Administration, Department than do their civilian counterparts; pharmacologic therapy to patients. of Justice. Schedules of controlled substances: Temporary placement of three synthetic cathi- (2) Chemists are able to manufacture nones in Schedule I. Final Order. Fed Regist. variations of known habit-forming REFERENCES 2011;76(204):65371-65375. 1. Bray RM, Fairbank JA, Marsden ME. Stress and sub- 20. Drug Enforcement Administration, Department of substances; (3) Modern technology stance use among military women and men. J Drug Justice. 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BMJ Case Rep. 2010. 39. Sammler EM, Foley PL, Lauder GD, Wilson SJ, Scroll down on our homepage to take this Goudie AR, O’Riordan JI. A harmless high? Lan- cet. 2010;376(9742):742. Quick month’s Quick Poll: 40. Prosser JM, Nelson LS. The toxicology of bath salts: A review of synthetic cathinones. J Med Toxi- How well can you identify designer col. 2012;8(1):33-42. Poll 41. Thornton SL, Gerona RR, Tomaszewski CA. www.fedprac.com synthetic cathinone street names? Psychosis from a bath salt product contain-

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