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Violent behavior and hallucination in a 32-year-old patient.

CASE

A 32-year-old white male was brought to the emergency department by police after a sudden, dangerous outburst. He had allegedly assaulted his girlfriend and attempted to run her over with his car. Subsequently, the patient reportedly stole and/or damaged numerous other motor vehicles. Several security and law enforcement officers were required to subdue the patient and bring an end to his hallucination-driven rampage, which lasted about 2 hours. The patient's medical history included chronic back pain, hypertension, and a long history of substance abuse, including alcohol, tobacco, and marijuana. A physical examination revealed the following: blood pressure, 132/88 mmHg; heart rate, 135 beats/min; respiratory rate, 18/min; body temperature, 98.7[degrees]F; oxygen saturation, 98% on room air. He was markedly anxious, distressed, and sweating profusely. His pupils were normal in size and reactive to light. The patient had mild abrasions on his hands, arms, and shoulders, but he had no severe injuries. He progressively became more agitated in the emergency department and required 10 mg ziprasidone intramuscularly and 2 mg lorazepam intravenously for sedation. Intoxication with psychoactive substances was suspected; however, the results of routine screening tests of serum and urine samples were negative for alcohols, amphetamines, cocaine, and opioids.

DISCUSSION

For cases in which drug abuse is high on the differential but the results of routine drug screening are negative, physicians and laboratorians should consider the analytical sensitivity and specificity of the assays they have used to perform the screen. For example, although a patient may have overdosed on oxycodone, does the laboratory's general opiate immunoassay detect this synthetic opioid? Local availability and use of illicit drugs, including designer drugs, also need consideration. Phencyclidine can induce a clinical presentation similar to the one described above, but it is rarely used in our region and is therefore not included in the routine drug screening at our hospital. Overdose with prescription medications (as in the case of oxycodone) may also give a negative screen result for drugs of abuse. It may be necessary to use more-specific analytical methods, such as mass spectrometry, to detect the latest derivatives of designer drugs, for which immunoassays are not available. Other limitations of immunoassay-based drug screening include lack of analytical specificity for individual compounds, the high cost of reagents, lot-to-lot variation, and a relatively high susceptibility to interferences.

PATIENT FOLLOW-UP

An astute resident physician had seen recent suspected cases of intoxication with "bath salts"--synthetic cathinones packaged as hygiene products, insect repellent, or plant food--and recognized in this patient the signs of intoxication reportedly associated with this class of drugs (1). The resident contacted the laboratory and asked whether in-house toxicology tests would be capable of detecting synthetic cathinones in serum or urine. Roche Diagnostics, the manufacturer of the amphetamine-screening test, indicated that cross-reactivity with synthetic cathinones had not been tested.

Poison control centers in the US received 303 calls regarding drug exposures attributed to "bath salts" during 2010. Between January 1 and August 31, 2011, the number of these calls increased drastically, to 4720 (2). The psychoactive drugs being marketed as "bath salts" are synthetic derivatives of cathinone, the active compound found in Catha edulis, a plant endemic to East Africa and the Middle East (3). Scores ofcathinone derivatives more potent than the herbal compound have been described (4). Structures for a few common synthetic cathinones are given in Fig. 1.

[FIGURE 1 OMITTED]

Synthetic cathinones are believed to be synthesized from ephedrine or pseudoephedrine by underground chemists and then packaged and marketed as bath salts, insect repellent, plant food, or stain remover (5). A multiplicity of colorful brand names have been used (e.g., Cloud 9, Vanilla Sky, Ivory Wave, White Lightning) on packages for sale by gas stations, head shops, adult book stores, and Internet suppliers (1, 5,6). These drugs are taken orally, intranasally, intravenously, or rectally and have highly addictive potential. Like other sympathomimetics, synthetic cathinones appear to stimulate the central nervous system via inhibition of norepinephrine and dopamine reuptake mechanisms. Toxic or negative effects associated with synthetic cathinone abuse include intense hallucinations, hyperthermia, hypertension, tachycardia, and other extreme sympathomimetic and behavioral effects. Preparations of synthetic cathinones may be sold as mixtures or coingested with other drugs, complicating the clinical picture.

Despite structural similarities to other sympathomimetic amines (Fig. 1), routine immunoassay-based drug screens for amphetamines have not detected synthetic cathinones. Advanced detection methods based on LC-MS or GC-MS are not routinely available. Although sending samples to a reference laboratoryis not useful for emergency situations or short-term hospital care, testing for synthetic cathinones may be vital to forensic investigations or for differential diagnosis of psychiatric conditions. In addition, as yet unrecognized long-lasting health effects maybe connected with abuse of this class of drugs, as has been suggested for chronic abuse of amphetamines (7, 8). Thus, it maybe important for clinicians to have appropriate laboratory testing available to confirm the presence of one or more of the synthetic cathinones.

Regional differences in drug availability have been noted. Methcathinone and mephedrone (4-methyl-N-methylcathinone) have been the most commonly reported cathinone derivatives in Eastern and Western Europe, respectively, in the past 2 decades. Most recently, Spiller et al. found 3,4-methylenedioxypyrovalerone (MDPV) [4] to be the predominant synthetic cathinone detected in 19 "bath salts" cases at 2 poison control centers in the central part of the US during 2010 (5). Public health officials, law enforcement officials, and legislators in several states and in Europe have acted quickly to ban members of this new class of drugs. On October 21, 2011, the US Drug Enforcement Administration issued a final order to place 3 synthetic cathinones temporarily in Schedule I: mephedrone, 3,4-methylenedioxy-N-methylcathinone (methylone), and MDPV (9).

CASE RESOLUTION

The patient confessed to snorting an unknown brand or quantity of "bath salts" approximately 6 hours before presentation in the emergency department. The patient's first serum sample was sent to NMS Labs for MDPV and mephedrone analysis. MDPV in serum was detected and quantified by use of liquid chromatography-tandem mass spectrometry (LC-MS/MS) (10). One hundred microliters of deuterated MDPV ([d.sub.8]-MDPV) (0.5 ng/[micro]L in methanol; Toronto Research Chemicals) were added as internal standard to 0.2 mL of calibrators, controls, and patient serum. This step was followed by addition of 10% trichloroacetic acid and vortex-mixing. The samples were centrifuged, the supernatants were transferred to autosampler vials, and 10 [micro]L of the supernatant was injected into the liquid chromatography instrument for analysis. A Waters TQD mass spectrometer equipped with a Waters Acquity UPLC[R] constituted the LC-MS/MS instrumentation. The liquid chromatography instrument was equipped with an Aquity UPLC HSS [T.sub.3] (1.8 [micro]m, 2.1 x 100 mm) analytical column. The mobile phases were 1 mL/L formic acid in water (mobile phase A) and 1 mL/L formic acid in methanol (mobile phase B); linear-gradient conditions are given in Table 1. The tandem mass spectrometer was operated in the positive electrospray mode, with 2 transitions monitored: MDPV, 276.2 m/z [right arrow] 126.2 m/z (quantification ion) and 276.2 m/z [right arrow] 175.2 m/z; [d.sub.8]-MDPV, 284.2 m/z [right arrow] 134.2 m/z and 284.2 m/z [right arrow] 175.2 m/z). Ion ratios were also monitored. The method had a limit of detection of 0.02 [micro]g/L and an analytical measurement range of 10-5000 [micro]g/L. Other analytical parameters, including imprecision, bias, interference studies, and analytical stability all met defined laboratory criteria. Mephedrone analysis was performed with a similar LC-MS/MS method.

While testing was in progress, the patient was treated for rhabdomyolysis and acute renal failure. MDPV was detected at 75 [micro]g/L (reporting limit, 10 [micro]g/L); mephedrone was not detected. This result confirmed the patient's admission to "bath salts" use prior to the incidents described in this case and suggested that MDPV intoxication was a causal factor in his extreme behavior.

CONCLUSION

This case study illustrates the major threat that abuse of synthetic cathinones poses to both the individual and the public, especially when hallucinations and violent behavior are manifested. Clinical laboratories should be aware of current designer drugs and be prepared to facilitate testing when appropriate. Our inquiries to 8 manufacturers of amphetamine drug screen tests revealed that only 3 of them had some data on the cross reactivity of select synthetic cathinones. These 3 products demonstrated insufficient cross-reactivity to meet the clinical need in cases of designer drug intoxication at the concentrations previously reported (5). The geographic distribution and structural features of designer drugs change rapidly, more rapidly than immunoassays can be developed and validated.

The ideal analytical method for comprehensive drug screening would involve mass spectrometry, which is currently the only analytical approach available for detection of synthetic cathinones or other designer drugs. Analytical reference standards become available relatively quickly, owing to the close collaboration ofsuppliers, poison control centers, and government agencies. Thus, mass spectrometry methods can be validated rapidlyfor detection of the latest iterations ofdesigner drugs. Although current mass spectrometry methods also have limitations for routine drug screening in many laboratories, namely the cost of instrumentation and increased turnaround times, they can provide up-to-date and comprehensive drug screening for emergency situations when in-house mass spectrometry methods can be made available.

QUESTIONS TO CONSIDER

1. What drugs should be considered in cases in which drug abuse is suspected but the results of all drug screens are negative?

2. What are the limitations of immunoassay-based drug screening?

3. What would be the ideal analytical method for comprehensive drug screening?

POINTS TO REMEMBER

* "Bath salts," a new form of designer drug, are synthetic cathinones packaged as hygiene products, insect repellent, or plant food. Three synthetic cathinones are now temporarily in Schedule I: mephedrone, methylone, and MDPV.

* Patients with extreme sympathomimetic syndrome, hallucinations, and violent behavior may have taken one of many possible synthetic cathinones.

* Street names for this class of drugs vary widely and may represent mixtures of drugs.

* Routine screening for drugs of abuse may not detect synthetic cathinones.

* Testing for synthetic cathinones should be facilitated with close communication between physicians and laboratory professionals.

Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.

Authors' Disclosures or Potential Conflicts of Interest: Upon manuscript submission, all authors completed the author disclosure form. Disclosures and/or potential conflicts of interest:

Employment or Leadership: None declared.

Consultant or Advisory Role: None declared.

Stock Ownership: None declared.

Honoraria: None declared.

Research Funding: None declared.

Expert Testimony: None declared.

Patents: None declared.

Other Remuneration: R.A. Middleberg, AACC symposium.

References

(1.) Ross EA, Watson M, Goldberger B. "Bath salts" intoxication. N Engl J Med 2011;365:967-8.

(2.) American Association of Poison Control Centers. Poison control centers applaud DEA's ban of bath salts. http://www.aapcc.org/dnn/Portals70/ DEA%20Ban%20on%20Bath%20Salts%209.8.2011.pdf (Accessed November 2011).

(3.) Caravati EM, McCowan CL, Marshall SW. Plants. In: Dart RC, ed. Medical toxicology. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2004. p 1707-8.

(4.) Prosser JM, Nelson LS. The toxicology of bath salts: a review of synthetic cathinones. J Med Toxicol 2012;8:33-42.

(5.) Spiller HA, Ryan ML, Weston RG, Jansen J. Clinical experience with and analytical confirmation of "bath salts" and "legal highs" (synthetic cathinones) in the United States. Clin Toxicol (Phila) 2011;49:499-505.

(6.) Coppola M, Mondola R. 3,4-methylenedioxypyrovalerone (MDPV): chemistry, pharmacology and toxicology of a new designer drug of abuse marketed online. Toxicol Lett 2012;208:12-5.

(7.) Newton TF, Kalechstein AD, Hardy DJ, Cook IA, Nestor L, Ling W, Leuchter AF. Association between quantitative EEG and neurocognition in methamphetamine-dependent volunteers. Clin Neurophysiol 2004;115: 194-8.

(8.) Paulus MP, Hozack NE, Zauscher BE, Frank L, Brown GG, Braff DL, Schuckit MA. Behavioral and functional neuroimaging evidence for prefrontal dysfunction in methamphetamine-dependent subjects. Neuropsychopharmacol ogy 2002;26:53-63.

(9.) Department of Justice, Drug Enforcement Administration. Schedules of controlled substances: temporary placement of three synthetic cathinones into Schedule I. Codified at 21 CFR Part 1308. Fed Regist 2011;76:65371-5.

(10.) Westphal F, Junge T, Rosner P, Sonnichsen F, Schuster F. Mass and NMR spectroscopic characterization of 3,4-methylenedioxypyrovalerone: a designer drug with a-pyrrolidinophenone structure. Forensic Sci Int 2009;190: 1-8.

Commentary

Michael E. Mullins *

In late 2010, "bath salts" appeared on the scene in North America and exploded with 6138 human-exposure calls to US poison control centers in 2011 (1, 2). Although only 1717 cases have been reported to poison centers as of June 30, 2012, the number of cases has increased for 6 consecutive months (3). Because the American Association of Poison Control Centers database depends on voluntary reporting, the current numbers certainly underestimate the magnitude of the epidemic as emergency physicians become more familiar with bath salt exposures.

The regulatory response by state and federal authorities was much swifter than in previous drug trends. Until we have complete data for 2012, we may not know the full effect of the legal restrictions on bath salts.

From data provided by the US Drug Enforcement Administration, the most frequently seized "bath salts" are mephedrone (4-methyl-N-methylcathinone) and MDPV (3,4-methylenedioxypyrovalerone). Others include methcathinone (N-methylcathinone), methylone (methylenedioxy-N-methylcathinone), and 4-MEC (4-methyl-N-ethylcathinone) (2).

Cathinone derivatives (bath salts) and amphetamine derivatives have strikingly similar 2-dimensional structures, often differing principally in the ketone at the f carbon. Yet, the cathinones tend not to produce positive results in urine screens for amphetamine.

Because advanced laboratory techniques are usually not routinely and rapidly available in most hospitals, the emergency physician maybe left in a diagnostic quandary when a patient with apparent sympathomimetic toxidrome (agitation with tachycardia, hyperthermia, and/or hyperthermia) fails to display cocaine metabolites or amphetamines in the urine drug screen. Fortunately, the treatment is similar and usually includes benzodiazepines or antipsychotic tranquilizers, repletion offluids and electrolytes (especially potassium), and sometimes control of temperature or blood pressure (3).

Randox Toxicology has recently marketed an immunoassay for cathinone derivatives (5), and Ameritox has developed a mass spectrometry test (6). These tests may be useful for emergency physicians and for law enforcement, especially in areas with a high prevalence of bath salt use.

Division of Emergency Medicine, Washington University School of Medicine, St. Louis, MO.

* Address correspondence to the author at: Washington University School of Medicine, Campus Box 8072, 660 S. Euclid Ave., St. Louis, MO 63110. E-mail mullinsm@wusm.wustl.edu.

Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.

Authors' Disclosures or Potential Conflicts of Interest: No authors declared any potential conflicts of interest.

References

(1.) Bronstein AC, Spyker DA, Cantilena LR Jr, Green JL, Rumack BH, Dart RC. 2010 Annual report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 28th annual report. Clin Toxicol (Phila) 2011;49: 910-41.

(2.) U.S. Department of Justice, Drug Enforcement Administration, Office of Diversion Control. Special report: synthetic cannabinoids and synthetic cathinones reported in NFLIS, 2009-2010. https://www.nflis.deadiversion.usdoj.gov/ DesktopModules/ReportDownloads/Reports/SynCannabSynCath.pdf (Accessed July 2012).

(3.) American Association of Poison Control Centers. Poison Help: bath salts data, updated July 6, 2012. http://www.aapcc.org/dnn/Portals/0ZBath%20Salts%20 Data%20for%20Website%207.06.2012.pdf (Accessed July 2012).

(4.) Spiller HA, Ryan ML, Weston RG, Jansen J. Clinical experience with and analytical confirmation of "bath salts" and "legal highs" (synthetic cathinones) in the United States. Clin Toxicol 2011;49:499-505.

(5.) Randox Toxicology. Mephedrone/methcathione ELISA. http://www. randoxtoxicology.com/Products/Mephedrone-Methcathinone-ELISA-p-313 (Accessed July 2012).

(6.) Ameritox. Bath salts: With dangerous drug use on the rise, Ameritox launches critical new test to help detect designer drug. http://www.ameritox.com/bathsalts-with-dangerous-drug-use-on-the-rise- ameritox-launches-critical-new-test-to-help-detect-designer-drug/ (Accessed July 2012).

Commentary

Gwendolyn A. McMillin *

Designer drugs such as "bath salts" are not detected by routine toxicology tests. As demonstrated by this case report, a patient suspected of intoxication with a designer drug is managed with supportive care, suggesting that identification of the specific toxicant may not contribute to making management decisions for the patient experiencing acute poisoning. Detection of a particular toxicant, however, may affect long-term management decisions and may have forensic and/or social implications.

Collection of both blood and urine samples is recommended to maximize the likelihood of drug detection. An analytical method that does not detect drug metabolites may not be appropriate for urine, a specimen in which metabolites are likely to predominate. The patterns of metabolites that appear in the urine after the use of "bath salts" are not well known. In the presented clinical case, a blood sample was sufficient to successfully identify the synthetic cathinone involved. It is important to note that the cathinones are unstable in whole blood and sample extracts under neutral conditions, a consideration that makes sample handling critical for detection (1).

The authors indicate that mass spectrometry is the best technology for detecting designer drugs. Although mass spectrometry is a valuable tool and several published methods using this technology are available, targeted methods designed to detect specific masses are not analytically sensitive for all designer drugs. In addition, the chemistry of the specific drug(s) will dictate the most appropriate methods of sample preparation and extraction. Underground chemists frequently make chemical modifications to drugs, making detection a continuous challenge for laboratories. A method designed to detect a wide range of masses (full-scan mode) coupled with several approaches to sample preparation may be required to detect use of a designer drug (2).

In summary, the optimal approach for the detection of designer drug use is not well defined and requires coordination of sample collection and handling, as well as application of specialized analytical methods.

Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.

Authors' Disclosures or Potential Conflicts of Interest: No authors declared anypotential conflicts of interest.

References

(1.) Sorensen LK. Determination of cathinones and related ephedrines in forensic whole-blood samples by liquid-chromatography-electrospray tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 2011;879: 727-36.

(2.) Dickson AJ, Vorce SP, Levine B, Past MR. Multiple-drug toxicity caused by the coadministration of 4-methylmethcathinone (mephedrone) and heroin. J Anal Toxicol 2010;34:162-8.

Department of Pathology, School of Medicine, University of Utah, Salt Lake City, UT.

* Address correspondence to the author at: ARUP Laboratories, 500 Chipeta Way, Salt Lake City, UT 84108. Fax 801-584-5207; e-mail gwen.mcmillin@aruplab.com.

Received June 17, 2012; accepted June 28, 2012.

DOI: 10.1373/clinchem.2012.191122

Steven M. Truscott, [1] Neil E. Crittenden, [2] Monica A. Shaw, [2] Robert A. Middleberg, [3] and Saeed A. Jortani [1] *

Departments of [1] Pathology and Laboratory Medicine and [2] Medicine, University of Louisville School of Medicine, Louisville, KY; [3] NMS Labs, Willow Grove, PA.

* Address correspondence to this author at: University of Louisville Hospital, 511 S. Floyd St., Rm. 204, Louisville, KY 40202. Fax 502-852-7674; e-mail sjortani@louisville.edu.

Received December 12, 2011; accepted March 28, 2012.

DOI: 10.1373/clinchem.2011.179507

[4] Nonstandard abbreviations: MDPV, 3,4-methylenedioxypyrovalerone; LC-MS/ MS, liquid chromatography-tandem mass spectrometry.

Received July 15, 2012; accepted August 3, 2012.

DOI: 10.1373/clinchem.2012.191114
Table 1. Linear-gradient conditions for LC-MS/MS
detection of MDPV.

Time,        Flow rate,      Mobile        Mobile
min            mL/min      phase A, %    phase B, %

0-2.20         0.400          90.0          10.0
2.20-2.30      0.400          20.0          80.0
2.30-3.00      0.400          5.0           95.0
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Title Annotation:Clinical Case Study
Author:Truscott, Steven M.; Crittenden, Neil E.; Shaw, Monica A.; Middleberg, Robert A.; Jortani, Saeed A.
Publication:Clinical Chemistry
Article Type:Clinical report
Geographic Code:1USA
Date:Apr 1, 2013
Words:3362
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