“Bath Salts”: New Legal Designer Drug Sept, Presenter: Pragnesh Patel, MD Attending Mentor: Rakesh Patel, MD

Disclosure Statement of Financial Interest Financial Interest I,Pragnesh Patel, DO NOT have a financial interest/arrangement or affiliation with one or more organizations that could be perceived as a real or apparent conflict of interest in the context of the subject of this presentation. DO NOT have a financial interest/arrangement or affiliation with one or more organizations that could be perceived as a real or apparent conflict of interest in the context of the subject of this presentation.

► Case Summary ● A 49 y/o. CM with no past medical history was brought to ER by the EMS due to ○ severe agitation ○ violent behavior ○ delirium ○ with several sights of injury ● Initial evaluation revealed ○ severe hypoxia ○ severe agitation and combative behavior ○ hyper stimulation ○ hyperthermia (107.2)

► Case Summary (continued ) ● The patient was admitted to the ICU with s/p intubation & aggressive supportive measures ● During his stay in the ICU, he developed series of complication leading to demise of patient ● The toxicology department detected Methylenedioxypyrovalerone (MDPV) in the urine (family members also verified patient’s ongoing abuse of “Bath Salts”)

► So What are “Bath Salts?” ● These aren’t your average “Bath Salts” that you pour into the bathtub to soak in after a long, hard day to relax, but ● “Bath Salts” are intended to be ○ snorted, ○ smoked or ○ injected – and users are getting high off of them. ● Never meant or approved for human consumption ● Alternative use are ○ plant food ○ decorative sand ○ toy cleaner

► Source ● Remember it is a man-made/designer drug ○ Khat (plant from Africa), source of psychostimulant cathinone OR ○ Europe, but origins are still unclear ● First appearance in 2004 ● In 2010, was reportedly sold as a legal drug alternative and marketed in the United States as "Bath Salts”

► Source ( continued ) ● most common brand name used ○ Ivory Wave ○ White Lightning ○ Hurricane Charlie ○ Vanilla Sky ○ Charge ○ White Knight

► Use and Availability of “Bath Salts” ● “Bath Salts” are ○ snorted ○ injected ○ smoked, or even ○ oral consumption ○ rectal use ● Easy & widespread availability ○ on the Internet ○ local convenience stores ○ smoke shops

► Use and Availability of “Bath Salts” (continued) ● A small packet of the chemicals typically costs as little as $20.

► Appearance ● pure white to light-brown hygroscopic powder slight odor ● if left exposed to air for any significant length of time, ○ changes color (darken slightly) ○ changes odor (potato-tuber or earthy) ○ rapid degradation, and ○ change in other properties ● Pyrrolidine is responsible for earthy odor

► Pharmacological Use ● MDPV has no history of FDA approved medical use ○ ring analog of compound Pyrovalerone ● Medical use of Pyrovalerone ( in 1960s) ○ treatment of chronic fatigue ○ anorectic ○ addictive/abusive properties ● MDPV produces, ○ primary stimulant effect ○ mild entactogenic qualities

► Chemistry ● The best synthetic route probably involves the 4-step alkylation-oxidation bromination-amination methodology.

► Metabolism ● Hepatic ○ Phase 1 through CYP450, 2D6, 2C19 and COMT ○ methyl catechol and pyrrolidine ○ Phase 2 glucuronization ○ uridine 5 diphospho-glucuronosyl-transferase ● Renal ○ excreted in urine (major fraction) ● GI ○ fecal matter (only small fraction)

► Metabolism ( continued ) ● No free pyrrolidine will be detected in the urine. ● “Bath Salts” or its active metabolites will not appear on usual drug screen, but it requires “ Gas Chromatography ” technique for detection.

► “Bath Salts”, double punch on brain receptors ● Louis J. De Felice and his colleagues of Virginia Commonwealth University's School of Medicine in Richmond conducted research ● Based on research conclusion & presentation at 56th Annual Meeting of the Biophysical Society (BPS), held Feb in San Diego, California ● Article was also published on February 24, 2012 at 1:58 AM. " This combination of effects is particularly novel and unexpected.” ● effects on the brain’s dopamine transport system. ● producing combined effects similar to both methamphetamine (METH) and cocaine.

► “Bath Salts”, double punch on brain receptors (continued) ● methamphetamine & cocaine ○ operate in the brain in completely opposite ways ○ different kinetics ○ exacerbate the effect of either drug applied alone ● first component ○ mephedrone ○ like METH - causes the brain to release more dopamine ● second component ○ MDPV ○ like cocaine - is a dopamine reuptake inhibitor ● increase dopamine availability to receptors to both compounds

► “Bath Salts”, double punch on brain receptors (continued) ● Conclusion of research, the combination that is found in “ Bath Salts” ○ produce feelings of euphoria & other effects ○ long-lasting stimulation by MEPH and inhibition by MDPV is novel & unexpected ○ powerful physiological and neurological effect on users

► Unique properties (Based on following studies and research) ● According to rat studies led by pharmacologist Annette E. Fleckenstein, PhD, and colleagues at the University of Utah (Meth-Like Craving, Ecstasy-Like Brain Damage Found in Rat Studies of Bath Salts) ● Like meth, rats quickly develop a craving for mephedrone ● Like meth, mephedrone increases brain levels of dopamine ● Like ecstasy, mephedrone increases brain levels of serotonin

► Unique properties (continued) ● Like ecstasy, repeat doses of mephedrone damages the brain's ability to respond to serotonin ● Like both ecstasy and meth, mephedrone causes the body to overheat ● Conclusion of this study was : “its ability to cause dopamine release greater than MDMA may be particularly problematic in that, in comparison to MDMA, this drug may have enhanced abuse liability more resembling dopamine-releasing agents such as meth."

► Psychonaut Web Mapping Research Group. MDPV Report. London, UK: Institute of Psychiatry, King’s College London; (In process of publishing in the American Journal of Medicine) ● European project, involving 8 research centers in 7 countries, which identifies and categorizes novel drugs. ● It tracks trends in drug use based on information available on the Internet. ● Both mephedrone and methylenedioxypyrovalerone have been found in products advertised as bath salts. ● Details of this study can be found at

► Description of effects ● Physiological responses ◦ tachycardia ◦ hypertension ◦ vasoconstriction ◦ insomnia ◦ headache ◦ tinnitus ◦ dizziness ◦ overstimulation ◦ nausea/vomiting ◦ stomach cramps ◦ bruxism ◦ increased body temperature, chills, sweating ◦ pupil dilation ◦ breathing difficulty ◦ agitation ◦ hypertonia

► Description of effects (continued) ● Extended binges on MDPV have also been reported to produce severe come down effects similar to that of methamphetamine, characterized by ○ depression ○ lethargy ○ headache ○ anxiety ○ postural hypotension ○ lightheadedness ○ weakness of the muscles ○ severely bloodshot eyes ● usually subside within 4 to 8 hours

► Psychological effects ◦ euphoria ◦ increased alertness and arousal ◦ increased energy and motivation ◦ altered vision/visual distortions ◦ diminished perception ◦ decreased need for sleep ◦ irritability ◦ extreme paranoia ◦ mental stimulation/increased concentration ◦ increased sociability ◦ sexual stimulation/aphrodisiac effects ◦ mild empathogenic effects ◦ delusions of super-human strength and invincibility ◦ audio-visual hallucinations ◦ suicide, aggressive and violent behavior

► Duration of effects (Note: Duration of effects is highly dose-dependent.) Although LD50 is not known, although it is suggested that non-fatal overdose would be possible at relatively low dose compare to other stimulants. Stage Oral Insufflated Onset mins mins Coming Up mins mins Plateau mins mins Coming Down mins mins After Effects Hours Total duration: Hours Total duration: Hours

► Use In Combinations With Other Compounds ● Cannabis ● Alcohol ● Amphetamine ● GHB ● LSD or other hallucinogens ● Benzodiazepines ● Opiates

► Addictive/Abusive Properties of “Bath Salts” ● extreme/highly addictive property ● intense craving ● binging

► Long Term Effects of “Bath Salts” ● unknown, could be permanent ○ what damages ? ○ how long damage might last ? ○ long-term ramifications? ● limited studies and trial on humans ○ small changes in chemical composition can produce extremely different side effects ●further clinical research is required ○ to determine the long-term effects ○ how to effectively sedate patients suffering from toxic psychotic states

► “Bath Salt” Madness As per American Institute of Physics, “If you take the very worst of some of the other drugs– like LSD and Ecstasy with their hallucinogenic-delusional type properties As well as the stimulant properties of cocaine and Meth PCP with extreme agitation, superhuman strength and combativeness -if you take all the worst of those and put them all together this is what you get. It’s ugly.”

► “Bath Salts” are growing problem

► Google Insights for Search ● shows volume patterns for specific keywords across specific regions and time frame since 2004 ● graph with the search volume, indicating interest over time (GMT) for MDPV ● Plotted on scale from 0 to 100; the totals are indicated next to bars by the search terms, a breakdown of how the categories are classified, lists of the top searches and top rising searches, a world heat map graphically displaying the search volume index with defined regions, cities and towns.

► Google Insights for Search

► Dangers/Lethality of Using “Bath Salts” for Drug Use ● One man, Neil Brown, of Fulton, Miss., got high off the “Bath Salts” and then slashed his face and stomach. He survived, but authorities said other people have not been so lucky. In Brown's case, he said he had tried every drug from heroin to crack and was so shaken by terrifying hallucinations that he wrote one Mississippi paper urging people to stay away from the advertised bath salts. "I couldn't tell you why I did it," Brown said, pointing to his scars. "The psychological effects are still there.“

► Dangers/Lethality of Using “Bath Salts” for Drug Use (continued) ● In southern Louisiana, the family of a 21-year-old man says he cut his throat and ended his life with a gunshot while he was under the influence of the “Bath Salts”. ● Dr. Richard Sanders, a general practitioner working in Covington, La., said his son, Dickie, snorted some of the chemicals and endured three days of intermittent delirium. Dickie Sanders missed major arteries when he cut his throat. As he continued to have visions, his physician father tried to calm him. But the elder Sanders said that as he slept, his son went into another room and shot himself.

► Legislatures Worldwide: As per ACMD’s report on cathinone derivatives, following and many other nations have banned MDPV and/or Cathinone. ◦ United Kingdom ◦ Denmark ◦ Sweden ◦ Finland ◦ Ireland ◦ Hungary ◦ Netherland ◦ France ◦ Germany ◦ Australia ◦ Austria ◦ Portugal ◦ Poland ◦ Spain

► Legislatures (continued) United States : As per National Conference of State Legislatures (Updated July 11, 2012), following and other 42 states have banned MDPV & substituted cathinones ● Louisiana ● Florida ● New Jersey ● Kentucky ● Tennessee In state of TN: it a class A misdemeanor to knowingly produce, manufacture, distribute, sell, offer for sale or possess with intent to produce, manufacture, sell, or offer to sell any capsule, pill or other product composed of or containing any amount of the enumerated synthetic derivatives or analogues of methcathinone, or any combination of them.

► Nationwide Efforts

► Management/Treatment ● Supportive treatment key factor ● Sedatives e.g. benzodiazepines ● Antipsychotics

► “Bath Salt” Rehab ● “Bath Salts” Residential Addiction treatment centers across the nation are starting to see patients turning up with familiar addictive behaviors related to “Bath Salts”. ○ Medical detox ○ Counseling/Intensive Psychotherapy

► Learning Objectives ● Physicians should be aware that abuse of “Bath Salts” produces sympathomimetic toxidromes, and we advocate supportive treatment. ● Physicians should incorporate questions about such products when taking a social history and be prepared to counsel on safety and adverse effects.

References: 1.Deniker P, L. H. (1975). Abuse of Pyrovalerone by drug addicts. Annales Medico- Psychologiques, Institute of Psychiatry, King College. (2009). Psychonaut Web Mapping Research Group. MDPV report. 3.Schmidt MM, S. A. (2010). "Legal Highs"- on the net - Evaluation of UK- based websites, products and product information. Forensic science international, American Journal of medicine, 206(1-3): Westphal F, J. T. (2009). Mass and NMR spectroscopic characterization of Methelenedioxypyrovalerone - A designer drug with alpha-pyrroliinophenone structure. Forensic Science International, 190(1-3). 5. retrieved June 2011http:// 6. retrieved June 2011http://