Drug Abuse & Society (RX 462) Presentations-Spring 2014

1. RX462 Drug Abuse & Society Presentations: Spring 2014 Brian J. Piper, Ph.D., M.S. Department of Basic Pharmaceutical Sciences, psy391@gmail.com or piperbj@husson.edu

2. Contents Drug Author Classification Page psilocybin J. Graffam Hallucinogen 4-44 JWB-018 Matthew Rodney Hallucinogen 45-63 ayahuasca James Barbour Hallucinogen 64-80 mephedrone Anonymous #1* Stimulant 81-105 MDA Anonymous #2* Stimulant/ Hallucinogen 106-121 crack cocaine Joshua Prue Stimulant 122-143 Catha edulis Anonymous #3* Stimulant 144-164 areca nut Anna Levesque Stimulant 165-184 * name removed per student request

3. Contents (continued) Drug Author Classification Pages Kava kava Anan Hussein depressant 184-214 “krokodil” Alyssa Duron depressant 215-233 valerian Dale Stewart depressant 234-245 fenfluramine Anonymous #4* anorectic 246-264 * name removed per student request Each presenter was encouraged to include information about: -History -Epidemiology -Pharmacokinetics -Pharmacodynamics -Toxicology Disclaimer: All information is for educational purposes only. These presentations are not intended to encourage/discourage use.

4. Psilocybin/Psilocin J. Graffam

5. Psilocybin/ Psilocin “Magic Mushrooms” Hallucinogens Psychedelic Entheogen Psychotomimetic http://proudestjunkie.blogspot.com/2011/10/benefits-of-magic-mushrooms.html

6. Long ago….1,2 Earliest believed use- 7000 years ago Northern Algeria Shamanistic Mushroom Men

7. Not as long ago...1 ~400 years ago Aztecs used Teonanácatl for spiritual rituals Europeans ruined that http://www.fs.fed.us/wildflowers/ethnobotany/Mind_and_Spirit/teona nacatl.shtml

8. 19551,3 R. Gordon Wasson 1st outsider to participate in a mexican ritual Life magazine article brought mushrooms to America http://www.gnosticmedia.com/SecretHistoryMagicMushroomsProject

9. 19561,2,3 Roger Heim identified the mushroom as the Psilocybe genus

10. 19571,2,3 Albert Hoffman identified the psychoactive ingredient Psilocybin and its metabolite Psilocin

11. 19582,3 Hoffman synthesized Psilocybin Sandoz Labs sold the drug as Indocybin

12. 1960s2 Indocybin used for research into the mind Schizophrenia model American’s hippy movement was coming to life

13. 19701,2 Schedule I

14. Epidemiology3,4 No one is really sure Psychedelic use- ~20% PLoS One published 2013- 130,152 responders 14,413 mushroom users

15. How it supplied It’s illegal to own mushrooms…. But not the spores…

16. Typical oral doses2 Psychedelic effects- 15mg High dose- >25mg 2 grams of dried shrooms is a good dose

17. Intravenous2 1-2mg IV Really for research uses only

18. Kinetics- Oral2,4 Intestinal phosphatases cleave off phosphate Effects start 20-40 minutes Effects peak 80-90 minutes Aiming for psilocin levels 4-6ng/mL Effects last 4-6 hours

19. Kinetics IV2 Tissue phosphatases activate drug Effects start- 1-2 minutes Peak in 5 minutes Only last 20 minutes however

20. Metabolism4

21. Kinetics2,4 t1/2- 2.5 hours Most excretion in first 4 hours Totally excreted in 24 hours

22. Pharmacodynamics2,4 Very selective Ki 5-HT2A= 6 nM 5-HT1A= 190 nM 5-HT2C= 410 nM No dopamine (Well very little)

23. 5-HT2A Signaling1,6 But lets see why this induces a psychedelic trip

24. “Opening the thalamic filter”1,6 “It becomes easier to notice things that would normally not reach your awareness, for all senses.”

25. 5-HT2A isn’t the whole story7 5-HT2A-mGluR2/3 Heterodimers

26. 5-HT2A-mGluR2/38 Other hallucinogens but same receptor

27. Hallucinogen specific gene expression8 Early growth response elements

28. Induced by hallucinogens4,8 c-fos, BDNF, egr-1 and -2, arc Synaptic firing Gliogenesis Neurogenesis Plasticity Learning/memory

29. Other neurotransmitters2 5-HT increase in dopamine- decreased raclopride binding Haloperidol- Decreased psychotomimetic effects, but not visual effects Ketanserin/Risperidone- Block effects Sooo… Other NTs matter, but 5-HT2A mediates it all

30. “Set and Setting”9 The most important factors for a good trip!!!

32. Effects of Psilocybin2,4,9,10 Enhanced perception Altered self-perception; depersonalization Derealization- Dream like state Hallucinations Anxiety

33. /u/grbaic

34. Toxicities2,4,10,11 No organ toxicities No changes in lab values (small elevation in prolactin) LD50 rats- 280mg/kg 1 death- psilocin blood levels of 4µg Another death from Wolfe-Parkinsons White Syndrome- MI

35. Toxicities2,4,5,10 Long term psychological problems- Anxiety, depression, depersonalization, HPPD- very very small chance- Healthy pt risk- 0.08% Pt with psychiatric disorder- 0.18% PLoSONE- no increased risk of psychiatric disorder Anxiety, Panic attacks, hypertension, renal failure

36. Hypertension10 Not exactly hypertensive crisis, but something to worry about

37. Lets take a look at the WPWS...11 Yeah the kid died but… Renal failure…? never heard of that one before. Lets investigate.

38. Ohh… well then...

39. Toxicities2,4,5,10 Long term psychological problems- Anxiety, depression, depersonalization, HPPD- very very small chance- Healthy pt risk- 0.08% Pt with psychiatric disorder- 0.18% PLoSONE- no increased risk of psychiatric disorder Anxiety, Panic attacks, hypertension, renal failure

40. Therapeutic uses11 OCD- Kinda; worked extremely well during the trip and for some time after

41. Therapeutic uses Smoking for nicotine addiction In progress- check out John-Hopkins stuff High long term success rate Using the psychedelic nature of the drug for mental empowerment to quit https://www.youtube.com/watch?v=RHc60goAxv8

42. Abuse2,13 Not an issue really at all monkey models show there is no seeking of the drug Tolerance is rapid!- 38% decrease in 5-HT2Ain just a couple doses

43. Citations 1. Gadiot C. Cognitive mechanisms of psilocybin: Review and theoretical framework for future research. [Honor’s Thesis]. Middelburg, Netherlands: Roosevelt Academy; 2010. 2. Filip T, Tomáš P, Jiří H. Psilocybin – Summary of knowledge and new perspectives. Eur Neuropsychopharmacol. 2014;24(3):342-356. 3. Hoffman A. Teonanácatl and Ololiuqui, two ancient magic drugs of Mexico. Bulletin on narcotics. 1971;1:3-14. 4. Jerome L. Psilocybin: Investigator’s Brochure. Multidisciplinary Association of Psychedelic Sciences. 2007. Available at http://www.maps.org/research/psilo/psilo_ib.pdf. 5. Krebs TS, Johansen P-Ø. Psychedelics and mental health: A population study. PLoS ONE. 2013;8(8):e63972. 6.Vollenweider FX. Brain mechanisms of hallucinogens and entactogens. Dialogues Clin Neurosci. 2001;3(4):265–279. 7. Gonzalez-Maeso J. GPCR oligomers in pharmacology and signaling. Molecular Brain. 2011;4:20. 8. Moreno JL, Holloway T, Albizu L, Sealfon SC, Gonzalez-Maeso J. Metabotropic glutamate mGlu2 receptor is necessary for the pharmacological and behavioral effects induced by hallucinogenic 5-HT2A receptor agonists. Neurosci Lett. 2011;493:76–79. 9. Studerus E, Gamma A, Kometer M, Vollenweider FX. Prediction of psilocybin response in healthy volunteers. PLoS One. 2012; 7(2): e30800. 10. Griffiths RR, Johnson MW, Richards WA, McCann I, Jesse R. Psilocybin occasioned mystical-type experiences: Immediate and persisting dose-related effects. Psychopharmacology (Berl). 2011;218:649–665. 11. Borowiak KS, Ciechanowsld K, Waloszczyk P. Psilocybin mushroom (Psilocybe seilanceaïa) intoxication with myocardial infarction. Clinical Toxicology. 1998;36:47-49. 12. Moreno FA, Wiegand CB, Taitano EK, Delgado PL. Safety, tolerability, and efficacy of psilocybin in 9 patients with obsessive-compulsive disorder. J Clin Psychiatry. 2006;67:11. 13. Buckholtz NS, Zhou D, Freedman DX, Potter WZ. Lysergic acid diethylamide (LSD) administration selectively downregulates serotonin2 receptors in rat brain. Neuropsychopharm. 1990;3:137-148.

44. JWH-018 Presented by Matthew Rodney https://recovergateway.files.wordpress.com/2012/09/k2.jpg http://yourteenmag.com/wp-content/uploads/2012/02/spice.jpg

45. Introduction1 • JWH-018 is one member of a growing class of powerful synthetic cannabinoids often marketed in a combination known as “spice” or “K2” • Sold as herbs and spices laced with chemicals and typically smoked • Until 2011, a “legal high” • Similar psychotropic effects to Δ-9- tetrahydrocannabinol (THC), the primary active component of marijuana, but MUCH more potent • MUCH more serious adverse effects; life-threatening http://countyourculture.com/wp-content/uploads/2010/12/jwh-018-napsubs.png

46. History1 • In the 1960s, Israeli medicinal chemist at Hebrew University Raphael Mechoulam isolated THC from marijuana and elucidated the inner workings of the endocannabinoid system • Research on THC continued for the ensuing decades to further understand the endocannabionoid system and discover medical applications of the drug http://www.arizonamedicalmarijuanablog.com/wp-content/uploads/2012/09/drmechoulam1.jpg

47. John W. Huffman (hence “JWH”)1 • In the early 1990’s, medicinal chemist John W. Huffman of Clemson University received a grant from the National Institute of Drug Abuse (NIDA) to study cannabinoids • Together with his team, he developed hundreds of cannabinoid mimetic chemicals, including JWH-018 and JWH-073 • The distinguishing feature of most of the drugs in this class is that they are full CB1 agonists, where the naturally occurring THC is a partial CB1 agonist • Within a few years, street chemists synthesized these drugs and mass marketed them as “herbal incense” under generic trade names “Spice” and “K2” http://www.ces.clemson.edu/earnest/fall_wint_05/facStaff/images/Huffman.gif

48. From “legal high” to Schedule I1,2 • Synthetic cannabinoids were initially unregulated and could be bought online or in smoke shops • JWH-018 one of the most popular since it’s relatively easy to synthesize and potent • Cases of serious toxicity began appearing in the news and became widely circulated • Government got involved to crack down on usage • Five common synthetic cannabinoids including JWH-018 temporarily criminalized in U.S. in 2011by emergency powers • Formally classified as Schedule I in 2012 by Synthetic Drug Abuse Prevention Act • Street chemists avoid prosecution by developing new slightly modified synthetic cannabinoids that haven’t yet been criminalized and can’t be detected in drug tests

49. Spice/K21 • Sold as various inert herbs which physically resemble marijuana laced with synthetic chemicals • Primarily smoked, though sometimes also ingested orally. No reports of snorting or injecting • Rarely sold on the street as a pure chemical – Many unknown chemicals sold together – Synergy increases potency and adverse effects • Pure powder form formerly available online “Bonsai Fertilizer” http://www.adsinusa.com/adphotos.htm?id=3826o4302

50. Can you tell marijuana apart from spice? http://seminolepreventioncoalition.org/_images/k2-spice-image1.jpg http://nocamels.com/wp-content/uploads/2013/09/bigstock-Medical-Marijuana-48404087.jpg

51. “Spiced Out” by PippUK3 • “I imagined some chemistry boffin tinkering slightly with the proposed structure of a hypothetical THC analogue, a la Shulgin or Nichols. Except this guy just happened to have successfully suppressed all known euphoric properties of the original, and even intensified the dysphoric.” • “But, here is this cannabinoid and its given me a dose of paranoia, and my mouth is as dry as the inside of Ghandi's flip flop. As I laid there in bed I went on to have a full on panic attack, the like of which I have never had before.” • “The paranoid thoughts reached a crescendo of pointless gnashing of 'what if's and other self loathing nonsense that seemed to suddenly embody themselves in my minds eye, and my breathing became shallow and fast.”

52. PippUK continued3 • “…my heart beat began to ramp up frighteningly and I could feel the very sudden strong jerks of that poor muscle in my chest. And I felt that each breath was scarcely enough to deliver the oxygen I needed. I was really quite scared at that point.” • “… this JWH-018, if it is the active compound in Spice, did well and truly whupp this hardened weedsmoker most surprisingly.”

53. Structure http://www.emcdda.europa.eu/attachements.cfm/att_90881_EN_JWH-018.gif JWH-018 http://www.godandscience.org/images/thc.gif http://lipidlibrary.aocs.org/Lipids/amides/Figure1.png

54. Pharmacodynamics1,4 • JWH-018 is a full agonist of CB1 receptors in CNS – CB1 receptors found on GABA-ergic and glutaminergic neuron axons. – THC is a partial CB1 agonist • In vivo mouse studies show that JHW-018 has MUCH higher affinity for CB1 receptor than THC (10 times higher) with many active metabolites that retain affinity equal to or greater than that of THC – A 3 mg injection of JWH-018 showed as much of a reduction on mouse exploratory behavior over 10 hours as 30 mg of THC • Synthetic cannabinoids often come in unknown combinations with synergistic effects

55. Effects1 • CNS – Deficits in working memory – Euphoria – Sedation – Anxiety – Irritability – Confusion – Psychosis – Seizure Physical Nausea Diaphoresis Mydriasis Xerostomia Palpitations Tachycardia Convulsions http://www.anylabtest-san-antonio.com/wp-content/themes/lab/images/k2-drug-test.jpg

56. Toxicity1,5,6,7 • JWH-018 causes profound toxicity not seen with marijuana • Multiple case reports of acute myocardial infarction in healthy teenagers after use • Case report of seizure within as little as 30 minutes after use of pure JWH-018 • Psychotic symptoms with long term use in those exhibiting no symptoms before • Exacerbation and reemergence of psychotic symptoms in those predisposed to it • Some of the synthetic cannabinoids besides JWH-018 sometimes sold in spice (JWH-015 , JWH-133) can suppress immune function by agonism of CB2 receptors

57. Huffman says…8,9 • "Apparently somebody picked it up, I think in Europe, on the idea of doping this incense mixture with the compound and smoking it." • "You can get very high on it. It's about 10 times more active than THC." • "It's like playing Russian roulette. You don't know what it's going to do to you." • "You're a potential winner of a Darwin award.“ • “People who use it are idiots.” http://a.abcnews.go.com/images/Blotter/ht_john_huffman_jef_110606_wmain.jpg

58. Pharmacokinetics1,10 • Pharmacokinetic profile not well understood – No in-depth studies done in humans • Involves CYP450 enzymes – CYP2C9 and CYP1A2 especially • Phase 2 enzymes involved in elimination, namely glucoronidases • Eliminated primarily in urine • Highly fat soluble (like THC)

59. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3936256/figure/F2/

60. Epidemiology1,11,12 • According to a recent “Monitoring the Future” internet survey, 11% of high school seniors admitted to using spice • 8% of college students admitted use in another survey in Miami, Florida • Males use it more often than females • 3 types of users identified – Regular weed smokers – Occasional drug users trying to avoid prosecution – Curious experimenters trying out drugs • Very often used along with marijuana (surprise!) and other drugs such as alcohol and cigarettes

61. Conclusion • Legal efforts to prevent use of synthetic cannabinoids continue due to progressive development of new entities • Highly dangerous designer drug • Not a substitute for weed! • Don’t try this at home…or anywhere! http://img.wikinut.com/img/1.txrs6m86_kfzkj/jpeg/724x5000/Hippie-hair.jpeg http://www.rsc.org/images/C0AY00200c-300-FOR-TRIDION_tcm18-181877.jpg http://skullappreciationsociety.com/wp-content/uploads/2012/05/joe_king_skull_2.jpg

62. Citations • 1. Seely KA, Lapoint J, Moran JH, Fattore L. Spice drugs are more than harmless herbal blends: a review of the pharmacology and toxicology of synthetic cannabinoids. Prog Neuropsychopharmacol Biol Psychiatry. 2012;39(2):234-43. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3936256/ • 2. Palmer K, Houck L. Citing Imminent Hazard to Public Safety, DEA Temporarily Places Synthetic Cannabinoids Into Schedule. http://www.fdalawblog.net/fda_law_blog_hyman_phelps/2011/03/citing-imminent-hazard-to- public-safety-dea-temporarily-places-synthetic-cannabinoids-into-schedule-.html. March 2, 2011 • 3. PippUK. "Spiced Out: An Experience with Spice Products (Various) (ID 76319)". Erowid.org. Jan 25, 2009. erowid.org/exp/76319 • 4. Brents LK, Reichard EE, Zimmerman SM, Moran JH, Fantegrossi WE, Prather PL. Phase I hydroxylated metabolites of the K2 synthetic cannabinoid JWH-018 retain in vitro and in vivo cannabinoid 1 receptor affinity and activity. PLoS ONE. 2011;6(7):e21917. • 5. Mir A, Obafemi A, Young A, Kane C. Myocardial infarction associated with use of the synthetic cannabinoid K2. Pediatrics. 2011;128(6):e1622-7. • 6. Lapoint J, James LP, Moran CL, Nelson LS, Hoffman RS, Moran JH. Severe toxicity following synthetic cannabinoid ingestion. Clin Toxicol (Phila). 2011;49(8):760-4. • 7. Hurst D, Loeffler G, McLay R. Psychosis Associated With Synthetic Cannabinoid Agonists: A Case Series. Am J Psychiatry 2011;168:1119-1119. • 8. Fake Pot that Acts Real Stymies Law Enforcement. http://www.nbcnews.com/id/35444158#.U2G1xPldW0M. February 2, 2011. • 9. Bryner J. Fake Weed, Real Drug: K2 Causing Hallucinations in Teens. http://www.livescience.com/6149-fake- weed-real-drug-k2-causing-hallucinations-teens.html. March 03, 2010 • 10. 4. Chimalakonda KC, Seely KA, Bratton SM, et al. Cytochrome P450-mediated oxidative metabolism of abused synthetic cannabinoids found in K2/Spice: identification of novel cannabinoid receptor ligands. Drug Metab Dispos. 2012;40(11):2174-84.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3477201/ • 11. Vandrey R, Dunn KE, Fry JA, Girling ER. A survey study to characterize use of Spice products (synthetic cannabinoids). Drug Alcohol Depend. 2012;120(1-3):238-41. • 12. Castellanos D, Singh S, Thornton G, Avila M, Moreno A. Synthetic cannabinoid use: a case series of adolescents. J Adolesc Health. 2011;49(4):347-9.

63. AYAHUASCA James Barbour

64. DMT • N,N-Dimethyltryptamine • Psychedelic Hallucinogen • Tryptamine – Monoamine Alkaloid DMT 5-HT 4-PO-DMT

65. Psychedelic Effects • Experience is recognized as a ‘trip’ – Dissimilar from LSD, Psilocybin, and other psychedelics • Has been described as a link between ‘our reality’ and a ‘spiritual reality’ • Time perception severely altered • 5-HT2A Agonism: MOA for hallucinations • Oddly similar consistencies in ‘trip’ – Sounds – Entities – Environment

66. Subjective Interpretations of ‘Trip’ “The first thing I noticed was a burning in the back of my neck. Then there was this loud intense hum. It was like the fan at first, but separate. It began engulfing me. I let go into it and then . . . WHAM!” “DMT has shown me the reality that there is infinite variation on reality. There is the real possibility of adjacent dimensions… It's not a hallucination, but an observation. When I'm there, I'm not intoxicated. I'm lucid and sober."

67. Common ‘Trip’ Features “There was the usual sound: pleasant, a roar, a sort of an internal hum.” “There is a sound, a bzzzz. It started off (subtly) and got louder and louder and faster and faster." “It started with a sound. It was high-pitched like a tightly taut wire." “There was the sound of the entire universe, more like a hum. It was pervasive, overwhelming." SOUNDS

68. Common ‘Trip’ Features “That was real strange. There were a lot of elves. They were prankish...” "There were lots of beings. They were talking to me but they weren't making a sound." “They were reptilian and humanoid, trying to make me understand, not with words, but with gestures.” “Then I felt like I was suddenly in the presence of an alien or of aliens, vaguely humanoid." "They were like clowns or jokers or jesters or imps. There were just so many of them doing their funny little thing.” ENTITIES OBSERVED

69. Common ‘Trip’ Features “It's a different world. Amazing instruments. Machine-type things. There was one person operating some of this stuff. I was in a big room; he was in another part of it.” “There was a movement of color. The colors were words. I heard what the colors were saying to me." ENVIRONMENT

70. DMT Biological Distribution • Proposed existence in a variety of plants and animals – Mammals (Humans, Rats, Rabbits) – Many plants (Psychotria viridis) • L-Tryptophan metabolite • Biological importance unclear but often theorized – Dreams – Birth/Death

71. DMT in Mammals • Pineal Gland – Theorized ‘storage compartment’ – Hypothesized release upon entrance/exit of life • Monoamine Oxidase – Blocks DMT from being orally active via First-Pass Metabolism – Removes active DMT from synaptic cleft by enzymatic degradation • Limits duration of ‘trip’ to roughly 10-15 minutes

72. AYAHUASCA + = Psychotria viridis (DMT containing plant) Ayahuasca (B. Caapi) Contains Harmaline MAO-I (RIMA) AYAHUASCA DECOCTION

73. General Properties • Extended DMT ‘trip’ – Roughly 3-5 hours depending on dose • Delayed Onset – Tmax peak: 110 minutes +/- 30 minutes • Enhanced control/grasp of ‘trip’ “I think that the shamans in South America use other plants to fill out and make the DMT more reasonable. Pure DMT seems empty or hollow."

74. History • Napo Province of Ecuador – Estimated use began around 1500-2000 B.C. – Shamanistic rituals • Expansion to urban Brazil (1500s) – Santo Daime (1930s) – Uniao do Vegetal (UDV, 1961) • Research scientists introduced ayahuasca to western civilizations

75. Use and Potential Abuse • Use of DMT has grown in recent history • Global Drug Survey 2010 (22,289 respondents) – Lifetime prevalence = 8.9% – Past year prevalence = 5.0% – 472 ‘last new drug used for first time’ – New users = 24% • Low abuse potential due to low urge to use more (although effects seen as desirable)

76. Legislative Regulations • DMT is a Schedule I Controlled Substance in it’s pure form (i.e. solution, crystallized, etc.) • Plants used in the brewing of Ayahuasca are not regulated. However, there are legal issues surrounding their use in brewing of decoction • Religious groups have protested for use ceremonially – UDV – Santo Daime

77. Toxicology • Not thoroughly investigated • Self-limiting (by person) • Possible Serotonin Syndrome (20x avg. dose) • Naïve exposure to DMT – Effects on physiology markedly increased • Serum ACTH, BP, HR, etc. • Chronic exposure to DMT – Effects on physiology become less dramatic – No impact on dose dependent hallucinations

78. “Spiritual Enlightenment” “I was trying to look out, but they were saying, 'Go in.' I was looking for God outside. They said, 'God is in every cell of your body.’ And I was feeling it, totally open to it, and I kept opening to it more, and I just took it in…That God is in everything and that we are all connected, and that God dances in every cell of life, and that every cell of life dances in God."

79. Death and Dying “Everyone should try a high dose of DMT once. I don't know if the beings today were saying "Try death once" or "Try life once." That place is so full and so complete that the idea of this place is to try and be as complete as possible. Yet when I came back into my body it was so heavy and so confining. Also, time here seems so strange. Eternity is an attribute of the place. It would have to be."

80. Presented by Anonymous #1

81. History 2,8 http://www.thenakedscientists.com/HTML/uploads/RTEm agicC_Gatecrasher.jpg.jpg • First Synthesized by Saem de Burnaga Sanchez in 1929 • Rediscovered in Early 2000 • Became Popular among UK clubbers 2007 • Spread Through Europe then the US • Had many Street Names • Meow • Miaow Miaw • Bubbles (mixed w/methylone) • Meph • … Saem de Burnaga Sanchez, http://cannabisymas.com/

82. • Popularity boomed exponentially – ‘Legal High’ • Less legal complications – Easy access • Local Stores / Mom and Pop shops • Internet – Cheaper then its alternatives History 2,8

83. Mephedrone suspected deaths in the UK – May 2010 2

84. MDMA, Piperzine, Cathinone Derivatives Seizure records Jul 2005 – Mar 2010 Europe2

85. Legal Status2,8,9 • Uncontrolled until 2008 – Sweden first country to outlaw Mephedrone – Denmark Followed – 2009 Estonia – 2010: Germany, Netherlands, UK …

86. USA9 • Component of Bath Salts – Marketed as not for human consumption – Legal for a period of time • 2011 made Schedule 1 drug under Title 21 FDA, designation number 1248 (temporary scheduling). usamania.wikispaces.com

87. Dosage Form & Administration2,8 • Mephedrone comes in many different forms: – Capsules – Tablets – White Powder • Administration – Intranasally – Orally – Smoke – Inject – Rectally

88. Pharmacological Effects10 • Euphoria • Energy • Empathy (feeling of closeness) • Visual and auditory hallucinations • Paranoia • Anxiety Mark Dominique, PharmD, LCSW Husson UniversityApril 10, 2014 news.vanderbilt.edu

89. Side Effects2,4,6,8  Delirium  Aggression  Agitation  Tachycardia  Anxiety  Panic attacks  Paranoia  Hyperthermia  Excessive Sweating  Stroke  Hyperthermia  Hallucination  Seizures  Elevated CK, LFT  Suicidality  Cerebral edema  Insomnia  Myocardial infarction  SVT  Vasoconstriction  Hypertension  Rhabdomyolysis  Cyanosis  Arrhythmias  Metabolic acidosis Mark Dominique, PharmD, LCSW Husson UniversityApril 10, 2014

90. Self-Reported Side Effects of Mephedrone users in the UK Club Scene (Online Survey, N = 947)8

91. Bath Salts Toxicity Tx10 • Supportive – Fluid – Cooling – Vitals – Electrolytes • Agitation – Lorazepam 2 mg PO or IM – Antipsychotics 2nd line starcasm.net

92. Mephedrone vs Cocaine A Better High?8

93. 4-methylmethcathinone Cathinone

94. Structural Comparison with other Psychoactive Agents MDMA Methamphetamine Cocaine Tertiary Amine Secondary Amine

95. Synthesis7 Stereoselective Synthesis *** Don’t try at Home

96. Metabolism6 N-Demethylation 1. Mephedrone 2. Nor-mephedrone 3. Nor-dihydro-mephedrone 4. Nor-dihydromephedrone 5. Carboxytolyl-mephedrone 6. Nor-OH-tolyl-mephedrone 7. HO-tolyl Mephedrone Oxydation Reduction Can be detected in Urine!!!

97. Effects of Mephedrone on DA & 5HT3 • Sprague-Dawley rats (290-400g) • Binge injected with mephedrone, – 4X 10 or 25 mg/kg s.c. every 2h. • MDMA, Cocaine and Methamphetamine groups also injected • Control group injected with Saline • Rats sacrificed 1 h after last dose • Self administration models for mephedrone and methamphetamine also conducted for 8 days

98. Results3

99. Results cont.3

100. Results cont.3

101. Dopamine Nerve Ending Neurotoxicity1 • Female C57BL/6 mice (20-25g). • Injected with 20 or 40 mg/kg of mephedrone q2h X 4 • Regimen is known to cause neurotoxicity with methamphetamine • Control group treated with saline. • The mice were sacrificed at 2 or 7 days and analyzed for nerve damage. • Day 2 & 7 mephedrone did not change the striatal DA content • tyrosine hydroxylase and dopamine transporter (indicators of drug induced nerve damage) were also not affected. • Activation of microglia and astrocytes (regional indicators of striatal damage) was also not present

102. Conclusion • Mephedrone has a short history as a recreational drug. • It is currently Controlled in most of the western hemisphere • It increases dopamine and 5HT levels • Does not appear to cause dopamine nerve damage • Has high potential for abuse • Has a variety of serious side effects – May cause Death • Further studies needed

103. Reference 1. Angoa-Pérez M, Kane MJ, Francescutti DM, et al. Mephedrone, an abused psychoactive component of 'bath salts' and methamphetamine congener, does not cause neurotoxicity to dopamine nerve endings of the striatum. J Neurochem. 2012 Mar; ;120(6):1097-107. 2. Europol–EMCDDA Joint Report on a new psychoactive substance: 4-methylmethcathinone (mephedrone)". European Monitoring Centre for Drugs and Drug Addiction. 2010 3. Hadlock GC, Webb KM, McFadden LM, et al. 4-Methylmethcathinone (mephedrone): neuropharmacological effects of a designer stimulant of abuse. J Pharmacol Exp Ther. 2011; Nov;339(2):530-6 4. Martínez-Clemente J, López-Arnau R, Carbó M, Pubill D, et al. Mephedrone pharmacokinetics after intravenous and oral administration in rats: relation to pharmacodynamics. Psychopharmacology. 2013; 229(2):295-306. 5. Meyer MR. Metabolism and pharmacokinetics of designer cathinones. Biological Psychiatry. Conference: 67th Annual Scientific Convention and Meeting of the Society of Biological Psychiatry Philadelphia, PA United States. Conference Start: 20120503 Conference End: 20120505. Conference Publication: (var.pagings). 2012.

104. Reference cont. 6. Ribeiro E, Magalhaes T, Dinis-Oliveira RJ. Mephedrone, the new designer drug of abuse: Pharmacokinetics, pharmacodynamics and clinical and forensic issues. Acta Medica Portuguesa. 25 (2) (pp 111-117), 2012. 7. Schifano F, Albanese A, Fergus S, et al. Mephedrone (4-methylmethcathinone; 'meow meow'): chemical, pharmacological and clinical issues. Psychopharmacology (Berl). 2011 Apr;214(3):593-602. 8. Winstock AR, Mitcheson LR, Deluca P, et al. Mephedrone, new kid for the chop? Addiction. 2011;106(1):154-61 9. 2009 National Report (2008 data) To the EMCDDA by the Reitox National Focal Point – Denmark . 2009 10. Mark Dominique, PharmD, LCSW Husson University, April 10, 2014

105. 3,4-Methylenedioxyamphetamine (MDA) Anonymous #2 Drug Abuse April 8, 2014

106. Also Known As • Love Drug • Love Pill • Sass • Sass-a-frass • Not to be confused with: – MDMA – Ecstasy wikipedia.org

107. Other Information • Systematic (IUPAC) name – (R) 1-(benzo[1,3]dioxol-5-yl)propan-2-amine • Clinical data – Legal status • Schedule I (US) • Schedule III (CA), Class A (UK), Prohibited (S9) (AU), – Routes of Administration • Oral • Sublingual • Intranasal • Intravenously • Rectally

108. MDA History • Synthetic Amphetamine Derivative • Metabolite of MDMA – Pheylethylamine Hallucinogen • First synthesized in 1910 – G. Mannish & W. Jacobson – Smith Kline & French licensed in 1930 • Parkinson’s disease • Antidepressant and/or anorectic – Truth Drug – Cough Suppressant in 1958 by H.D. Brown • Designer club drug in the 60’s – Used by young adults – Use associated with raves and dance clubs

109. PD • Causes an increase in the release – Serotonin – Dopamine – Norepinephrine

110. PK • Largely unknown • Duration of effects – ~ 8 - 12 hours – Some effects can last ~48 hours • Absorption – Readily absorbed in the GI tract

111. Online User Account • “With 100 mg, the coming on was gradual and pleasant, taking from about 1-1 ½ hours to do so. The trip was intense….One thing that impressed itself upon me was the feeling I got of seeing the play of events, of what I thought to be significance of certain people coming into my life, and why my ‘dance’ is unique.” • “After taking 140 mg, I vomited quite abruptly, and then everything was OK….The tactile sense is beautiful, but there seems to be some numbness as well, and I feel that nothing erotic would be doable. Intimacy, yes, but no performance I’m pretty sure. I saw the experience start drifting away only four hours into it and I was sad to see it go. I was an all-around delightful day.”

112. MDA Effects • Positive Effects – Elevated mood – Stimulation – Feelings of comfort and acceptance – Feelings of love and empathy – Increased musical appreciation – Increased sensory awareness • Neutral Effects – Visual distortions – Mild visual hallucinations – nystagmus • Negative Effects – Elevated heart rate – Elevated blood pressure – Restlessness – Anxiety – Changes in body temperature regulation – Excessive teeth grinding – Difficulty concentrating – Muscle tension – Erectile dysfunction – N & V

113. Long Term Negative Effects • Psychological – Depression, severe anxiety, paranoia sleep disturbances • Physical – Muscle tension, teeth clenching, nausea, blurred vision, rapid eye movements, chills, faintness • High doses – Sharp increase in body temp, muscle breakdown, kidney & cardiovascular system failure*** • Long-Term use – Liver damage, brain damage • Brain damage is due to the destruction of serotonin producing neurons which leads to problems regulating mood, pain, sleep, and aggression

114. MDMA vs. MDA • Frontal Cortex – 2 weeks after receiving 8 doses (20 mg/kg) of MDMA or MDA – Control group saline only

115. MDMA vs. MDA Parietal Cortex

116. MDMA vs. MDA Visual Cortex

117. Epidemiologic Use in Maine

118. References • Buchanan JF, Brown CR. 'Designer drugs'. A problem in clinical toxicology. MedTox Adverse Drug Exp 1988; 3:1. • Colado MI, Williams JL, Green AR,. The hyperthermic and neurotoxic effects of Ectasy (MDMA) and 3,4 Methylenedioxyamphetamine (MDA) in the Dark Agouti (DA) rat, a model of the CYP2D6 poor metabolizer phenotype. BJ Pharm. 1995; 118:1281-9. • Hensley D, Cody JT,. Simultaneous Determination of Amphetamine, Methamphetamine, Methylenedioxyamphetamine (MDA), Methylenedioxymethamphetamine (MDMA), and Methylenedioxyethylamphetamine (MDEA) Enantiomers by GC-MS. J An Tox. 1999; 23: 1-6. • Liu RH, Liu HC, Lin DL. Distribution of Methylenedioxymethamphetamine (MDMA) and Methylenedioxyamphetamine (MDA) in Postmortem and Antemortem Specimens. J An Tox 2006; 30: 545-550. • Maurer HH, Kraemer T, Springer D, Staack RF. Chemistry, pharmacology, toxicology, and hepatic metabolism of designer drugs of the amphetamine (ecstasy), piperazine, and pyrrolidinophenone types: a synopsis.Ther Drug Monit 2004; 26:127. • Noogle FT, DeRuiter J, Coker ST, Clark CR,. Synthesis, Identification, and Acute Toxicity of some N-Alkyl Derivatives of 3,4- Methylenedioxyamphetamine. 1987. 70(6):981-6. • O’Heam E, Battaglia G, De Souza EB, Kuhar MJ, Molliver. Methylenedioxyamphetamine (MDA) and Methylenedioxymethamphetamine (MDMA) Cause Selective Ablation of Serotonergic Axon Terminals in Forebrain; Immunocytochemical Evidence for Neurotoxicity. J NeuroSci 1988; 8:2788-2803. • Poklis A, Mackell MA, Drake WK. Fatal intoxication from 3,4-methylenedioxyamphetamine. J Forensic Sci 1979; 24:70. • DeLetter EA, Espeel MF, Marijke EC, et. al., Immunohistochemical demonstration of the amphetamine derivatives 3,4- methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxyamphetamine (MDA) in human post-mortem brain tissues and the pituitary gland. Int J Legal Med. 2003; 117:2-9. • Stout PR, Horn CK, Klette KL,. Rapid Simultaneous Determination of Amphetamine, Methamphetamine, 3,4- Methylenedioxyamphetamine, 3,4.Methylenedioxymethamphetamine, and 3,4-Methylenedioxyethylamphetamine in Urine by Solid- Phase Extraction and GC-MS: A Method Optimized for High-Volume Laboratories. J Analy Tox 2002; 26:1-9. • Todd G, Noyes C, Flavel SC, et. al., Illicit Stimulant use Is Associated with Abnormal Substantia Nigra Morphology in Humans. PLoS ONE. 2013; 8:1-8

119. Crack Cocaine Joshua Prue

120. Objectives - Differentiate between cocaine and crack cocaine - Know the different routes of administration and pharmacokinetics of cocaine - Know which receptors crack works on - Explore patterns of use throughout the United States

121. Cocaine1,2 - Cocaine refers to the powdered form of the drug, cocaine hydrochloride. - Common street names include: blow, coke, dust. - Most commonly snorted, but can also be dissolved in water and injected intravenously. - Obtained from the leaves of the coca plant. http://moroccantimes.com/wp-content/uploads/2014/03/cocaine.jpg

122. Crack Cocaine1,2 - Most commonly called crack. - Cocaine HCl must be converted into its base form, crack, in order to be smoked. - Widely considered the most addictive form of cocaine.

123. History of Crack1,2,3 - Crack use was first observed in the mid 1980s. - Primarily seen in the projects of Miami, New York, and Los Angeles. - Created as a means to get a stronger high off less drug. - Associated with low socioeconomic status.

124. Epidemiology2 -Most common in: -Males - 20s - Unemployed - Urban areas http://1.bp.blogspot.com/-D4-VcT-tdyU/T6nfkqfzPNI/AAAAAAAABp8/1rhDqieTh94/s1600/Tyrone2.jpg

125. Smoking Crack1,2 - Cocaine base has a melting point of 98oC. - Vaporized at a lower temperature, which destroys little of the product. - Cocaine HCl melts at 195oC. At this temperature, much of the drug is destroyed before vaporization occurs. http://i.huffpost.com/gen/1143888/thumbs/s-BUY-ROB-FORD-CRACK-VIDEO-large.jpg?6

126. Pharmacokinetics2,4 Cocaine - After nasal insufflation, cocaine is absorbed through the vasculature in the nasal mucosa. - Absorption is self-limiting due to its vasoconstrictive properties. - Peak ‘high’ occurs 30-60 minutes after insufflation -Effects last nearly 30 minutes

127. Pharmacokinetics1,2,4,5 Crack - When smoked, drug is absorbed through the alveoli directly into circulation. - Effects are seen within seconds. - ‘High’ is more intense and comes on much more quickly. - Lasts roughly 5-10 minutes.

128. Neurotransmitter Effects1,2,4,5,6 - Cocaine is a CNS stimulant that causes a large release of dopamine within the brain. - Cocaine also binds the dopamine transporter, inhibiting the reuptake of dopamine from the synapse. - Higher concentrations of dopamine in the synapse leads to increased binding of the postsynaptic dopamine receptors. - Cocaine also interferes with the reuptake of norepinephrine, causing sympathomimetic effects.

129. Psychological Effects1,5 -Delirium -Psychosis -Paranoia -Dependence -Addiction -Depression

130. Addiction to Crack1,2,4,5,6 - Snorting cocaine takes longer to get into the system and to the brain than crack does based on sites of administration and ease of absorption. - Faster effects after administration coupled with a stronger high lead to addiction more quickly.

131. Addiction5 - The subject develops rapid tolerance, requiring more and more each time to get the desired effect. - Withdrawal symptoms can commence soon after first dose wears off.

132. Withdrawal2 Symptoms generally onset quickly: -Extreme fatigue -Intense cravings -Irritability -Sweating -Psychosis -Depression -Anhedonia http://www.brighteyecounselling.co.uk/images/alcohol-withdrawal.gif

133. Physiological effects http://drugabuse.com/wp-content/uploads/crack_cocaine_main_physiological_effects_image-279x300.png Physiological effects of crack

134. Effects of Prolonged Use5 -Tolerance -Mood disturbances -Aggression -Delirium -Psychosis -Heart attack -Heart disease -Stroke -Respiratory failure -Brain seizures -Sexual dysfunction -Death http://www.drugabuse.gov/publications/research-reports/cocaine/what-are-long-term-effects-cocaine-use

135. Stroke in “Crackheads”7 -Study included ONLY african americans. -Observational study to compare variables of crack smoking and non-crack smoking individuals suffering strokes. -Found that the stroke victims with a past history of crack use were younger, had fewer risk factors, and were predominantly male.

136. Monitoring the Future8 - Use (last 12 months) among adolescents is at record lows. - Less than 2% -More than half of adolescents believe crack poses a risk for significant harm to the user, even if only once. - Nearly 90% of adolescents disapprove of the use of crack. http://www.home.isr.umich.edu/wp-content/uploads/2012/12/MTF-logo-high-res-300x194.jpg

137. Cocaine Usage in the U.S.9 - In 2008, approximately 1.9 million Americans were cocaine users. - 359,000 (18.9%) of these were crack users. - Out of the 2 million drug- related emergency room visits, 482,188 were related to cocaine. http://www.crainsnewyork.com/apps/pbcsi.dll/storyimage/CN/20100727/FREE/100729851/AR/0/Emergency-Room-sign.jpg?q=100

138. References 1. Morton WA. Cocaine and Psychiatric Symptoms. Prim Care Companion J Clin Psychiatry. 1999;1(4):109-113. (Accessed on April 14, 2014) 2. Gorelic, DA. Cocaine use disorder in adults: Epidemiology, pharmacology, clinical manifestations, medical consequences, and diagnosis. In: UpToDate, Saxon AJ (Ed), UpToDate, Waltham, MA. (Accessed on April 14. 2014.) 3. Reinarman C, Levine HG. Crack in America, Demon Drugs and Social Justice. Univ of California Press; 1997. (Accessed on April 14, 2014) 4. Gold Standard, Inc. Cocaine. Clinical Pharmacology. Updated October 13, 2009. Available at:http://www.clinicalpharmacology- ip.com.husson.idm.oclc.org/Forms/Monograph/monograph.aspx?cpnum=145&sec=mondesc&t=0. Accessed: April 13, 2014. 5. Crack cocaine. University of Maryland Center for Substance Abuse Research. Updated October 29, 2013. Available athttp://www.cesar.umd.edu/cesar/drugs/crack.asp#brain. Accessed April 13, 2014. 6. National Institute on Drug Abuse. The neurobiology of drug addiction: section IV, the action of cocaine. Revised January 2007. Available at: http://www.drugabuse.gov/publications/teaching-packets/neurobiology-drug-addiction/section-iv-action-cocaine. Accessed April 13, 2014.

139. References 7. Leece P, Rajaram N, Woolhouse S, Millson M. Acute and chronic respiratory symptoms among primary care patients who smoke crack cocaine. J Urban Health. 2013;90(3):542-51. (Accessed April 13, 2014) 8. Johnston, LD. O’Malley, PM. Miech, RA. Bachman, JG. Schulenberg, JE. Monitoring the future: 2013 Overview. Available at: http://www.monitoringthefuture.org/pubs/monographs/mtf-overview2013.pdf. (Accessed April 13, 2014) 9. National Institute of Drug Abuse. Cocaine. May 1999. Available at: http://www.drugabuse.gov/sites/default/files/cocainerrs.pdf. (Accessed April 13, 2014)

140. Catha edulis By: Anonymous #3 http://www.forestryimages.org/browse/detail.cfm?i mgnum=5359745

141. • A seedless flowering plant from an evergreen tree or large shrub • Grown and harvested in a variety of climates year round • Other names – Qat: Yemen and Saudi Arabia – Khat: Ethiopia – Mirra: Kenya – Qaad: Somalia – Jaad: Somalia General1 http://www.bluelight.org/vb/content/84-UK-Herbal-Stimulant-Khat-to-be-Banned

142. How and Why2,3,4 • Leaves, shoots and stalks are chewed into a ball and parked in the cheek. • Juices are swallowed with saliva and absorbed into the blood stream. • Provides a natural stimulation. • Leaves have a aromatic odor and a slightly sweet and astringent taste. • Other user routes of administration: – Smoking – Making a drink from the dried leaves

143. Chemical2 • Ingredients in the juices of the plant: – More than 40 alkaloids • Phenylalkylamines and Cathedulins (major alkaloids) • Cathinone and Cathine (stimulating alkaloids) – Flavonoids – Sterols – Amino acids – Terpenoids – Glycosides – Tannins – Vitamins – Minerals https://www.caymanchem.com/app/template/Articl e.vm/article/2164

144. History5,6 • Origin: Eastern Africa and the Arabian Peninsula. – From Ethiopia to Yemen before 6th Century A.D. • Became popular in the Islamic community – Conflicting evidence about acceptance • Quran: no consumption of intoxicating substances • Some believe Mohammad “specifically encouraged” its use • Arabian Community – Sexual depressant given to men who guarded the virginity of young women before their contract marriages. – Social lubricant and used to help employees stay awake at work. • Cash crop in Yemen

145. http://maps-africa.blogspot.com/2012/05/east-africa-map-pictures.html

146. Epidemiology7 • An observational cross-sectional survey in Jazan (Gizan) in Saudi Arabia • Distributed to a intermediate and upper secondary schools – 72 schools participated, 3,923 students • 56.3% male • 43.7% female – Academic year 2011-2012 – Full time students, ages 13-21 • Conclusion: – 20.5% chewed khat with the number of males significantly higher than females

147. Popularity4,8 • Yemen – In the capital, it is estimated that 80% of the males, 50% of the women, and 15-20% of children under 12 use Khat daily • East Africa and the Arabian Peninsula countries – In the 1990s, ~10 million people use Khat daily • Ethiopia – About 50% of the men use Khat daily – 5:1 male to female use ratio • Immigrants to Europe and North America – Use Khat more in their new countries compared to their home countries. • Worldwide – Use has increased and become almost equal in both genders

148. http://www.dailymail.co.uk/news/article- 2357420/Journey-khat-fields-Kenya-produced-streets UK.html http://arij.net/en/khat-sends-secondary-students- psychiatric-clinics-and-liver-treatment-centres http://darmuseum.org.kw/dai/home/special- event-activities/event-trips/yemen/

149. Causes2 • Different geographical locations, climate, and environment determines what compounds are found in the leaves and what effects they may have on the GI and nervous system. • Cathinone and cathine are held responsible for the effects on the central nervous system. – Increased alertness, arousal, euphoria and elation, tolerance, and dependence (CNS) – Constipation, acute cardiovascular effects, and urine retention (PNS) • Urine retention is thought to be caused by the cathinone compound stimulating the alpha1- adrenergic receptors

150. Effects2,8 • Cathinone’s effects occur in about 15 minutes • A period of a talkative and excited mood with an inability to concentrate occurs first • Within 15-45 minutes of Khat chewing, the cathinone released can cause a minor and temporary rise in blood pressure and heart rate. • Oral administration half life: 3 hours • Max plasma concentration in 1-2 hours • Near the end of the effects, the user may feel depressed, irritable, difficulty sleeping, and a loss in appetite. • The sluggish and drowsy effects can be felt the following morning.

151. Khat vs. amphetamine8 • Cathinone is structurally similar to amphetamine • Cathinone’s effects occur in 15 min compared to amphetamine’s 30 min. • Amphetamine is twice as potent as cathinone and 7-10 times more potent than cathine. http://www.bluelight.org/vb/archive/index.php/t-559984.html

152. Toxicology2,3,4 • Negative side effects: increased blood pressure, tachycardia, anorexia, gastric disorders, constipation, depression, irritability, migraines, insomnia, and liver damage. • Contrary to historical use as a sexual depressant, many regular users state that they feel an increased libido and use it to augment their sexual experiences • Oral lesions such as hyperkerotosis and oral cancer can be caused by chewing Khat. • A study has suggested within 1 hour of exposure, Khat increased the cytosolic reactive oxygen species (ROS) and decreased the levels of intracellular glutathione (GSH). • Insufficient amount of research completed to definitively describe the mechanism that Khat uses to produce it’s toxic effects in the human body.

153. Social4,5,6,8 • Acceptance of Khat chewing is varied among cultures • Saudi Arabia – Khat chewing is illegal but many chew anyway because it is deeply rooted in their culture. • Yemen – An important cash crop and a large part of their economy • Con: a large amount of time is spent buying and chewing Khat. A khat chewing gathering can last from 3-7 hours – ~40% of all drinkable water is used to help grow Khat – Khat use has been associated with use of other drugs, alcohol, tobacco smoking, and risky sexual behaviors • Internationally – Cathinone (C1) and Cathine (C3) are scheduled substances – Catha edulis is not controlled so it is hard to control its growth and development

154. Khat and other substances8 • Khat and Tobacco – Not enough studies to say with definitive conclusion but it is believed that Khat and tobacco use has a larger effect on cognitive functions and the regulation of emotions than using Khat alone. • Khat and Alcohol – Unsure of effects in the body but users claim that the alcohol helps calm them down from the stimulating effects of Khat. • Khat and Withdrawal – Not enough studies to prove withdrawal symptoms occur but there is some evidence of a low tolerance level and withdrawal syndrome occurring • Symptoms: inertia, trembling, sedation, depression, nightmares, and hypotension

155. http://download.thelancet.com/pdfs/journ als/lancet/PIIS0140673607604644.pdf?id= qaaJDqNwuzIZOcWSeNRwu

156. http://download.thelancet.com/pdfs/journals/lancet/PIIS0140673607604644.pdf?id=qaaJDqNwuzIZOcWSeNRwu

157. References 1. Alsanosy RM, Mahfouz MS, Gaffar AM. Khat chewing habit among school students of Jazan region, Saudi Arabia. PLOS One. 2013; 8(6): e65504. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3679146/pdf/pone.0065504.pdf. Accessed April 8, 2014. 2. Wabe NT. Chemistry, pharmacology, and toxicology of Khat (Catha edulis Forsk): A review. Addict Health. 2011; 3(3- 4): 137-149. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3905534/. Accessed April 8, 2014. 3. Lukandu OM, Costea DE, Neppelberg E, et.al. Khat (Catha edulis) induces reactive oxygen species and apoptosis in normal human oral keratinocytes and fibroblasts. Toxicol Sci. 2008; 103(2): 311-324. http://www.ncbi.nlm.nih.gov/pubmed/?term=Khat+(Catha+edulis)+induces+reactive+oxygen+species+and+apoptosi s+in+normal+human+oral+keratinocytes+and+fibroblasts. Accessed April 8, 2014. 4. Wedegaertner F, al-Warith H, Hillemacher T, et.al. Motives for khat use and abstinence in Yemen- a gender perspective. BMC Public Health. 2010; 10: 735. http://www.biomedcentral.com/1471-2458/10/735. Accessed April 8, 2014. 5. Reda AA, Moges A, Biadgilign S, Wondmagegn BY. Prevalence and determinants of Khat (Catha edulis) chewing among high school students in Eastern Ethiopia: A cross-sectional study. PLOS One. 2012; 7(3): e33946. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3316517/pdf/pone.0033946.pdf. Accessed April 8, 2014. 6. Saeed A. Catha Edulis (Khat), A sex depressant, euphoriant in history. Anc Sci Life. 1986; 45-48. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3331378/pdf/ASL-7-45.pdf. Accessed April 8, 2014. 7. Mahfouz MS, Alsanosy RM, Gaffar AM. The role of family background on adolescent khat chewing behavior in Jazan region.Ann Gen Psychiatry. 2013; 12:16. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3679779/. Accessed April 8, 2014. 8. Hoffman R and al'Absi M. Khat use and neurobehavioral functions: Suggestions for future studies. J Ethnopharmacol. 2010; 132(3): 554-563. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2976806/. Accessed April 8, 2014.

158. Areca Nut Anna Levesque Drug Abuse and Society April 08, 2014 http://onlinelibrary.wiley.com

159. General Overview1,2 • Common names – Areca catechu – Areca Nut – Betel Nut – Paan – Paan-gutkha pinglang – Supari – Tamol (fermented) • NOT A NUT – drupe • Larger than an olive • Grows on areca palm tree in tropical and subtropical areas www.andamanplantations.com

160. General Overview1,2 • Primary ingredient in Betel Quid – Betel leaf – Areca nut – Slacked lime (calcium hydroxide) – (Tobacco) – Preparation varies greatly • Green unripe • Raw ripe • Baked • Roasted • Boiled • Fermented scatterolight.blogspot.com screening.iarc.fr

161. History & Epidemiology1,2,3,4 • Ancient practice in many parts of Asia – South/Southeast Asia • Pakistan, Sri Lanka, Bangladesh, Thailand, Cambodia, Malaysia, Indonesia, China, Papua New Guinea – Asia Pacific Islands – Use dates back 8776 years ago in Western Thailand – Tun-huang manuscripts: used as medicine in China a century ago • More recent use in Africa, Europe, North America – South/East Africa, the UK, Australia – Migrated communities • 200-400 million users worldwide • 10-20% of people in the world are potential users www.artsconnected.org

162. History & Epidemiology1,2,3,4 • Popular among both men and women • Generally more common among elderly • Often used by children • Became available commercially in the last two decades • Industry worth about $500 million USD (India) • May be more commonly used by people of lower socioeconomic status, less education www.freeenterprise.commedical-dictionary.thefreedictionary.com

163. Reasons for Use2,3,5 Backed By Scientific Evidence • Euphoria/antidepressant • Salivation/thirst quenching • Strengthens gums/fortifies teeth • Aid cognitive performance/alertness • Antihelminthic • Analgesic/sedative Lacking Scientific Evidence • Reduced salivation • Stimulates appetite • Suppresses hunger • Aid digestion • Dispel nausea • Anti-diarrheal • Morning sickness Stimulant (arecoline) AND a relaxant (arecaidine and guvacine) www.indiamart.com

164. Pharmacokinetics2,6 • Usually chewed • Some reports of being smoked • Roasted, flavored, and served to guests after meals • Dose-response relationship for each effect is not completely understood • Interactions: DRUG RESULT Flupenthixol and procyclidine Rigidity, bradykinesia, jaw tremor Fluphenazine Tremor, stiffness, agitation Prednisone and salbutanol Inadequate control of asthma

165. Pharmacodynamics3,5,6 • Main neuroactive alkaloid: Arecoline – Resembles muscarine and pilocarpine – Potent muscarinic agonist at M1,2,3 – Weak ganglionic nicotinic agonist at acetylcholine receptors • Arecaidine is most potent at M2 • Work together to increase the release of catecholamines from chromaffin cells www.indiamart.com www.medicalisotopes.com Arecoline Arecaidine

166. Pharmacodynamics3,5,6 • Causes central cholinergic stimulation • Sympathetic activation caused by increased plasma concentrations of norepinephrine and epinephrine • Effects are dose-dependent • Addiction and withdrawal seen in heavy users • Can cause cholinergic toxicity, toxic psychosis, and other neurologic issues www.nlm.nih.govpetedharane.com

167. Toxicology3,5,6 • Acute significant toxicity is rare; likely underreported • 42,000 patients called Taiwan Poison Control Center – 17 possible betel quid cases (most consumed 1-6 nuts) • 15 recreational • 1 attempted suicide • 1 medicinal – 11 experienced nausea, vomiting, dizziness, tachycardia, and/or palpitations – 6 experienced coma, respiratory failure, and/or myocardial infarctions – 1 died (previously healthy 44 year-old male; chewed one betel quid) • Other adverse events: hypotension, sweating, chest discomfort, abdominal colic, numbness, death, exacerbation of extrapyramidal effects www.cia.gov

168. Toxicology3,5,6 • Treatment of overdose is usually symptomatic • May be treated with stomach lavage, activated charcoal, IV fluid, and electrolyte replacement therapy • Atropine not recommended but may be used if severe acute cholinergic crisis • Recovery typically in 24 hours en.wikipedia.org

169. Toxicology7 Rat Study: • Healthy male and female Wistar albino rats, 10-12 weeks old • Fasted overnight, administered raw areca nut extract • Male LD50: 2321.96 mg/kg • Female LD50: 2257.52 mg/kg • Signs of toxicity – Depression – Profuse salivation – Tremors – Burrowing – Hunched back – Muscular incoordination – Weakness – Altered gait – Convulsions – Writhing movement of the neck – Severe diarrhea – Labored breathing/gasping – Death www.junsungls.com

170. Society’s Perspective2,8 • Fourth most commonly used psychoactive substance in the world – Right after caffeine, nicotine, and alcohol • Completely socially acceptable in many countries • Use ceremonially in courtship, weddings • Offered when greeting or leaving as a gesture of relaxation • Available on the internet http://www.ebay.com/sch/i.html?_trksid=p2050601.m570.l1313&_nkw=areca+nut&_sacat=0&_from=R40

171. Effect on Health8,9,10 • Strong association with major oral health issues • Main factor in Oral Submucosal Fibrosis (OSF) – Arecoline upregulates αVβ6 integrins and causes activation of TGF-β pathway, which increases collagen production • Submucosal fibrosis is highly precancerous • Areca nut extract (ANE) increases reactive oxygen species, which initiates pyknotic necrosis, which is exacerbated by inhibition of GSK3-β by SB216763 • ANE is cytotoxic, causes formation of vacuoles • Arecoline is genotoxic and causes DNA damage and downregulates cyclin-dependent kinase inhibitors p21 and p27 • Causes many problems in the oral cavity including ulcers, thickened epithelium, brownish discoloration, submucosal fibrosis, pseudomembranous wrinkle alteration • In the cells, causes ballooning, epithelial hyperplasia, massive inflammatory infiltration, basal nuclei hyperkeratosis, pyknosis, and dysplasia www.oralsubmucousfibrosis.com

172. Pathogenesis in OSF9

173. Effects on Health11,12 • Linked to oral and esophageal cancer, hepatocellular carcinoma, liver cirrhosis, obesity, type II diabetes, hypertension, hyperlipidemia, metabolic syndrome, chronic kidney disease • Strongly associated with cancer • Difficult to determine pathway in carcinogenesis due to compounding factors • Study showed that raw areca nut (RAN) induced stomach cancer in mice • Increases levels of p53, Bax, Securin, and p65 in esophageal and stomach cells • Downregulates mitotic checkpoint proteins • More likely to produce reactive oxygen species when used in betel quid because the lime makes saliva alkaline; develop cancer earlier www.darshanenterprise.com

174. Future Expectations8 • Will be banned in many states and countries

175. Case Report5 • Newborn of a healthy, 38-year old woman who was a chronic areca nut user • Born after 38 weeks (9.5 months) gestation; normal weight and length • Presented with irritability and hypertension 48 hours after normal delivery • Normal serum chemistry and electrolytes • Negative for HIV, hepatitis C, hepatitis B, toxoplasma, rubella, syphilis • Negative for opiates, cocaine, cannabis, amphetamines, benzodiazepines, barbiturates, ethanol Lopez Lopez

176. Case Report5,13 • At 3 days old, Finnegan scores were >8 • Started on phenobarbital 15 mg/kg IM followed by 8 mg/kg per day orally • Withdrawal improved after 5 days of treatment Lopez Lopez

177. References 1. Gupta PC, Ray CS. Epidemiology of Betel Quid usage. Ann Acad Med Singapore. 2004;33:31-36. 2. Strickland SS. Anthropological perspectives on use of the Areca Nut. Addict Biol. 2002;7(1):85-97. 3. Deng JF, Ger J, Tsai WJ, et al. Acute toxicities of Betel Nut: Rare but probably overlooked events. J Toxicol Clin Toxicol. 2001;39(4):355-60. 4. Ji WT, Lee CI, Chen JYF, et al. Areca Nut extract induces pyknotic necrosis in serum-starved oral cells via increasing reactive oxygen species and inhibiting GSK3-beta: An implication for cytopathic effects in Betel Quid chewers. PLoS One. 2013;8(5):1-10. 5. Lopez-Vilchez MA, Seidel V, Farre M, et al. Areca-Nut abuse and neonatal withdrawal syndrome. Pediatrics. 2006;117(1):129-31. 6. Fugh-Berman A. Herb-drug interactions. Lancet. 2000;355(9198):134-8. 7. Lohith TS, Shridar NB, Jayakumar K, et al. Acute oral toxicity of raw Areca Nut extract in rats. Indian J. Anim. Res. 2013;47(5):431-434. 8. Gupta PC, Ray CS. Epidemiology of Betel Quid usage. Ann Acad Med Singapore. 2004;33:31-36. 9. Khan I, Kumar N, Pant I, et al. Activation of TGF-beta pathway by Areca Nut constituents: A possible cause of oral submucosal fibrosis. PLoS One. 2012;7(12):1-12. 10. Ji WT, Lee CI, Chen JYF, et al. Areca Nut extract induces pyknotic necrosis in serum-starved oral cells via increasing reactive oxygen species and inhibiting GSK3-beta: An implication for cytopathic effects in Betel Quid chewers. PLoS One. 2013;8(5):1-10. 11. Kurkalang A, Banerjee A, Ghoshal N, et al. Induction of chromosome instability and stomach cancer by altering the expression pattern of mitotic checkpoint genes in mice exposed to Areca-Nut. BMC Cancer. 2013;13:315. 12. Lin WY, Chiu TY, Lee LT, et al. Betel Nut chewing is associated with increased risk of cardiovascular disease and all-cause mortality in Taiwanese men. Am J Clin Nutr. 2008;87(5):1204-11. 13. Klein J. Identifying neonatal abstinence syndrome (NAS) and treatment guidelines. University of Iowa Children’s Hospital. Published February 11, 2013.

178. Kava Kava Anan Hussein

179. Kava [1] • Piper methysticum. • The many names of Kava – Awa – Ava – Gea kavain – Maluk – Sakau – Yagona http://www.kratom- k.com/product_images/t/793/Kava_Root__17445_zoo m.jpg

180. History[2] • Originated in South Pacific Islands • Introduced to the West by Capt. Cook • Widespread use in Australia, Europe, and America.

181. http://3.bp.blogspot.com/- 9MGUQRhJcVg/ULJ_dWaN21I/AAAAAAAAAAY/X_DypYrA0NU/s1600/map.gif

182. Kava Uses [3] Beverage used traditionally in ceremonies. The Review of Nature Products states that Kava “produces mild euphoric changes, characterized by feeling of happiness, fluent and lively speech, and increased sensitivity to sounds.” http://www.hollyanissa.com/wp-content/uploads /2012/07/Week30.jpg

183. Kava in the West [2] • In western countries kava used medicinally. • Know for its psychoactive effects – Anxiety – Insomnia https://encrypted- tbn2.gstatic.com/images?q=tbn:ANd9GcQpOnqTkho9pC3ElvvEQwa7ERjwodKBap0E8wU0 LF-Wzi1T_m8JVg

184. Kava preparation [4] • So how is kava prepared ? http://3.bp.blogspot.com/_6i2sW4aFUeE/TG4FYbA9- aI/AAAAAAAAAEs/6_Qvok9yWmU/s1600/IMG_0457.jpg

185. http://api.ning.com/files/0N4byQT3Y2JD-ZpmjVZ55- GYnW8Xr-ZAfaEO7h5grQA_/kavaceremonywakaya.jpg

186. Economics of Kava [1] • Kava is not only the traditional drink for many villages, but it is considered a significant cash crop in some islands. • Kava also produces a major cash yield in Tonga, Samoa, and Vanuatu. • In Hawaii kava is used for medicinal and religious purposes, the “kahunas” (medical people whom communicate with God) used kava to cure many disease and ailments, such as chills and colds, general debility, sharp headaches, weary muscles, and displacement of the womb.

187. http://informedfarmers.com/wp-content/uploads/2010/10/crops.jpg

188. MOA [5,6] • MOA not clear • One theory is that Kava exert some effect on GABA-A binding sites, and an inhibitory effects on dopamine and norepinephrine. • In vitro study by Mathews done on human liver showed different kavalactones from Kava extract inhibiting CYP enzymes including CYP 2C9, 2C19, 2D6, 3A4, and 1A2.

189. Kavalactones [6]

190. Kava interactions [6] • Kava and alcohol – cause an increase in toxicity of kava and/or alcohol • Kava and benzodiazepines – increase the effects of benzos • Kava and levodopa – reduces the effects of levodopa

191. PK/PD [2,7] • A study on kawain found Peak levels at 1-2 hours. • Distribution half life of 50 minutes. • Elimination half-life of 9 hours. • Metabolites and kavalactones such as Kawain are excreted renally mostly in human urine, and some excreted in feces.

192. Safety/Toxicity [2] • There is a widespread concern regarding hepatotoxicity with Kava use. Reports of liver damage, cirrhosis, hepatitis, and liver failure have been documented in Western countries including Switzerland, and Germany. http://www.mimscience.org/mims/wp- content/uploads/2012/02/liver.png

193. Reports of toxicity [8] • Pipermethysticine (PM) present in Kava leaves and stems is a potential cause of hepatotoxicity. • In Fischer trial 334 rats were given 10 mg/kg PM daily demonstrated oxidative stress changes in two weeks. The oxidative stress was shown to increase cytosolic superoxide dismutase enzymes and hepatic glutathione.

194. And more [8] • Kavalactone Flavokavin B is a cytotoxic agent present in Kava root. Flavokavin B causes hepatocellular toxicity through mitogen- activated protein Kinase (MAPK) signaling pathway which leads to oxidative stress and results in apoptosis of the cell.

195. Pause !! • Kava toxicity • Always present or a creation of the West?

196. Side effects [2,8] • In general well tolerated • Kava Dermopathy – dry, scaly skin with yellow pigmentation on the hands and feet. https://encrypted- tbn2.gstatic.com/images?q=tbn:ANd9GcTIY83_n 7JkhrrmLZs6y3R9c808UCefvgsdhSQTlJn5shwm3 xVM

197. Act of Vanuatu [9,10] • Nov. 7 of 2002 • States that only noble kava cultivars with a long history of safe traditional and medicinal use must be met before export from Vanuatu. • Also, according to the Act, 2 day cultivars and Wichmanni (wild kava) do not satisfy the appropriate legislation for desired kava effect and are prohibited for export.

198. Noble Kava Cultivars of Vanuatu [9] Noble cultivar Origin Ahouia Tanna Asiyai Aneityum Biyai Aneityum Borogoru Maewo Gegusug Gaua Kelai Epi Leay Tanna Melomelo Ambae Palasa Santo

199. Regulation Globally [11] • Australia - Kava is legal to possess & sell, but it is illegal to import into Australia without a license, since it’s listed as a “Schedule IV”. • Germany - Germany is where the original Kava ban that sparked worldwide banning of Kava originated. Germany moved to lift its ban in 2007 after almost everyone else in the world did. • Canada - may export Kava to Canada, as long as it’s to individuals who are using it for personal consumption, and NOT to any businesses. • Banned in some other countries like Britain, and France.

200. How about U.S [2] • Kava is not approved by the FDA, but has not been taken off the market in the U.S either despite health concerns about its safety.

201. Kava abuse !! [12] • Duke University Medical Center states Kava doesn’t have any dependence or withdrawal effects. • In clinical settings, 280 mg/day of kavalactones were given, and a follow up data for 4 weeks showed no effect on heart rate, blood pressure, or sexual dysfunction. No differences between kava and placebo were found.

202. Kava Addiction [12,13] • Pilot study and a survey were done to determine if kavalactones decrease the craving associated with drug abuse. The substances used included alcohol, cocaine, tobacco, and heroin. • The findings suggest that kava may reduce the craving associated with the aforementioned substances, which makes kava a great future candidate to help with addiction.

203. • Kava is used medicinally for which of the following: a) Depression b) Anxiety c) Erectile dysfunction d) PMS

204. Quiz • True or False • Kava is banned from many countries due to its addictive properties. • Kavas’ toxicities are most likely due to: a) Its ingredients b) Its preparation c) Because Caucasians cant tolerate drugs the way islanders do. d) I don’t know because I wasn't paying attention

205. References 1. Davis R.I, Brown J.F. Kava (Piper methysticum) in the South Pacific: its importance, methods of cultivation, cultivars, diseases and pests. Australian Centre for International Agricultural Research. 1999; No. 46, 32. http://ageconsearch.umn.edu/bitstream/113917/2/tr046_pdf_19769.pdf. Published 1999. Accessed Apr 20, 2014. 2. Basch E, Basch S, Bent S, Boon H, Bryan K, Cost D, Ernst E, Isaac R, Rogers A, Rourk E, Schadde S, Shkayeva M, Sollars D, Strominger Z, Tanguay-Colucci S, Tsourounis C, Ulbricht C, Varghes M, Weissner W, Woods J. Kava (Piper methysticum). Natural Standard. http://husson.naturalstandard.com.husson.idm.oclc.org/databases/herbssupplements/kava.asp Updated 4.8.2014. Accessed Mar 15, 2014. 3. Pepping J. Kava: Piper methysticum. AJHP. 1999; vol(56):957. file:///C:/Users/Anan/Downloads/36023842%20(3).pdf. Published May 1999. Accessed Apr 15, 2014. 4. Singh Y. Kava: an overview. Journal of Ethnopharmocology. 37 (1992);13-45. file:///C:/Users/Anan/Downloads/36023308%20(1).pdf. Published 1992. Accessed Apr 20, 2014. 5. Abadi S, Papoushek C, Evans M. Is kava extract effective for treating anxiety? Canadian Family Physician. 2000;20:84-9. http://www-ncbi-nlm-nih- gov.husson.idm.oclc.org/pmc/articles/PMC2018572/pdf/11570299.pdf Published Sep, 2001. Accessed Mar 15, 2014

206. 6. Ankea J, Ramzana I. Pharmacokinetic and pharmacodynamic drug interactions with Kava (Piper methysticum Forst. f). J Ethnopharmacol. 2004 Aug;93(2-3):153-60. doi:10.1016/j.jep.2004.04.009. 7. Mathews J, Etheridge A, Valentine J, Black S, Coleman D, Patel P, So J, Burka L. Pharmacokinetics and Disposition of the Kavalactone Kawain: Interaction With Kava Extract and Kavalactones in Vivo and in Vitro. DMD. October 2005 vol. 33 no. 10 1555-1563. doi:10.1124/dmd.105.004317 8. Rowe A, Zhang L, RamzanI. Toxickinetics of Kava. Adv Pharmacol Sci. 2011; 2011: 326724. doi: 10.1155/2011/326724. 9. Teschke R. Kava and the Risk of Liver Toxicity: Past, Current, and Future. AHPA. 2011; 26:12. http://www.ahpa.org/portals/0/pdfs/11_0303_March2011_AHPA_Report_Kava_Special_Report. pdf Published Mar, 2011. Accessed Apr 6, 2014. 10. Teschke R, Sarris J, Glass X, Schulze J. Kava, the Anxiolytic Herb: Back to Basics to Prevent Liver Injury?. Br J Clin Pharmacol. Mar 2011; 71(3): 445–448. doi: 10.1111/j.1365-2125.2010.03775.x 11. Makaira. Kava-Worldwide Legal Status. Kona Kava Farm. http://www.konakavafarm.com/blog/kava-news/kava-worldwide-legal-status/ . Posted Jul 24, 2009. Accessed Apr, 2014. 12. Connor KM, Davidson JR, Churchill LE. Adverse-effect profile of Kava. CNS Spectr 2001 Oct:6(10):848, 850-3. http://www.ncbi.nlm.nih.gov/pubmed/15334034. Accessed Apr, 2014. 13. Steiner G. Kava as an anticraving agent: preliminary data. Pac Health Dialog. 2001 Sep;8(2): 335-9. http://www.ncbi.nlm.nih.gov/pubmed/12180513?report=abstract. Accessed Apr, 2014

207. Krokodil: “World’s Deadliest drug” Alyssa Duron video.foxnews.com

208. Objectives • Explain the history of Krokodil (desomorphine) and its relation to morphine. • Explain its proposed mechanism of action. • Describe the reasoning behind the making of desomorphine and the results its trials in animals and in chemotherapy patients. • Provide toxicology data and its reported harms and risks. • Define epidemiology and usage patterns in Eastern Europe. • Discuss the effects of Krokodil on its users.

209. The search for novel morphine analogues1 • 1929: Committee on Drug Addiction (U.S.A) • Lead by Dr. NB Eddy, Secretary of the Drug Addiction Committee. • Search for non-addictive, strong analgesic • 200 analogues synthesized in first decade • Tested some drugs in the prison population. • Potency assessed by reversal of analgesia. • Important findings: • Parallel between analgesic effect and addiction liability. • Schedule I compound since 1936 in the U.S.2

210. Desomorphine vs. morphine3 Desomorphine Morphine Difference between desomorphine and morphine is the absence of the secondary hydroxyl group and the saturated double bond.

211. Mechanism of action •

212. Addiction & tolerance properties of Desomorphine • 8-10x more potent than morphine on a weight basis.2 • 15x more sedating4 • 10x the analgesic effect4 • 3x more toxic4 • May have less of an effect on G.I. tract1 • LD50 in mouse is 27mg/kg IV or 104 mg/kg SQ5 • Half life is roughly 1-2 hr in comparison to morphine at 4-5 hr.12

213. First experiment in dogs6 1 2 7 8 2 mg/kg Desomorphine 5 mg/kg Desomorphine 10 mg/kg Morphine sulfate 50 mg/kg Morphine sulfate Study run from October 23 – December 28, 1933 and given every day but Sundays. After study, observed daily for 2 weeks for withdrawal symptoms. Summary: Depressant effect of both desomorphine doses was >10 mg/kg morphine dose and slightly less than the 50 mg/kg morphine dose. No specific withdrawal symptoms observed in either group. In both groups: moderate salivation, decrease in body temperature, decrease in RR, decrease in weight observed.

214. 1936: first trial in man6

215. 1936: Eddy & Himmelsbach7 • Observational trial in 1936. Desomorphine was substituted for morphine in 5 morphine addicts. • 200 mg per day in one, and 400 mg per day in others. • Interval was every 6 hours for 8-21 days of substitution. • Findings include: • Increasing the dose of desomorphine did not compensate for its short duration of action. • Efficacy in comparison to morphine is likely similar. • Abstinence symptoms from desomorphine developed much faster than after withdrawal of morphine. • At least equal to symptoms of morphine abstinence syndrome but appeared sooner.

216. Patented in 1932 as “permonid” – Patented as Permonid by Hoffman-La Roche in Switzerland.2,3 – Available as an ampulla and suppository for post-op pain2,3: • Fast onset of action • Decreased tendency to cause respiratory depression and nausea. • Was continued in Switzerland until 1981 for one single patient who had a rare disease who needed 0.16 g daily (80 ampules) and did not develop any somatic side effects from this medication.3 zikkir.com

217. Krokodil: homemade heroin substitute – First publicized use in Siberia in 2002.2 – Name “krokodil” (or crocodile in English) comes from2: • Scaly appearance of user’s skin (necrosis, gangrene) when infection occurs. • Name of its derivative chlorocodide. – Made similarly to ephedrine to methamphetamine.2 – Ingredients include: codeine, iodine, red phosphorous.2 • Product has toxic by-products found inside (i.e. paint thinner, lighter fluid, gasoline, lead, zinc, iron, HCl, iodine, red phosphorous).2 Airspacemag.com

218. Constant cooking process8 • Process takes only 10-45 min but has to be completed throughout the day since –Short duration of action. • Pack of 10 codeine tabs costs 120 Rubles ($3.35) and produces a yield equivalent to 500 Rubles of heroin. • Production results in a liquid drug ready for frontloading. Animalnewyork.com Businessweek.com

219. Environmental risk factors8 – Processing chemicals and codeine (could be) purchased easily and is (was) not controlled. • OTC sale prohibited in Russia June 1, 2012.9 – Opium poppy fields were prevalent throughout the region, but seasonal growth. – More control and restriction of substance abuse in the 1970’s-80’s in the USSR. – Closed borders lessened drug trade, particularly Afghan heroin. En.wikipedia.org

220. Reported krokodil usage patterns10 http://rospravosudie.com/society/narko

221. http://rospravosudie.com/society/narko Marijuana Heroin Desomorphine Hashish Amphetamine Codeine Morphine Translation: Alex Sinkov

222. Toxicities & effects The life expectancy of the individual using is estimated to be as low as 2-3 years.11 Localized4 • Thrombosis • Open ulcers • Phlebitis • Gangrene • Skin and soft tissue infections • Limb amputations Systemic4 • Pneumonia • Blood poisoning • Coronary artery burst • Meningitis • Rotting gums, nose, ears, lips • Liver and kidney problems Neurological4 • Speech impediments • Motor skill impairments • Personality changes

223. Ibtimes.com Mrconservative.com Motherjones.com Dailymail.co.uk

224. Stories of addiction12 • A user in a focus group in Odessa was asked if he was worried about getting HIV. He replied, “No.” When asked what he biggest worry was, he replied, “Withdrawl.” His second biggest worry was “Police.” He said, “Police and withdrawl are today. If I get HIV I will still live 10 more years.” • “I was taken to a hospital when I was fever sick with a fever and couldn’t walk and they refused to treat me. They told me to go buy syringes, bandages, and medications. They asked me for money, and when I didn’t have any I was asked to leave the clinic by the doctors.”

225. References • 1. Furst S, Hosztafi S. The chemical and pharmacological importance of morphine analogues. Acta Physiologica Hungarica 2008;95(1):3-44. • 2. National Medical Services, Inc. Analytical Specifications-DESOMORPHINE. 2012. • 3. Gahr M, Freudenmann RW, Hiemke C, Gunst IM, Connemann BJ, Schonfeldt-Lecuona C. Desomorphine goes “Crocodile.” J Addict Dis. 2012;31(4):407-12. • Image: Goldfrank LR, Nelson LS, Lewin HA, Howland MA, Hoffman RS, Flomenbaum NE. Goldfrank’s Toxicologic Emergencies, 9th ed: http://www.accessemergencymedicine.com. • 4. Drug Enforcement Administration, Office of Diversion Control. Desomorphine: Dihydrodesoxymorphine; dihydrodesoxymorphine-D; Street Name: Krokodil, Crocodil. Drug & Chemical Evaluation Section. 2013. • 5. Eddy NB, Howes HA. Studies of morphine, codeine, and their derivatives: Desoxymorphine-C, Desoxycodeine-C, and their hydrogenated derivatives. Pharmacol Exp Ther. November 1, 1935;55:257-267. • 6. Eddy N, Himmelsbach CK. Experiments on the tolerance and addiction potentialities of dihydrodesoxymorphine-D (“Desomorphine”). Publ. Hlth Rep., Wash. 1935;118:1260-1292. • 7. Eddy N, Halbach H, Braenden O. Synthetic substances with morphine-like effect; clinical experience: potency, side- effects, addiction liability. Bull Wld Hlth Org. 1957;17:569-863. • 8. Grund J-P, Latypov A, Harris M. Breaking worse: the emergence of krokodil and excessive injuries among people who inject drugs in Eurasia. Int J Drug Policy. 2013;24:265-274. • 9. Andrey Rylkov Foundation for Health and Social Justice. Over-the-counter sales of drugs that contain codeine prohibited in Russia. June 1, 2012. http://en.rylkov-fond.org/blog/drug-policy-and-russia/drug-policy-in-russia/codeine- prohibition/. • 10. KOAEKC. RosPravosudie. Angel dust on the map of Russia. 2013. http://rospravosudie.com/society/narko. • 11. Lemon TI. Homemade heroin substitute causing hallucinations. Afr J Psychiatry. 2013;16:411. • 12. Booth RE. ‘Krokodil’ and other home-produced drugs for injection: a perspective from Ukraine. Int J of Drug Policy. 2013;24:275-280.

226. Image: Wikipedia

227. • Perennial flowering plant, Europe & N. Asia – Has been introduced into other continents • Known as baldrian, valerian, all-heal, etc. • 1 to 2 meter single stem, white or pink bloom • Other members of valeriana are not used – Differing chemistry and chemical density • Medicinal formulations from roots – Pungent oil isolated from rhizome & root – Various compounds with possible activity – As oil extract or powdered radix dried at <40°C Valeriana officinalis1

228. • Used as medicinal herb throughout history1 – Use varied over time, becoming more specific • Ancient Greeks advocated use for many problems2 – “[GI distress], flatulence, nausea, liver problems, convulsions, urinary tract disorders, poisonings… body odor, vaginal yeast infection” • Dioscorides mentioned as diuretic – 55AD1 • Fabio Colonna, epilepsy, phytobasanos – 15921 • Antiepileptic, sedative, and hypnotic1,2 – Tissot argued first line Tx for epilepsy in 1770’s – Lost some credibility as antiepileptic after 18c Historical Use

229. • Popular in continental Europe in 18-19c – Used as anticonvulsant & antimigraine • Lost favor in 20c, now an alternative medicine – Recognized as mild sedative hypnotic in Germany – Commonly sold OTC herbal in U.S. and Europe • Commonly taken in tea or as capsule • Commercial components differ (!) – European products – valepotriates & volatile oil • Demonstrate relaxation/sedation • No decrease in mental concentration – U.S. products contain little or no valepotriates • Used for restlessness due to nervousness/anxiety Shift Toward Modern Use2

230. • Clinical data supports use as sedative – Often used as alternative to benzodiazepines – Particularly for anxiety-induced sleep problems – Supported by GABA binding and in vivo studies • Some pharmacopoeias: Spasmolytic adjuvant – Has been used with belladona, etc. – Smooth muscle spasmolysis (eg. IBS) • Still used as antiepileptic (no strong data) • WHO monograph suggests limit 10g/day • Active compound unknown – synergy? – Many constituents are GABA binding2 Current Use3

231. Constituents of Valerian Products2 Spasmolytic, psychostimulant, sedative, alcohol antagonist Sedative, spasmolytic, muscle relaxant, antidepressant

232. • Conjecture: sesqueterpine metabolite – Ideal scenario – 0.9% of root • Anticonvulsant, sedative, muscle relaxant • Chemically similar to valproic acid – Unsurprisingly, similar indications • Strong sweat or cheese odor – Amide derivative lacks this odor (isovaleramide) – Use of amide has precedent – valpromide for VPA Isovaleric Acid1

233. Assessment N Product Objective Results Subjective Results improvement of sleep quality 128 Valerian (aqueous) 200mg Sleep latency decreased by 37% vs 23% placebo (p=0.01) 43% vs 25% “better than usual” sleep (p<0.05) 37% vs 28% report fewer awakenings (p<0.05) Sedative (effect on driving) 109 Valepotriates No impairment, insignificant improved stress reaction Performance & mood under stress 48 Valerian 100mg No reduction in pulse rate during stress ↓ subjective feelings of somatic arousal Evidence for Efficacy2 USPSTF – probably safe, probably effective as sleep aid, possibly as spasmolytic

234. 530-1060mg qhs 145-290mg qhs 100-200mg qhs 350mg qhs 1-2g TID

235. Toxicity2 • Considered safe despite lack of definite evidence • Insufficient evidence for chronic toxicity • Side effects uncommon during trials • Reported chronic adverse effects vary – Headache, excitability, anxiety, cardiac disturbance • Attempted suicide – Case for excess use – 40-50 470mg capsules (>18g) – Fatigue, abdominal pain, tremors, mydriasis – Activated charcoal – full recovery <24 hours – Unknown capacity for interaction with sedatives • Assume interaction, use caution

236. • No evidence of endemic problem use • Anecdotal evidence of excess use varied – Generally combined with other legal herbals – Generally sedative, occasional psychedelic reports • ~11.2g in tea + 1tbsp in water over ~1 hour4 – “my heartbeat pounded inside my head. I struggled to put my clothes on and then immediately laid down for a few minutes. It took about 15 before my head stopped pounding and I stopped dripping with sweat… Still not relaxed enough, I took a tablespoon of powdered valerian and stirred it up in a glass of water. I chugged it down in one drink, nearly gagging from the taste… I could hardly breathe, my lungs felt solid and my heartbeat weak.” Illicit Use

237. 1. Eadie M. Could valerian have been the first anticonvulsant? Epilepsia (Series 4). 2004;45(11):1338-1343. Available from: Academic Search Complete, Ipswich, MA. Accessed April 7, 2014. 2. Caron M, Riedlinger J. Valerian: A practical review for clinicians. Nutrition In Clinical Care.1999;2(4):250-257. Available from: Academic Search Complete, Ipswich, MA. Accessed April 7, 2014. 3. WHO Monographs on selected medicinal plants – vol. 1. Geneva. 1999 4. Stray Tom. "In Excess: An Experience with Valerian (ID 28576)". Erowid.org. May 19, 2006. erowid.org/exp/28576 Sources

238. Fenfluramine Anonymous #4

239. History • Trade Names: Pondimin, Ponderax, Adifax • 3-trifluoromethyl-N-ethylamphetamine • Racemic mixture of dextrofenfluramine & levofenfluramine • Weight loss medication introduced in 1973 • Combined with Phentermine to create the ultimate weight loss drug Phen-Fen • Withdrawn from US market in 1997 http://www.dailymail.co.uk/new s/article-2543989/Not-FDA- approvals-created-equally-Study- reveals-medications-far-safety- testing-others.html

240. Epidemiology • “Miracle weight-loss drug” • 1.2-4.7 million people used fenfluramine for 3- 12 months • 1 in 3 adults are considered overweight • Weight-loss drugs usually associated with short-term weight loss

241. Social • Appetite suppression • Used by men and women of all ages • C-IV medication • Legal damages led to $13 billion to patients from the makers • Phen-Fen: – Both analogues of amphetamine – Phentermine affects dopamine – Fenfluramine affects serotonin – Allowed for two ways to suppress appetite http://s3.amazonaws.co m/answer-board- image/933a5d06-a566- 4033-9931- 4d815a247347.jpg

242. Pharmacokinetics • 20mg oral tablet • Onset of action: 1-2 hours • t1/2: 20 hours • Effects last: 4-6 hours • Dose: 1 tablet three times daily • Max daily dose: 120mg • Metabolism: de-ethylation to norfenfluramine which is then deaminated and oxidized to m- trifluoromethylbenzoic acid • Excretion: urine

243. Pharmacodynamics • Rapidly releases serotonin & inhibits serotonin reuptake – Serotonin involved in memory, cognition, mood, anxiety, impulsivity, aggression, sleep, pain, and neuroendocrine function • Changes seen in rats, mice, guinea pigs, squirrel & rhesus monkeys and baboons

244. Fenfluramine and Serotonin

245. Fenfluramine and Serotonin • Male Sprague-Dawley Rats • Examined relationship between drug induced 5-HT release and long-term 5-HT depletion in their brains • In vivo: dFEN and mCCP elevated extracellular 5-HT in the nucleus accumbens • In vitro: dFEN and mCCP potent inhibitors of 5-HT uptake; High dose dFEN associated with depletion of 5-HT levels but mCCP was not – Different mechanisms behind 5-HT release and depletion

246. Toxicity • Led to valvular heart disease – Prevalence: 0.1-30% • High levels of circulating serotonin associated with carcinoid syndrome  valvular heart disease • Increased exposure positively correlated with risk of cardiac side effects

247. Toxicity • ADRs: Agitation, drowsiness, confusion, fever, flushing, tremor, hyperventilation, abdominal pain, sweating • <5mg/kg is toxic • High Doses: confusion, ventricular extrastoles, coma, ventricular fibrillation, death • OD: dilated non-reactive pupils, normal or elevated BP

248. Toxicity • Disruption of heart valve serotonin receptors lead to: – Pulmonary hypertension and thickening of the leaflet and cordae tendineae • Norfenfluramine is a 5-HT2B receptor agonist – High concentration in cardiac valves – Overstimulation or inappropriate stimulation of these receptors leads to valvular cell division – Leading to the thickening of the leaflet http://media.tumblr.com/tumblr_lgkwtrpVxN1qfcmjd.jp g

249. Left: thickened mitral valve (MV) during diastole. Right: demonstrates severe mitral regurgitation (MR) during systole

250. Prevalence of Aortic/Mitral Regurgitation • Variation in prevalence between studies based on FDA criteria • True prevalence between 2-12%

251. What now? • Belgium • Added to treatment for Dravet Syndrome – Epilepsy resistant to many medications • 12 patients • 0.34 (0.12-0.90) mg/kg/day in addition to antiepileptic drugs • Decrease in seizure activity in all patients – 4 seizure free for 2 years • No cardiac side effects to date

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