1. FSC402H Cocaine and Other Stimulants 0ctober 28, 2003

2. STIMULANTS A COMPOUND WHICH INCREASES BRAIN ACTIVITY  COCAINE  AMPHETAMINES  AMPHETAMINE & METHAMPHETAMINE  MDMA & MDA  PMA  EPHEDRINE & PSEUDOEPHEDRINE  CAFFEINE, NICOTINE, + + +

3. COCAINE

4. COCAINE - cocaine comes from the coca plant - grows primarily in Andean Region in South America U.S. government Public Domain photo

5. COCAINE -extracted cocaine - whitish powder - bitter - crystalline - odorless - numbing Public domain photo from Indiana University

6. COCAINE - HISTORY records date back to 3000 B.C. – believed to be a gift from God 15 th Century – Coca Plantations – Incas – Peru Early 1500s – Spanish take over Inca plantations - landowners must pay 10% of crop as tax

7. COCAINE - HISTORY Late 1500s – Labourers in Spanish Silver mines supplied with coca leaves 1580 - coca leaves brought to Europe – Not much interest 1600 - mid 1800’s – few mentions of coca in literature

8. COCAINE - HISTORY 1850 – used in throat surgery 1855 – cocaine first extracted 1863 – Angelo Mariani – Vin Mariani patented = coca extract + Bordeaux Wine 1870 – Vin Mariani sold (7.2 mg cocaine/oz.)

9. COCAINE - HISTORY 1870 Parke Davis – manufactures fluid extract of coca 1883 – Theodor Aschenbrant reports in German Medical Journal re: administration of cocaine to Bavarian Army to enhance endurance **** Read by SIGMUND FREUD**** Publishes ÜBER COCA 1884 – used as anaesthetic in eye surgery

10. COCAINE - HISTORY 1886 – COCA COLA = cocaine + caffeine 1891 – cocaine removed from coca cola

11. COCAINE - HISTORY

12. 1905 – snorting becomes popular 1910 – first record of nasal damage from cocaine 1912 – 5000 cocaine related deaths – U.S. 1914 – listed as a narcotic – over the counter sales stopped 1920-1970 – cocaine use subsides

13. COCAINE - HISTORY 1970 - Comprehensive Drug Abuse Prevention & Control Act (U.S.) - Cocaine is put in Schedule II (high potential for abuse but has medicinal use) 1985 – est. 5.7 million Americans chronic cocaine users (3% of population) 1992 – est. 1.5 million Americans chronic cocaine users Levine – recent survey – 11.3% of Americans >12 have used cocaine

14. COCAINE - HISTORY 1981 – 1 kg. Cocaine = $55,000 1984 – 1 kg. Cocaine = $25,000 Production of Cocaine by Merck 1862 – ¼ lb 1883 – ¾ lb 1884 – 3179 lb 1886 – 158,352 lb 100 kg coca leaves  1 kg paste  800 g cocaine HCl

15. COCAINE - HISTORY

16. COCAINE - MEDICINAL COCAINE - MEDICINAL Topical Anaesthetic – upper respiratory tract & eye vasoconstrictive properties are desirable - Rapid absorption - Dosage = varies and depends on area to be anaesthetized - Maximum – 200 mg/ 70 kg adult - - Supplied as 4% and 10% solutions -2-4%  eye; 5-10%  nasal pharnyx

17. COCAINE - ILLICIT Cocaine HCl: Coke, Snow, Nose Candy, Dust, White Lady, Blow, Flake, Gold Dust, Happy Dust, Toot Freebase Cocaine: Crack, Rock Cocaine + Heroin: speedball Cocaine + Phencyclidine: Tick - to increase alertness, relieve fatigue, feel stronger, feel more decisive, - used to counteract the “down” feeling of tranquilizers or alcohol - used for euphoric effects

18. COCAINE - ILLICIT Speedball – Cocaine + Heroin

19. COCAINE - ILLICIT Modes of Administration Snorting Smoking Injection (intravenous) Oral

20. COCAINE - ILLICIT InhaledIVIntranasalOral Peak (min) 20-30 1-5 30-60 50-90 Subjective 3-515-30 15-6045-90 effects*(min) Time to Onset immediate min>30 min (inhale + IV) (2mg/kg – 115-246 mg dose)

21. COCAINE - ILLICIT Duration of Effects Dependent on mode of administration and dose The faster the onset, the stronger the high, the shorter the duration

22. COCAINE - ILLICIT Metabolism: Half life cocaine = 30-90 minutes Enzymatic Hydrolysis Cocaine  Ecgonine Methyl Ester cholinesterase Cocaine + EtOH  Coca ethylene

23. COCAINE - ILLICIT Metabolism: Half life cocaine = 30-90 minutes Half life benzoylecgonine = 5-7 hours Spontaneous Hydrolysis Cocaine  Benzoylecgonine - both enzymatic and spontaneous breakdown can be minimized with use of NaF and refrigeration (4 o C) - pH dependent  pH =  breakdown - enzymatic hydrolysis affected > spontaneous

24. COCAINE - ILLICIT Affects area of brain associated with pleasure and reward - nucleus accumbens Interferes with reuptake of dopamine (DA) from synapse With chronic use -  DA transporters -  DA receptor

25. COCAINE - ILLICIT Blood Concentrations – Recreational Use InhaledIVIntranasal Dose(mg)422532 Cmax(mg/dL)0.006-0.030.02-0.080.004-0.009 Dose(mg)200 Cmax(mg/dL)0.25 Surgical Patients – Max. 0.05mg/dL

26. COCAINE - ILLICIT Blood Concentrations 300 mg cocaine, 5 hourly doses, oral Mean cocaine = 0.1 mg/dL Mean benzoylecgonine = 0.4 mg/dL Postmortem Cases – death not related to cocaine Mean benzoylecgonine = 0.02-0.24 mg/dL

27. COCAINE - ILLICIT Low Dose (<20mg) Effects: - euphoria, sense of well being - exaggerated reflexes - postponement of mental/physical fatigue - increase self confidence - increase speed on simple tasks - constricted peripheral blood vessels - dilated pupils - increased temperature - increased heart rate - increased blood pressure - increased respiratory rate - decreased appetite

28. COCAINE - ILLICIT - rapid, irregular heart beat - loss of coordination - collapse - cold sweat - blurred vision Higher Doses Result in: -all those of lower dose plus - dizziness - feeling of restlessness - anxiety - delusions - paranoia

29. COCAINE - ILLICIT Long term effects - addiction - irritability and mood disturbances (mood swings) - restlessness - paranoia - hypersensitivity to sensory stimuli (auditory hallucinations) - unreal sensations (crawling insects)

30. COCAINE - ILLICIT Long term effects - sleep/eating/sexual disorders - destruction of nasal passage (if snorting) - social problems - ADDICTION

31. COCAINE - ILLICIT Subject to Tolerance with continued use, require more of the drug to achieve the same effect Results in Withdrawal Effect on Cessation - apathy - long periods of sleep - irritability - depression - disorientation

32. COCAINE - ILLICIT Blood Concentrations – Fatalites ANYONE’S GUESS N= 59 cocaine related deaths Cocaine = not detected – 1.2 mg/dL Benzoylecgonine = 0.009 – 3.1mg/dL N = 3 I.V. deaths Cocaine = not detected – 0.3 mg/dL Benzoylecgonine = 0.11 – 0.74 mg/dL

33. COCAINE - ILLICIT Overdose - agitation - increased body temperature - hallucinations/delirium - convulsions - unconciousness - death - cardiac arrest or seizure, followed by respiratory arrest

34. COCAINE - ILLICIT John Entwistle (The Who) - Died June 27, 2002 - Age 57 - Medication for a heart problem - COD: “Heart attack, brought about by a significant amount of cocaine in his system, amount unknown?” - Ruled: Not overdose, accidental

35. COCAINE - ILLICIT Blood Concentrations – Interpretation - recreational concentrations overlap with fatal concentrations – dependent on tolerance - breakdown of cocaine in vitro to benzoylecgonine - route of administration - possible redistribution

36. COCAINE - ILLICIT Blood Concentrations – Interpretation Cause of death is often attributed to cocaine overdose based on: - scene - history - any amount of benzoylecgonine

37. COCAINE - ILLICIT Non-Biological – Interpretation - cocaine is everywhere Over a seven-year period, Dr. Jay Poupko and his colleagues at ToxicologyConsultants Inc. in Miami have repeatedly tested currency in Austin, Dallas,Los Angeles, Memphis, Miami, Milwaukee, New York City, Pittsburgh, Seattle and Syracuse. He also tested American bills in London. "An average of 96 percent of all the bills we analyzed from the 11 cities tested positive for cocaine.” From: PRESUMED GUILTY Copyright, 1991, The Pittsburgh Press Co.By Andrew Schneider and Mary Pat Flaherty The Pittsburgh Press

38. COCAINE - ILLICIT Cocaine Psychosis: = cocaine-induced excited delirium - Severe hyperthermia (104-108 o C) - Extreme agitation - Delirium - Bizarre and violent behaviour (fear, panic, shouting, physical violence, thrashing) - Extreme strength - Associated with binging

39. COCAINE - ILLICIT Cocaine Psychosis: - Very similar in presentation to sudden onset of deaths in schizophrenics - Death occurs as individual calms - Concentrations often lower than those expected from fatalities

40. COCAINE - ILLICIT Cocaine and Newborns: - Cocaine can cross the Placenta Approximately 1/3 of absorbed cocaine enters fetus - Effect on baby? - Some say tend to be smaller, less healthy - Simone & Koren – long term effects – none - report in Calgary Herald states 1/16 babies in Toronto show exposure to cocaine; 10/120 needed resuscitative efforts

41. COCAINE - ILLICIT Human Performance Fischman & Schuster 1980 – cocaine (100 mg intranasally) can reverse reaction time impairment induced by sleep deprivation - did not show increased reaction time by cocaine alone - first tested by Freud in 1885 – n = 1

42. COCAINE - ILLICIT Human Performance -  sensitivity to light - other studies -  performance - counteracts deficiencies caused by EtOH - CRASH that follows high

43. AMPHETAMINES Amphetamine (Benzedrine, Dexedrine, speed, metabolite of methamphetamine) Methamphetamine (Desoxyn, meth, crystal, crank, ice)

44. AMPHETAMINES Designer Amphetamines - Methylenedioxymethamphetamine (MDMA, ecstasy,adam, XTC) - Methylenedioxyamphetamine (MDA,eve, metabolite of MDMA) - Paramethoxyamphetamine (PMA)

45. AMPHETAMINES HISTORY 1930 – Benzedrine introduced into market - inhaler to treat nasal congestion 1937 – Tablet form available for narcolepsy and minimal brain dysfunction (ADHD) in children WWII – Large use in military 1950-70 – large increase in use 1970-now – decline in amphetamines, increase in designer amphetamines USE APPEARS TO BE REGIONAL

46. AMPHETAMINES HISTORY USE in Military reported to have been discontinued BUT… CBC News Online, January 14, 2003 -report on the bombing of Canadian troops in Afghanistan by U.S. Pilots “Defence lawyers for the pilots have said they would argue that the forcible use of the drug dextroamphetamine (Dexedrine) – known on the street as “speed”, in the military as “go-pills” – was to blame for the incident.”

47. AMPHETAMINE – MEDICINAL Dexedrine = Dextroamphetamine Sulphate Indications -adjunctive treatment of narcolepsy - 5-60 mg daily -hyperkinetic behaviour in children - 2.5-40 mg daily - epilepsy - parkinsonism

48. METHAMPHETAMINE – ILLICIT Illicit Amphetamines - names interchanged but mostly methamphetamine - methylated amphetamine enters brain more readily - supplied as cystals, chunks, powders, - off-white-yellow - loose, capsules, tablets - various sizes, colors - various INGREDIENTS, PURITY, DOSE

49. METHAMPHETAMINE – ILLICIT Modes of Administration: - Intranasal (snorted) - Smoked - Injected (intravenous) - Oral (tablet, capsule)

50. METHAMPHETAMINE – ILLICIT Time to Onset - dependent on method of administration IV = smoking < intranasal < oral (immediately) (min) (>30 min) Duration of Effects - generally 2-4 hours

51. METHAMPHETAMINE – ILLICIT Elimination: Methamphetamine half-life = 6-15 hours Amphetamine half-life = 7-34 hours Methamphetamine  Amphetamine  Norephedrine   Deamination; p-Hydroxylation; Conjugation - normal conditions – 43% excreted unchanged - acidic urine – 76% excreted unchanged - alkaline urine – 2% excreted unchanged

52. METHAMPHETAMINE – ILLICIT Blood Concentrations: Amphetamine: 10 mg – 0.0035mg/dL at 2 hours 30 mg – 0.011 mg/dL at 2 hours Methamphetamine: 10 mg – 0.003 mg/dL at 1 hour 30 mg – 0.009 mg/dL (0.006-0.03) N = 9 Fatalities not due to drugs Methamphetamine conc. = 0.14 – 1.3 mg/dL

53. METHAMPHETAMINE – ILLICIT Blood Concentrations: Drivers (Methamphetamine) N= 26 0.001– 0.19 mg/dL - showed signs of nervousness, rapid speech, confusion, agitation, irrational or violent behaviour

54. METHAMPHETAMINE – ILLICIT Effects: similar to cocaine - Euphoria - increased alertness - increased heart rate - irregular heart beat - increased respiratory rate - increased blood pressure - decreased appetite - loss of coordination - hyperthermia - perspiration - blurred vision - anxiety - delusions - feeling of restlessness

55. METHAMPHETAMINE – ILLICIT Effects of Chronic Use: - Malnutrition - skin disorder - disease from vitamin deficiency - weight loss - Paranoia, Mental illness

56. METHAMPHETAMINE – ILLICIT Concentrations in Fatalities: Amphetamine: 0.05 – 4.1 mg/dL Methamphetamine: 0.009 - 4.0 mg/dL

57. METHAMPHETAMINE – ILLICIT Effects of Overdose: - Agitation - Hyperthermia - Intracranial hemorrhage - Hallucinations - Confusion - Convulsions - Death (Cardiac Arrhythmia, Respiratory Failure)

58. METHAMPHETAMINE – ILLICIT Blood Concentrations – Interpretation - recreational concentrations overlap with fatal concentrations - dependent on tolerance - death may not be immediate – concentrations decrease - redistribution - chirality (d > l)

59. METHAMPHETAMINE – ILLICIT Human Performance - improves alertness and performance in lab studies - epidemiological evidence shows methamphetamine adversely affects skills required for driving

60. PARAMETHOXY- AMPHETAMINE (PMA) Designer amphetamine compound Taken orally in pill/tablet form Usually misrepresented as “Ecstasy”  May be more potent  Stimulant but with  hallucinogenic effects

61. PARAMETHOXY- AMPHETAMINE (PMA) Martin. J. Anal. Tox. J. Anal. Tox. 25:649-651, 2001 2 fatal cases in year 2000 History indicative teenagers taking XTC (MDMA) Found PMA – 0.06 - 1.3 mg/dL

62. EPHEDRINE -originally derived from an asiatic shrub, Ephedra equisetina http://www.shamanshop.net/store/proddetail.cfm/ItemID/6224.0/CategoryID/8500.0/SubCatID/0.0/file.htm

63. EPHEDRINE - originally grown and processed stem & leaf sections. Drunk as a tea. - 1887 – isolated ephedrine, the active constituent - Not popular until 1920’s in U.S. when used for bronchodilating and decogesting.

64. EPHEDRINE - Mormon sects, not allowed to drink coffee because of religious conviction, use Ephedra nevadensis as a coffee substitute. - 'Mormon tea' stimulates differently and has more sexual stimulating effects than coffee. -Ephedra is therefore used in tantric rites as a sexual stimulant.

65. EPHEDRINE Medicinal Use: - Decongestant Found In: - cold meds (alone or with other drugs) - Omni-Tuss; Balminil Nasal Ointment; I.D.M. solution; Ephedrine - anti-asthmatic - Tedral

66. EPHEDRINE Also found in -herbal compounds such as Ephedra and Ma Huang http://www.shamanshop.net/store/proddetail.cfm/ItemID/7386.0/CategoryID/8500.0/SubCatID/0.0/file.htm

67. EPHEDRINE Also found in Legally available energizers, nutritional supplements and dietary teas http://store2.yimg.com/I/mte1999_1724_226006

68. PSEUDOEPHEDRINE - naturally occuring, isomer of ephedrine - common ingredient in over-the-counter meds alone or with other drugs - Contact Cold; Sudafed; Triaminic; Dristan; Sinutab; Tylenol Sinus; Tylenol Allergy; NeoCitran; Actifed; Benadryl; Benalyn; CoActifed; Balminil; Robitussin; Advil Cold & Sinus; Drixoral - less adverse effects than ephedrine

69. EPHEDRINE - White powder - Usually supplied as tablets - Bitter taste - Soluble in water

70. EPHEDRINE - closely related in structure to methamphetamine - CNS actions much less potent - CNS actions much longer acting - peripheral actions similar to epinephrine

71. EPHEDRINE Dosage: Typical Adult Dosage: 30-60 mg orally 3-4 X/day

72. EPHEDRINE Dosage : From Web Site – Erowid Oral Ephedrine Dosage Threshold 5-10 mg Light10-20 mg Common15-30 mg Strong30-50 mg Heavy 50+ mg

73. EPHEDRINE Elimination: - half-life – 5-7 hours Ephedrine  Norephedrine - slowly metabolized in liver to non-active metabolites - parent and metabolites excreted in urine - mostly parent (70-80%) - increases slightly with acidity of urine

74. EPHEDRINE Blood Concentrations: Ma Huang (19.4 mg ephedrine) Peak conc. 0.08 mg/dL at 4 hours Single Oral 24 mg Peak conc. 0.01 mg/dL at 1 hour Chronic Oral 45 mg 0.0095-0.006 mg/dL 20 yr male – survived 2.3 mg/dL

75. EPHEDRINE Effects: - potent bronchial muscle relaxant - dilates bronchioles - increased energy - increased alertness - decreased appetite - vasoconstriction - increase blood pressure - increased heart rate

76. EPHEDRINE Effects at higher doses : - anxiety - heart palpitations - vomiting - tremors - insomnia - hyperthermia

77. EPHEDRINE Effects of chronic use: - allegedly linked to strokes, heart attacks - law suits in U.S. re: Ma Huang - amphetamine like psychosis (confusion, paranoia

78. EPHEDRINE Concentrations in Fatalities Sudden death in 3 yr old male – 0.27 mg/dL N = 5 0.35 – 2.1 mg/dL

79. EPHEDRINE Overdose : - restlessness - anxiety - dizziness - tremor - confusion - hallucinations - delerium - convulsions - aggressive behaviour - - cerebral hemorrhage - high heart rate - high blood pressure - irregular heart beat - hyperthermia - Death

80. EPHEDRINE Interpretation: - redistribution ??

81. EPHEDRINE Human Performance - improves mental and motor performance in those who are fatigued - does not enhance performance in those who are alert and attentive