Brian J. Piper, Ph.D.
Goals•   History•   Epidemiology•   Acute Effects•   Pharmacokinetics•   Pharmacodynamics•   Toxicology
History3,4-methylenedioxymethamphetamine (MDMA, aka ecstasy, X)• 1912: Synthesized by German pharmaceutical company   Merc...
Chemistry    • Entactogen: touching within (Nichols)                     MDMA (methylenedioxymethamphetamine)MDA (methylen...
Pharmacokinetics: Age                        Meyer, Piper,& Vancolli (i2008) Annals of the            Liver       New York...
Pharmacokinetics: Individual Differences Following        Oral Administration of MDMA                         Plasma MDMA ...
Epidemiology• Predictions  – Year (1996 – 2010)  – Sex  – Urban versus Rural  – Age (8th grade – 30)
Ecstasy = MDMA?
What is PMA?• paramethoxyamphetamine• "Death" "Mitsubishi Double Stack"  "Killer" "Red Mitsubishi"• cheaper substitute for...
MtF: Epidemiology           .
MtF: Epidemiology           .
MtF: Urban versus Rural             Year             Year
Epidemiology   Adults:    MtF
Absence of Sex  Differences
NHSDUH: New users fluctuate                        NHSDUH, 2011
Wastewater analysis• Australia was the world  leader for MDMA use• Samples collected  every 6th day (May-  June) in Adelai...
Short-term effects of Ecstasy• Psychological                  • Physiological  –   Empathy                      –   Increa...
Pharmacodynamics• MDMA increases neurotransmitters  (serotonin, norepinephrine, dopamine) &  hormones (cortisol, prolactin...
Serotonin• Serotonin is 5-hydroxytryptamine (5-HT)• The brain uses the amino acid tryptophan (found  in bananas, milk, yog...
Raphe nuclei• 5-HT cell bodies  (somas) are found in  the brainstem in the  raphe nuclei.• 5-HT axons descend  into spinal...
Serotonin Transporter (SERT)•   SERT is a protein found at the synapse    and along the axon that removes 5-HT    from the...
Neurochemical ProtectionCital = citalopram, an antidepressant drug   Piper et al. (2008). Neuropsychopharmacology,, 33, 11...
SERT Blockade Did Not Block      Hyperthermia      Piper et al. (2008). Neuropsychopharmacology,, 33, 1192-1205.
Partial Uncoupling of Behavioral & Neurochemical Toxicology       Piper et al. (2008). Neuropsychopharmacology,, 33, 1192-...
Long-term effects of High Dose MDMA       on 5-HT neurons (animal data)•    Weeks after MDMA treatment to     animals, the...
Serotonin fibers in the caudate nucleus of a control     squirrel monkey (A), a monkey that received 5 mg/kg        MDMA 2...
Tolerance/Sensitization• Design  – PD 35-60: 10 mg/kg x 2 (N=24/group)  – PD 67: “Binge” 5-10 mg/kg x 4 (N=8/group)    • T...
Paracelsus• All things are poison, and nothing is  without poison; only the dose permits   1493-1541  something not to be ...
Ecstasy Hangover                   Piper et al. (2006). JPET 317, 838-8
Adolescent MDMA prevents the   binge induced hangover.          Piper et al. (2006). Journal of Pharmacology & Experimenta...
The dose makes the poison  (Serotonin Transporter)            Piper et al. (2006). Journal of Pharmacology & Experimental ...
Adolescent MDMA blocks theneurotoxicity of a MDMA “binge”.                 Piper et al. (2006). Journal of Pharmacology & ...
Misinformation                 D = Dark region                 Lack of SERT                 Not “Holes in Brain”        D
MDMA Doses in Animals vs.         Humans• Humans take 150 mg pill(s)/75 kg = 2 mg/kg• Rats receive 10 mg/kg (or more)• Way...
Also: heart rate, respiration, lifespan.
Post-Traumatic Stress DisorderFour or more weeks of the following symptomsconstitute Post-Traumatic Stress Disorder (PTSD)...
MDMA & PTSD      • Psychotherapy and        randomized (125 mg        MDMA or dextrose)        double-blind study  Mithoef...
Clinician Adminitered PTSD Scale (CAPS)Impact of Events Scale-Revised (IES-R)
Results but …• Representative sample (20/134)?• Double-blind?
Videocasts• Ricaurte, George (2001). MDMA in  animals: Relationship to human ecstasy  use. Scroll to 74:30 to 1:08 from vi...
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Neuropharmacology: MDMA

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Lecture 19 from a college level neuropharmacology course taught in the spring 2012 semester by Brian J. Piper, Ph.D. (psy391@gmail.com) at Willamette University. Pharmacokinetics, pharmacodynamics, and epidemiology of MDMA (ecstasy).

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Neuropharmacology: MDMA

  1. 1. Brian J. Piper, Ph.D.
  2. 2. Goals• History• Epidemiology• Acute Effects• Pharmacokinetics• Pharmacodynamics• Toxicology
  3. 3. History3,4-methylenedioxymethamphetamine (MDMA, aka ecstasy, X)• 1912: Synthesized by German pharmaceutical company Merck by Anton Kollisch (1888-1916)• 1950’s: U.S. Army conducted animals studies to determine the lethal dose.• 1970’s: Mental health workers advocated using MDMA with psychotherapy. There are ongoing studies to use MDMA with talk therapy for anxiety related to post-traumatic stress disorder and among terminally ill cancer patients.• 1985: Drug Enforcement Agency (DEA) classifies MDMA as Schedule I• 2003: Illicit Drug Anti-Proliferation Act: this increase penalties for ecstasy distribution, possession, or place that condone illicit drug use
  4. 4. Chemistry • Entactogen: touching within (Nichols) MDMA (methylenedioxymethamphetamine)MDA (methylenedioxyamphetamine) Amphetamine
  5. 5. Pharmacokinetics: Age Meyer, Piper,& Vancolli (i2008) Annals of the Liver New York Academy of Sciences., 1139, MDMA -----> MDA 151-163.
  6. 6. Pharmacokinetics: Individual Differences Following Oral Administration of MDMA Plasma MDMA for each marmoset that received 1 mg/kg. 80 70 60 M D M A (n g /m l) Ng/ml 50 Lexi 40 Eric Zale 30 Autumn 20 10 0 0 20 40 60 Time
  7. 7. Epidemiology• Predictions – Year (1996 – 2010) – Sex – Urban versus Rural – Age (8th grade – 30)
  8. 8. Ecstasy = MDMA?
  9. 9. What is PMA?• paramethoxyamphetamine• "Death" "Mitsubishi Double Stack" "Killer" "Red Mitsubishi"• cheaper substitute for MDMA• slower onset, longer effects, more hallucinogenic• incidence of toxic side effects much higher than MDMA (narrow safety margin), e.g. hyperthermia
  10. 10. MtF: Epidemiology .
  11. 11. MtF: Epidemiology .
  12. 12. MtF: Urban versus Rural Year Year
  13. 13. Epidemiology Adults: MtF
  14. 14. Absence of Sex Differences
  15. 15. NHSDUH: New users fluctuate NHSDUH, 2011
  16. 16. Wastewater analysis• Australia was the world leader for MDMA use• Samples collected every 6th day (May- June) in Adelaide (SA)• Is it ethical to monitor recreational drugs in: – City – High Schools – Prisons
  17. 17. Short-term effects of Ecstasy• Psychological • Physiological – Empathy – Increase in heart rate – Increased energy – Increase in blood pressure – Openness – Reduced appetite – Increased sensitivity to – Bruxism: grinding teeth sounds & touch – Trismus: jaw clenching
  18. 18. Pharmacodynamics• MDMA increases neurotransmitters (serotonin, norepinephrine, dopamine) & hormones (cortisol, prolactin, oxytocin)
  19. 19. Serotonin• Serotonin is 5-hydroxytryptamine (5-HT)• The brain uses the amino acid tryptophan (found in bananas, milk, yogurt) to make 5-HT.• 5-HT has been implicated in mood (anxiety, depression & aggression), appetite, sexuality, and cognition. -> <-
  20. 20. Raphe nuclei• 5-HT cell bodies (somas) are found in the brainstem in the raphe nuclei.• 5-HT axons descend into spinal cord and ascend to the hippocampus and cortex.
  21. 21. Serotonin Transporter (SERT)• SERT is a protein found at the synapse and along the axon that removes 5-HT from the synaptic cleft.• SERT (shown in pink) brings 5-HT from the synaptic cleft back into the axon.• Serotonin reuptake inhibitors (e.g. Prozac or fluoxetine) prevent SERT from removing 5-HT.• The density of SERT is used as a index of the number of 5-HT axons and is altered by MDMA.
  22. 22. Neurochemical ProtectionCital = citalopram, an antidepressant drug Piper et al. (2008). Neuropsychopharmacology,, 33, 1192-1205.
  23. 23. SERT Blockade Did Not Block Hyperthermia Piper et al. (2008). Neuropsychopharmacology,, 33, 1192-1205.
  24. 24. Partial Uncoupling of Behavioral & Neurochemical Toxicology Piper et al. (2008). Neuropsychopharmacology,, 33, 1192-1205.
  25. 25. Long-term effects of High Dose MDMA on 5-HT neurons (animal data)• Weeks after MDMA treatment to animals, there is a reduction in 5-HT, 5-HT metabolites, and SERT which suggests a 5-HT axotomy (axons are cut).• Months to years after MDMA in monkeys, some brain areas still show a reduction in SERT and 5-HT (hypoinnervation). However, other areas show an abnormal increase in SERT and 5-HT (hyperinnervation).
  26. 26. Serotonin fibers in the caudate nucleus of a control squirrel monkey (A), a monkey that received 5 mg/kg MDMA 2 weeks (B), or 7 years (C) previously.Hatzidimitriou, G. et al. J. Neurosci. 1999;19:5096-5107
  27. 27. Tolerance/Sensitization• Design – PD 35-60: 10 mg/kg x 2 (N=24/group) – PD 67: “Binge” 5-10 mg/kg x 4 (N=8/group) • Temperature, Weight, and Serotonin Syndrome – PD 68: Motor Activity (“Hangover”) – PD 74: [3H]Citalopram binding
  28. 28. Paracelsus• All things are poison, and nothing is without poison; only the dose permits 1493-1541 something not to be poisonous.
  29. 29. Ecstasy Hangover Piper et al. (2006). JPET 317, 838-8
  30. 30. Adolescent MDMA prevents the binge induced hangover. Piper et al. (2006). Journal of Pharmacology & Experimental Therapeutics 317, 838-949. 317, 838-949.
  31. 31. The dose makes the poison (Serotonin Transporter) Piper et al. (2006). Journal of Pharmacology & Experimental Therapeutics 317, 838-949.
  32. 32. Adolescent MDMA blocks theneurotoxicity of a MDMA “binge”. Piper et al. (2006). Journal of Pharmacology & Experimental Therapeutics 317,
  33. 33. Misinformation D = Dark region Lack of SERT Not “Holes in Brain” D
  34. 34. MDMA Doses in Animals vs. Humans• Humans take 150 mg pill(s)/75 kg = 2 mg/kg• Rats receive 10 mg/kg (or more)• Ways to compare doses across species: – Body weight equivalence (1x) – Interspecies scaling (5x)
  35. 35. Also: heart rate, respiration, lifespan.
  36. 36. Post-Traumatic Stress DisorderFour or more weeks of the following symptomsconstitute Post-Traumatic Stress Disorder (PTSD):Re-experiencing: nightmares, flashbacks, intrusivethoughtsAvoidance: situation & associatedPhysical Arousal: sleep, concentration, irritabilitySignificant social or occupational impairmentHalf of patients are non-responders•3 min: http://www.youtube.com/watch?v=7aFs6695VyQ
  37. 37. MDMA & PTSD • Psychotherapy and randomized (125 mg MDMA or dextrose) double-blind study Mithoefer et al. J Psychopharmacology, 25, 439-452.
  38. 38. Clinician Adminitered PTSD Scale (CAPS)Impact of Events Scale-Revised (IES-R)
  39. 39. Results but …• Representative sample (20/134)?• Double-blind?
  40. 40. Videocasts• Ricaurte, George (2001). MDMA in animals: Relationship to human ecstasy use. Scroll to 74:30 to 1:08 from video at: http://nihvideoidol1.cit.nih.gov:8080/NIH/widgets/hyperlinking/autosuggest.jsp?seconds=0&filetype=FLASH&realplayer=http://videocast.nih.gov/flashvod.xml? id=6036&offset=0&url=http%3A%2F%2Fvideocast.nih.gov%2FSummary.asp%3FFile %3D10155&id=6036&links=MDMA,ECSTASI,ADVANC,CHALLENG,FUTUR,DAI,RESEARCH&v=c&fileid=10155&q=• Morgan, Michael (2001). Are the psychological problems associated with regular MDMA use reversed by prolonged abstinence? Scroll to 336:00 to 369:00 from video at: http://nihvideoidol1.cit.nih.gov:8080/NIH/widgets/hyperlinking/autosuggest.jsp? seconds=0&filetype=FLASH&realplayer=http://videocast.nih.gov/flashvod.xml?id=6036&offset=0&url=http%3A%2F%2Fvideocast.nih.gov%2FSummary.asp%3FFile %3D10155&id=6036&links=MDMA,ECSTASI,ADVANC,CHALLENG,FUTUR,DAI,RESEARCH&v=c&fileid=10155&q=

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