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).

1. Brian J. Piper, Ph.D.

2. Goals
• History
• Epidemiology
• Acute Effects
• Pharmacokinetics
• Pharmacodynamics
• Toxicology

3. History
3,4-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. Chemistry
• Entactogen: touching within (Nichols)
MDMA (methylenedioxymethamphetamine)
MDA (methylenedioxyamphetamine)
Amphetamine

5. Pharmacokinetics: Age
Meyer, Piper,& Vancolli (i2008) Annals of the
Liver New York Academy of Sciences., 1139,
MDMA -----> MDA 151-163.

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. Epidemiology
• Predictions
– Year (1996 – 2010)
– Sex
– Urban versus Rural
– Age (8th grade – 30)

8. Ecstasy = MDMA?

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. MtF: Epidemiology
.

11. MtF: Epidemiology
.

12. MtF: Urban versus Rural
Year
Year

13. Epidemiology
Adults:
MtF

14. Absence of Sex
Differences

15. NHSDUH: New users fluctuate
NHSDUH, 2011

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. 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. Pharmacodynamics
• MDMA increases neurotransmitters
(serotonin, norepinephrine, dopamine) &
hormones (cortisol, prolactin, oxytocin)

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. 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. 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. Neurochemical Protection
Cital = citalopram, an antidepressant drug Piper et al. (2008). Neuropsychopharmacology,, 33, 1192-1205.

23. SERT Blockade Did Not Block
Hyperthermia
Piper et al. (2008). Neuropsychopharmacology,, 33, 1192-1205.

24. Partial Uncoupling of Behavioral
& Neurochemical Toxicology
Piper et al. (2008). Neuropsychopharmacology,, 33, 1192-1205.

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. 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. 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. Paracelsus
• All things are poison, and nothing is
without poison; only the dose permits 1493-1541
something not to be poisonous.

29. Ecstasy Hangover
Piper et al. (2006). JPET 317, 838-8

30. Adolescent MDMA prevents the
binge induced hangover.
Piper et al. (2006). Journal of Pharmacology & Experimental Therapeutics 317, 838-949. 317, 838-949.

31. The dose makes the poison
(Serotonin Transporter)
Piper et al. (2006). Journal of Pharmacology & Experimental Therapeutics 317, 838-949.

32. Adolescent MDMA blocks the
neurotoxicity of a MDMA “binge”.
Piper et al. (2006). Journal of Pharmacology & Experimental Therapeutics 317,

33. Misinformation
D = Dark region
Lack of SERT
Not “Holes in Brain”
D

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. Also: heart rate, respiration, lifespan.

36. Post-Traumatic Stress Disorder
Four or more weeks of the following symptoms
constitute Post-Traumatic Stress Disorder (PTSD):
Re-experiencing: nightmares, flashbacks, intrusive
thoughts
Avoidance: situation & associated
Physical Arousal: sleep, concentration, irritability
Significant social or occupational impairment
Half of patients are non-responders
•3 min: http://www.youtube.com/watch?v=7aFs6695VyQ

37. MDMA & PTSD
• Psychotherapy and
randomized (125 mg
MDMA or dextrose)
double-blind study
Mithoefer et al. J Psychopharmacology, 25, 439-452.

38. Clinician Adminitered PTSD Scale (CAPS)
Impact of Events Scale-Revised (IES-R)

39. Results but …
• Representative sample (20/134)?
• Double-blind?

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=