Brian J. Piper, Ph.D.

Goals

• History

• Epidemiology

• Acute Effects

• Pharmacokinetics

• Pharmacodynamics

• Toxicology

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

Chemistry

• Entactogen: touching within (Nichols)

Amphetamine

MDA (methylenedioxyamphetamine)

MDMA (methylenedioxymethamphetamine)

Pharmacokinetics: Age

MDMA -----> MDALiver

Meyer, Piper,& Vancolli (i2008) Annals of the New York Academy of Sciences., 1139, 151-163.

Pharmacokinetics: Individual Differences Following Oral Administration of MDMA

Plasma MDMA for each marmoset thatreceived 1 mg/kg.

0 20 40 600

10

20

30

40

50

60

70

80

Eric

Autumn

Lexi

Zale

Time

MD

MA

(n

g/m

l)

Ng/ml

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 MDMA• slower onset, longer effects, more

hallucinogenic• incidence of toxic side effects much higher than

MDMA (narrow safety margin), e.g. hyperthermia

MtF: Epidemiology

.

MtF: Epidemiology

.

MtF: Urban versus Rural

YearYear

EpidemiologyAdults:

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 Adelaide (SA)

• Is it ethical to monitor recreational drugs in:– City– High Schools– Prisons

Short-term effects of Ecstasy

• Psychological– Empathy– Increased energy– Openness– Increased sensitivity to

sounds & touch

• Physiological– Increase in heart rate– Increase in blood pressure– Reduced appetite– Bruxism: grinding teeth– Trismus: jaw clenching

Pharmacodynamics

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

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. ->

<-

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.

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.

Neurochemical Protection

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

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, 1192-1205.

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).

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

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

Paracelsus

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

1493-1541

Ecstasy Hangover

Piper et al. (2006). JPET 317, 838-849.

Adolescent MDMA prevents the binge induced hangover.

Piper et al. (2006). Journal of Pharmacology & Experimental Therapeutics 317, 838-949. 317, 838-949.

The dose makes the poison (Serotonin Transporter)

Piper et al. (2006). Journal of Pharmacology & Experimental Therapeutics 317, 838-949.

Adolescent MDMA blocks the neurotoxicity of a MDMA “binge”.

Piper et al. (2006). Journal of Pharmacology & Experimental Therapeutics 317, 838-949.

Misinformation

D

D = Dark regionLack of SERTNot “Holes in Brain”

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)

Also: heart rate, respiration, lifespan.

Post-Traumatic Stress Disorder

Four or more weeks of the following symptoms constitute Post-Traumatic Stress Disorder (PTSD):Re-experiencing: nightmares, flashbacks, intrusive thoughtsAvoidance: situation & associatedPhysical Arousal: sleep, concentration, irritability

Significant social or occupational impairment

Half of patients are non-responders

•3 min: http://www.youtube.com/watch?v=7aFs6695VyQ

MDMA & PTSD

• Psychotherapy and randomized (125 mg MDMA or dextrose) double-blind study

Mithoefer et al. J Psychopharmacology, 25, 439-452.

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 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=