Ecstasy/MDMA

Ecstasy/MDMA Overview• MDMA = 3,4-methylene dioxy-N-

methyl amphetamine (Schedule 1)

• Shares properties of amphetamines and hallucinogens

• Associated with electronic music dance parties (“raves”)

• May have psychotherapeutic value (entactogens, empathogens)

• Associated with 5-HT neurotoxicity

• “Ecstasy” often adulterated (amphetamine, ketamine, PCP, caffeine), may consist of 0 - 100% MDMA

History• Synthesized, patented by Merck (1912,

1914)

• Studied as appetite suppressant but never marketed (50s and 60s)

• Researched by Army intelligence as potential truth serum (50s)

• Limited recreational use (60s)

• Psychotherapeutic use (mid-late 70s): called “penicillin for the soul”

• Use leaks out to expanding recreational use-acquires name of Ecstasy (early 80s)

• DEA places MDMA in Schedule I (1985-88)

• Use spreads to Europe, becomes part of raves, spreads back to U.S. (late 80s)

Hallucinogenic Psychotherapy Redux

“an easily controlled altered state of consciousness with emotional and sensual overtones, and with little hallucinatory effect”

UC Berkeley biochemist/toxicologist Alexander Shulgin, self-report after synthesizing and self-administering 120mg MDMA, 1978

Combination of

• Stimulant effects• Mild hallucinogen-like effects• More unique emotional effects

MDMA Psychotherapy

• 1970s research appeared successful, but poorly controlled

• Advantages over hallucinogenic therapy:– shorter-acting – more introspection– greater intimacy/trust– reduced anxiety/depression– less altered perception– more stable body image and ego

• Current overseas research suggests decreased drug use, other psychiatric improvements

Use of Ecstasy among 8th,10th and 12th graders

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95 96 97 98 99 '00 '02 '05

8th10th12th

Perceived Harmfulness of Obtaining Ecstasy

Reported by 12th Graders

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80

'00 '01 '02 '03 '04 '05

% whothinkMDMA isharmful

Methods of Ingestion

• Orally• Snorted (Powder)• Smoked• Injected

• Effect lasts 3-6 hrs• Average dose is 1-2

tablets (60-120 mg)

• 20 to 40 minutes• 5 to 10 minutes• 20 to 30 seconds• 10 to 20 seconds

Acute Effects (cont)

Mood (euphoria)

Alertness (sympathomimetic)

Heart rate, blood pressure, body temperature

Restlessness, locomotion

Sensory intensity

Fatigue, need for sleep (insomnia)

Appetite

Empathy, communication, talkativeness (empathogenesis)

Feelings of sensuality, affection (entactogenesis)

Self-consciousness, fear, embarrassment, defensiveness

Nystagmus, jaw-clenching, muscle tension (need for pacifiers)

Visual distortion, dizziness, headache, nausea, vomiting (more likely at higher doses)

Neurotoxicity

Raves

Raves(GHB, Meth, K, Rohypnol, NO, LSD)

• Setting– Club, Warehouse, Outdoors

– Psychedelic/Techno Décor

– Short notice

• “Tools”– Pacifier/lollipops

– Masks

– Inhalants (e.g. Vicks)

– Glowsticks

Raves (cont)

• Music and Dance

– DJed electronica

– Usually fast (average 120 bpm) and high energy

• Philosophy

– “Technoshamanism” – altering consciousness through technology

– PLUR (Peace, Love, Unity, and Respect)

Ecstasy experience

“The drug removes all your neuroses. It takes away the fear of response. There is an overwhelming sense of peace, you are at peace with the world. You feel open, clear, tender. I can’t imagine that anyone is angry under its influence, or selfish or mean or defensive. You have lots of insight into yourself, real insight, which you hold on to after the experience is gone”

Behavioral Effects

• Positive: mental stimulation, emotional warmth, empathy towards others, general sense of well-being, decreased anxiety

• Negative/Undesirable: anxiety, agitation, recklessness, nausea, chills, sweating, muscle cramping, blurred vision, jaw clenching, dehydration, high blood pressure, heart failure, kidney failure, arrhythmia, loss of consciousness, seizures, hyperthermia, hyponatremia (low sodium levels)

Ecstasy-Viagra• Clubgoers call a

combination of the two drugs "sextasy" - heightens sexual experience.

• the two drugs are a dangerous mix.

• can cause heart problems and open the door to sexually transmitted diseases.

Pharmacokinetics

• Dose: ~ 80-160mg (500mg – fatal)

• Route: Usually oral (high bioavailability from GI tract)

• Onset: 30-60 minutes

• Peak: ~1 hour

• Duration: 3-12 hours

Pharmacodynamics

• Indirect agonist for– 5-HT– DA and NE (less than 5-HT) – different from hallucinogens

• Mechanisms– Block reuptake (5x amph)– Reverse reuptake– Others like AMPH?

Neurobiological Effects

1) MDMA increases oxytocin levels, which may strengthen the therapeutic effects;

2) MDMA increases ventromedial prefrontal activity and decreases amygdala activity, which may improve emotional regulation and decrease avoidance, and

3) MDMA increases norepinephrine release and circulating

cortisol levels, which may facilitate emotional engagement and enhance extinction of learned fear associations.

DSM-IV Dependence Criteria by Pill Use

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Tolerance Withdrawal Takes substance inlarger amounts or

over longer period

Can't cut down or control use

Much time spentusing/recovering

from use

Important activities given up for substance

Substance useddespite knowing itcaused physical or psychological harm

1-99 pills (n=387) 100-499 pills (n=178) 500+ pills (n=69)

p<.0001

p<.0001 p<.0001

p<.0001

p<.0001

p=.0014p<.0001

rCBF differences between MDMA and placebo. Upper row: MDMA-induced increases in rCBF. a = ventromedial frontal cortex (including orbitofrontal and ventral anterior cingulate cortex), b = cerebellum, c = inferior temporal cortex, d = occipital cortex. Lower row: MDMA-induced decreases in rCBF. e = superior temporal cortex, f = insula, g = Thalamus, h = pre-/paracentral cortex, k = left amygdala

Neurotoxicity

• Effect: destruction of 5-HT axons

• Suspected consequences– Depression

– Personality changes (e.g. irritability)

– Cognitive impairment• Verbal memory in particular

Neurotoxicity (cont)

• Possible mechanisms/factors– Main candidate: Oxidative

stress• Exhausted energy sources

• Free radical metabolites

– Cofactor: Body temperature

• Indices– Tissue staining

– 5-HT and metabolite levels

– Reuptake transporter binding

THE END

MDMA MDMA

5-HT Axons Frontal

Methodological Issues

• Animal studies– Route of administration

– Dose/Frequency

– Drug content

– Species differences

• Human studies– Discussed in reader article

Use Statistics

• In 1998, 3.4 million Americans age 12+ (1.5%) had used Ecstasy at least once

• Heaviest number users in ages 18 - 25 (1.4 million, i.e. 5%)

• From 1999 - 2000, use increased among 8th, 10th, and 12th graders but decreased from 2000-2005

• African-American students used less than white or Hispanic students in 2000

Raves (cont)

• Ecstasy acute risks– Dehydration– Heat Stroke– Organ failure– Adulterants

• “Herbal Ecstasy”– Natural stimulant (e.g. ephedrine)– Similar acute risks– Placebo psychoactive effects

Ecstasy “Hangover”

• Effects– Depression– Memory impairment– Difficulty concentrating

• Possible causes– Neurotoxicity– Acute decrease in 5-HT levels– Concurrent drug use– Weekend contrast