Methylated Amphetamines- MDA and MDMA

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Methylated Amphetamines-MDA and MDMA

• Methylenedioxymethamphetamine (MDMA, Ecstasy,
  XTC)-MDA is a metabolite of MDMA and may be
  responsible for much of the MDMA effect.
• Synthesized in 1912
• Structurally related to amphetamines
• Sympathomimetic
• Weak in altering perceptual functions
• But strong effects on emotions - empathogen
• Used in combo with psychotherapy
• Of interest http//www.biopsychiatry.com/intervie
  w/index.html

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Ecstasy (MDMA) Physiological Effects

• Sympathomimetic
• Bruxism Trismusteeth grinding jaw clenching
  (pacifiers)
• Dehydration/Overhydration
• Hyperthermia
• Tachycardia

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Ecstasy (MDMA) Psychological Effects

• Increased alertness, arousal, insomnia--stimulant
  effects
• Euphoria, increased emotional warmth
• Increased empathy and insight?
• Hallucinogenic effects are largely absent

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History

• Patented by Merck in 1914
• Advocated by some as adjunct to psychotherapy
  (1970s-80s)
• A Designer DrugPicked up the name ecstasy
  became significant street drug (1980s)
• Schedule I drug (1986- The Analogue drug Act)
• Prototype club drug (1990s)

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MDMA Prototype Club Drug
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Pharmacodynamics

• Monoamine neurotransmission
• increase synaptic DA and 5-HT
• blocks 5-HT transporter
• enters neuron and causes release of 5-HT

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Ecstasy and brain Damage?Preclinical research

• Serotonin depletion, damage to serotonergic
  neurons reported in several species including
  rats and primates (see Morton, 2005 for a review)
  
• Effects were present in primate brain 7 years
  after MDMA exposure Hatzidimitrious et al., 1999)
  

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MDMA MDA neurotoxicity
5-HT immunoreactive fibers in rat parietal cortex
MDA
MDMA
Normal
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Are doses used in preclinical research too high?

• neurotoxic doses in non-humans (5-20 mg/kg twice
  or more/day for several days) are generally
  higher than would be typical of human use.
• However, people often take several tablets at a
  time or throughout a nights binge and a tablet
  may contain up to 300 mg 4-5 mg/kg in an average
  person.

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X Toxicity

• Malignant hyperthermia and dehydration
• Idiopathic toxic response (not common but nasty)
• Renal failure
• Rhabdomyolysis disintegration of muscle tissue
• seizures, arrhythmias, heart failure, stroke,
• Most MDMA-related fatalities have been attributed
  to symptoms of heat stroke and hyperthermia

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Residual (long-term) adverse effects?

• Topp et al. (1999) Australia study
• Physical side effects
• Loss of energy (65), Muscular aches (60)
• Hot/cold flashes (48), Numbness (47)
• Profuse sweating (43), Tremors (42)
• Psychological side effects
• Depression (56), rritability (63),
• Sleep difficulty (56), Confusion (47)
• Anxiety (45), Paranoia (40)
• Memory deficits?
• ( note issue of sample problems/poly-drug use
  etc..)

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What is PMA?

• Paramethoxy-amphetamine
• "Death" "Mitsubishi Double Stack"
• "Killer" "Red Mitsubishi"
• Substitute for MDMA
• Cheaper to make
• Slower, longer effects
• More hallucinogenic
• Incidence of toxic side effects much higher than
  MDMA (narrow safety margin)

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Myristin and Elemicin

• Found in nutmeg and mace
• Structurally similar to mescaline
• Significant nausea and vomiting
• The sickness usually limits use

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GlutamatergicPsychedelics

• AKA-Dissociative Anesthetics
• -Phencyclidine (PCP, Angel dust, Lovely)
• -Ketamine (Special K)

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Phencyclidine

• PCP
• Glutamate (NMDA) receptor antagonist
• Blocks the function of glutamate
• Used as an analgesic and anesthetic
• Can be administered by any route
• Oddly enough, animals self-administer
  (euphoria)

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PCP- physiological effects

• numbness, loss of motor coordination, slurred
  speech, blurred vision, Nystagmus
• Higher doses lead to
• hyper excitability or stupor
• coma
• seizures
• death
• A perfect example of a Schedule I drug
• High rate of psychotic episodes some long-term

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Subjective Effects of PCP/Ketamine

• Sensations of light coming through the body
  and/or colorful visions
• Complete loss of time sense
• Bizarre distortions of body shape or size
• Altered perception of body consistency
• Sensations of floating or hovering in space
• Feelings of leaving ones body
• Visions of spiritual or supernatural beings
• Emotions ranging from euphoria to hositlity
• true psychosis
• Hallucinations, paranoia, agitation, dissociation
  
• Dalgarno Shewan (1996)

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Ketamine

• Special K
• Very similar to PCP, not as powerful
• Liquid, but can be powdered for snorting or
  smoking
• Another perfect example of a Schedule I drug

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Dextromethorphan

• Active ingredient in most OTC cough medicine
• NMDA receptor blockade at high doses
• Mostly teenage males abuse it
• Like PCP and K at 20-30 X OTC dose
• Coricidin Bad news

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CholinergicHallucinogens
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Anticholinergic hallucinogens

• Atropine-Deadly nightshade, Datura, Jimson weed,
  and Mandrake, Atropa belladonna
• Scopolamine-from Datura, Jimson weed, Mandrake
  and Henbane

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CholinergicHallucinogens

• Acetylcholine receptor (muscarinic) antagonists
• Dissociatives that induces delirium ,
  hallucinations, and amnesia
• Classic anti-cholinergic symptoms
• Hot as hell
• Dry as a bone
• Mad as a hatter
• Blind as a bat
• Red as a beet
• Used in the treatment of motion sickness to
  dilate pupils during eye-exams.

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Datura
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Jimson weed
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Anticholinergic effects

• Dry mouth, blurred vision, loss of motor control
• Dream-like trance state
• Little or no memory of experience

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Muscarine/Muscimol

• Found in mushrooms (Amanita Muscaria)
• Muscimol is a GABAA agonist
• Trance-like, dreamy state with dreamlike
  illusions
• Like Ambien
• Muscarine is an Acetylcholine agonist (muscarinic
  receptors)
• Not psychotropic
• Peripheral effects sweating, limb twitching,
  seizure activity

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Salvia Divinorum

• Plant used by the Mazatec people of Southern
  Mexico Diviners sageleaves chewed or smoked
• Active substance salvinorum A (affects Kappa
  receptors)--most potent natural hallucinogen (100
  microgram ED50)

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Salvia Divinorum

• Brief (30-60 min) intense trip visual
  hallucinations, dissociative state, some bad
  trips, recent highly publicized suicide
• Marketed legally in US (in most states) as herbal
  dietary supplementcurrently under DEA review