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/interview/index.html

Ecstasy (MDMA): Physiological Effects

• Sympathomimetic• Bruxism & Trismus—teeth grinding & jaw

clenching (pacifiers)• Dehydration/Overhydration• Hyperthermia• Tachycardia

Ecstasy (MDMA): Psychological Effects

• Increased alertness, arousal, insomnia--stimulant effects

• Euphoria, increased emotional warmth• Increased empathy and insight?• Hallucinogenic effects are largely absent

Percent High School Seniors reporting MDMA use during their Senior year (Johnston, O'Malley,Bachman & Schulenberg, 2005)

96 98 00

Percent High School Seniors reporting MDMA use during their Senior year (Johnston, O'Malley,Bachman & Schulenberg, 2005)

96 98 00 02

Year

Per

cent

Usi

ng

2

4

6

8

04 06

History

• Patented by Merck in 1914• Advocated by some as adjunct to

psychotherapy (1970s-80s)• A “Designer Drug”…Picked up the name

“ecstasy” & became significant street drug (1980s)

• Schedule I drug (1986- The Analogue drug Act)• Prototype “club drug” (1990s)

MDMA: Prototype Club Drug

PharmacodynamicsPharmacodynamics

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

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)

MDMA & MDA neurotoxicityMDMA & MDA neurotoxicity

9.9

Normal MDAMDMA

5-HT immunoreactive fibers in rat parietal cortex

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 night’s binge and a tablet may contain up to 300 mg: 4-5 mg/kg in an average person.

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

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..)

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)

Myristin and Elemicin

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

GlutamatergicPsychedelics

AKA-Dissociative Anesthetics:-Phencyclidine (PCP, Angel dust, Lovely)

-Ketamine (Special K)

PhencyclidinePCPPCPGlutamate (NMDA) receptor antagonistGlutamate (NMDA) receptor antagonist

Blocks the function of glutamateBlocks the function of glutamate

Used as an analgesic and anestheticUsed as an analgesic and anestheticCan be administered by any routeCan be administered by any routeOddly enough, animals self-administer Oddly enough, animals self-administer

(euphoria) (euphoria)

PCP- physiological effects

• numbness, loss of motor coordination, slurred speech, blurred vision, Nystagmus

Higher doses lead to: Higher doses lead to: hyper excitability or stupor hyper excitability or stupor coma coma seizuresseizures deathdeath A perfect example of a Schedule I drugA perfect example of a Schedule I drug

• High rate of psychotic episodes some long-term

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 one’s body• Visions of spiritual or supernatural beings• Emotions ranging from euphoria to hositlity true psychosistrue psychosis

Hallucinations, paranoia, agitation, dissociation Hallucinations, paranoia, agitation, dissociation

Dalgarno & Shewan (1996)

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

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

CholinergicHallucinogens

Anticholinergic hallucinogens

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

• Scopolamine-from Datura, Jimson weed, Mandrake and Henbane

Acetylcholine receptor (muscarinic) antagonists

Dissociatives that induces delirium , hallucinations, and amnesiaClassic anti-cholinergic symptoms

Hot as hellDry as a boneMad as a hatterBlind as a batRed as a beet

Used in the treatment of motion sickness & to dilate pupils during eye-exams.

CholinergicHallucinogens

Datura

Jimson weed

Anticholinergic effects

• Dry mouth, blurred vision, loss of motor control

• Dream-like trance state• Little or no memory of experience

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

Salvia Divinorum

• Plant used by the Mazatec people of Southern Mexico: Diviner’s sage—leaves chewed or smoked

• Active substance = salvinorum A (affects Kappa receptors)--most potent natural hallucinogen (100 microgram ED50)

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 supplement—currently under DEA review

Salvia Divinorum