Ecstacy Flashcards
What category does ecstasy belong to?
ecstacy is an amphetamine even though it is often classified as a hallucinogen
what is the chemical name for ecstasy?
MDMA (3,4- methylenedioxymethamphetamine
how does the structure of ecstasy differ from that of amphetamines?
the presence of a methyelenedioxy ring
What happens if you modify the aromatic ring in MDMA?
modification of the ring produces reduction in stimulant effects and produces more seotonergic effects
what is the precursor to MDMA?
Sassafras trees are aromatic trees that grow across USA and east asia
safrole is an aromatic oil that is obtained from the distillation of the root bark of sassafras trees
SAFAROLE is the precursor to MDMA
how is ecstasy administered?
almost always taken in pill form
- stacking: taking multiple doses simultaneously (not good for naive users)
how much MDMA content in a tablet?
depends on the source but most MDMA content ranges from 10mg to 150 mg
effects felt between 75-125mg of MDMA
what is the usage rate of MDMA?
small % (less than 10%) will use once per week, may having trouble reducing use but seems to be more psychologically dependant than physiological because not a big withdrawal
often taken with alcohol, cannabis, and amphetamines
what are the psychological effects of MDMA?
- high lasts 2-3 hours
- positive mood change
- drop in defence mechanism and increase in empathy for others (entactogens) ..
- increase self esteem
- overall stimulant effect
- used in PTSD sometimes
what are some physiological effects of MDMA?
- rise in BP
- rise in HR
- hyperactivity
- hyperthermia
- jaw clenching/ bruxism (teeth grinding) due to excess serotonin release from facial nerves
in what ways is the mechanism of MDMA different than amphetamine?
ecstasy works the same except its effects are predominately mediated through serotonergic nerve terminals
this is due to that methylenedioxy ring
What is the mechanism of action for MDMA?
- blocks and reverses primarily of serotonin transporters
but also a bit of dopamine and noradrenaline - the potency is 5HT>NA>DA
- the affinity for MDMA for 5HT transporter is 10 times higher than for the noradrenaline
- high serotonin levels may lead to release of oxytocin –> a hormone that is related to feelings of empathy and bonding
- also seems to bind to TAAR receptors similar to amphetamines to reverse the role of transporters
- serotonin leaks from vesicles into the nerve ending cytoplasm
- partial inhibition of monoamine oxidase.. not a full one
- usually classified as a hallucinogen because of its agonistic actions at the serotonin (5HT) 2A receptor due to the methylenedioxy ring
what effect does ecstasy have on dopamine and serotonin levels?
in the NA of rats, theres a moderate increase in dopamine (200-300%) which is smaller compared to cocaine and amphetamines
- with MDMA theres 1400% serotonin level increase, which is present in the prefrontal cortex and other parts of the reward pathway
how reinforcing is MDMA?
- its not as reinforcing of a drug though and you do not see a lot of addiction. Animals will self administer but with breaking points that are lower than drugs like cocaine
what other receptors (3) does MDMA bind to?
- adrenergic receptors –> might be responsible for some cardiovascular effects and hyperthermia
- histamine type 1 receptors –> acH release when MDMA BINDS
- nicotinic acH receptor alpha-7 receptor –> acts as partial agonist to this and may lead to increased calcium levels in neurons as seen in amphetamines (can lead to excitotoxicity)
How is MDMA metabolized in the liver?
metabolized by the same enzyme that metabolizes amphetamines –> CYP2D6… 80% is metabolized and 20% is excreted unchanged
complex metabolism
forms as many as 9 metabolites of MDMA which have been found to produce apoptosis in neurons (toxic)
How does tolerance occur after use of MDMA?
ecstasy results in reduce transporter activity like AMPH
primarily on the serotonin transporter, but dopamine and noradrenaline also
also results in loss of transporters at the neuronal membrane
what are some of the negative effects of MDMA?
following injection can include: depression, anxiety, hallucinations and paranoia
withdrawal and or rebound can be severe
“suicide Tuesdays” following a week of clubbing
lethargy, irritability, memory loss and panic
the supply of neurotransmitters like serotonin and dopamine is exhausted and these are all dose dependant
What is serotonin syndrome?
- from abnormally high levels of serotonin
- rapid onset of serotonin causes increase HR, BP, muscle rigidity (esp. in lower limbs), severe perspiration, delirium, diarrhea, hyperthermia, rhabdomyolysis (muscle breakdown)
- can lead to kidney failure, convulsions, shock, and death
ecstacy is very dangerous if taking psychiatric drugs that work by increasing serotonin levels like prozac (SSRI) because it can cause a serotonin OD.
What three factors play a role in MDMA hyperthermia?
- this is the leading cause of death by MDMA
- experiments in animals and humans show a single dose can significantly increase body temp as much as 43 degrees C, in humans which is Fatal and its made worse because of all the physical exertion and warm environments that MDMA is taken in
Serotonin, noradrenaline and dopamine all three play a role in the hyperthermia
How does serotonin cause hyperthermia in MDMA use?
serotonin cause CNS dysregulation of the body temperature which leads to hyperthermia
how does noradrenaline cause hyperthermia in MDMA use?
noradrenaline has adrenergic alpha-1 receptors which cause vasoconstriction and retention of heat since heat can’t escape from BV onto skin as sweat and that causes hyperthermia
another thing is the adrenergic beta-3 receptor which causes mitochondrial uncoupling that generates heat (happens to animals during hibernation) and causes hyperthermia
how does dopamine cause hyperthermia in MDMA use?
dopamine receptors seem to play a part but we don’t know
what does long term body temperature dysregulation lead to?
the CNS effects of MDMA on thermoregulation may persist long after drug has left the body
when rats were exposed to single dose of MDMA and multiple doses over 3-4 days
4-6 weeks later, exposed to high ambient temperature displayed impaired ability to thermoregulate
small window of dosing produces long-lasting effects possible at CNS level but not seen in humans yet
What is hypoatremia? how does it occur with relation to MDMA usage?
- state of low sodium in the blood
- excessive thirst is triggered by hyperthermia
- water intoxication: huge water intake in short period leads to dilution of sodium in blood (water rushes into neurons and cells)
- also MDMA can trigger excessive release of ADH (antidiuretic hormone) which leads to water retention
- this can lead to cerebral deem which is brain swelling from cells absorbing too much water, vomitting, coma and respiratory arrest from edema pushing on the brain stem
what are some evidence pointing to neuronal death by MDMA use in animal studies?
animals studies showed that serotonergic neurons tend to die when exposed to MDMA
- Hatzidimitriou et al (1999) showed neuronal loss in squirrel monkeys after MDMA twice a day for four days
- 7- years years it caused some regeneration but not all
- still controversial in humans and could be due to the alternates in the pills like PMA that could be causing this
What are some evidence of neuronal death in humans?
compared the brain of recreational users to non-users
used on average 96 times over three years
used a radioactive drug that binds to serotonin transporter to see levels in the brain
there was shown to be marked deficits in several brain areas some as high as 50%
- there are fewer 5HT transporters in people who do ecstasy
what is the possible mechanism of toxicity caused by MDMA?
when 5-HT is being metabolized by MAO’s, hydrogen peroxide is generated
this can form hydroxyl radicals which can damage lipids and proteins
5-HIAL is a reactive and can also damage proteins and lipids and is produced when 5-HT is being metabolized….
5-HIAL is broken down by aldehyde dehydrogenase into 5-HIAA which means if a person is drinking this enzyme will be less involved in 5-HIAL breakdown and more in alcohol therefore, 5-HIAL builds up and becomes dangerous
damage to mitochondria results in damage to the nerve terminals and eventual cell death
metabolism of MDMA alone can produce quinones and semiquinones that produce a large amount of ROS
What are deaths associated with MDMA?
sudden illness and death can occur even after small doses and sometimes even first time and theres no clear relationship between dose and death
rare combinations of variability in genes for metabolic enzymes may lead to increase production of toxic metabolites (i.e. they might over metabolize 5-HT or produce a lot of metabolites in short amount of time) which might explain why small doses are Fatal for a small number of users compared to total number
87 ecstasy related deaths reported: 8 from heart/circulation 4 from liver damage 9 cerebral edema 30 hyperthermia 14 suicide/accidents 22 unknown
