Amphetamines

Question 1

what is amphetamine? what are three common drugs that are formed from amphetamines?

Answer 1

amphetamine is a type of drug but is also used to describe a family of structurally similar drugs derived from amphetamine

1. amphetamine –> stimulant
2. methamphetamine –> amphetamine derivative that enters the brain more rapidly
3. crystal meth –> methamphetamine hydrochloride crystals in smokeable form

Question 2

what were some of the original uses of amphetamines?

Answer 2

amphetamines like benzedrine sulphate were used as a nasal decongestant

Question 3

what are three main effects of amphetamines as a whole?

Answer 3

1. similar to cocaine
2. sensations of well-being, sometimes profound euphoria, illusion of being invincible
3. suppression of fatigue, increased alertness (results in hyper locomotion)

Question 4

Where do amphetamines come from? what are some of its benefits for clinical use?

Answer 4

they are purely synthetic
- originally synthetized in hopes of a new asthma medication (decongestant) but had stimulate properties

its cheaper and requires no harvesting

opens up airways (bronchodialation)

• keeps brain active to avoid mini seizures in individuals who have narcolepsy and can be given to calm someone who is hyperactive

has been used for weightless, depression, asthma, stimulant for pilots and soldiers, narcolepsy, ADHD (adderall)

Question 5

What is methamphetamine? why is it the amphetamine of choice?

Answer 5

methamphetamine has an extra methyl group which makes it easier to enter the brain and more difficult to metabolize which leads to profound euphoria

• results in less peripheral effects, more CNS with meth compared to amphetamine (i.e. has less agitation and more of a CNS high)
• it is smokable in its crystalline hydrochloride form
• would need to use amphetamine IV to get same rush as methamphetamine in smokeable form and this is associated with a lot of problems involving needles etc….

Question 6

how is methamphetamine synthesized?

Answer 6

majority entering CAN and USA are from mexico

smaller labs use pseudo ephedrine from cold remedies as a starting point of synthesis

typically produces 5-7kg of dangerous waste such as lithium (batteries), sodium, phosphorous (match heads), ammonia for every KG of product

there is a new shake and bake method where it requires less pseudo ephedrine and is done in a 2L pop bottle

the remaining waste is discarded and can cause explosions, and a flash fire If O2 enters the bottle to quickly

Question 7

what are the common patterns of use of meth?

Answer 7

orally, snorted, smoked or injected

Question 8

in what ways is meth ‘better’ than using cocaine? (experiment)

Answer 8

use patterns are similar to cocaine
but people who use cocaine gradually move onto METh bc of its longer lasting effects
longer lasting effects means that it is not administered as frequently as cocaine is

high doses produce rapid tolerance though seems to be due to rapid NT depression (running out of dopamine)

meth peaks in the brain around 10minutes after administration and still shows signal in the brain and feelings of high reported on a questionnaire, at 90 minutes

cocaine peaks around 3-5 minutes in signal activity in the brain and leaves fully in about an hour

there is also higher dopamine response peak with meth than cocaine

Question 9

what are 2 metabolites of amphetamine? and their properties? how is it broken down (by what enzyme and where)?

Answer 9

amphetamine is metabolized by the the liver by an enzyme called CYP2D6 by addition of “OH” to amphetamine to dissolve it better

• produces two active metabolites:
  1. 4-hydroxyamphetamine
  2. norephedrine

Question 10

what are 2 metabolites of methamphetamine? and their properties? how is it broken down (by what enzyme and where)?

Answer 10

CYP2D6 removes methyl from meth to make it into amphetamines and then makes the two active metabolites

1. 4-hydroxyamphetamine
2. norephedrine

OR

CYP2D6 adds a hydroxyl group to the meth and ends up making 4-hydroxymethamphetamine which ends up being converted into the two active metabolites mentioned above

Question 11

what are the properties of 4-hydroxymethamphetamine (4-HMA), 4-hydroxyamphetamine (4-HA), and norphedrine (NE)?

Answer 11

they are all stimulants in their own right

• NE mimics the effects of adrenaline at adrenergic receptors
• 4HA and 4HMA can stimulate noradrenaline release and inhibit MOA (break down of NE)

4HA and 4HMA can also activate TAAR (controls the reversal of function of the dopamine transporter)

10% of Caucasians are deficient in CYP2D6 and can’t metabolize meth and amphetamines very well

Question 12

In what ways is amphetamine affect on NT’s different from cocaine?

Answer 12

similar to cocaine, it increases levels of NT in synapse by blocking uptake of dopamine, noradrenaline and serotonin

but in comparison to cocaine:

• cocaine will cause dopamine build up once presynaptic neuron depolarizes to release dopamine in the cleft –> it needs a NT release
• amphetamines don’t require release of NT
• cocaine does not enter the presynaptic terminal and it blocks NT from outside (binds to transporter in synaptic cleft and does not enter the presynaptic neuron)

amphetamines enter the presynaptic neuron

Question 13

what are two ways that amphetamines enter the presynaptic neuron?

Answer 13

1. diffusion across the membrane

2. transportation by DAT (dopamine transporter) .. they hitch a ride with DAT (reverses its role)

Question 14

what are the steps to amphetamine mechanism?

Answer 14

1. AMPH can enter the presynaptic terminal by diffusion or via DAT
2. AMPH is transported by a vesicular monoamine transporter into vesicles in the presynaptic neuron
3. once inside, AMPH induce the vesicles in the presynaptic dock to spew out their dopamine into the cytoplasm
4. additionally, AMPH inhibits MAO so it can’t break down free dopamine
5. Presynaptic AMPH results in reversal of DAT so that it pumps free dopamine into the synapse (see TAAR) [instead of pumping dopamine back into the presynaptic from the synapse, it does the opposite and puts more dopamine in the synaptic cleft) and leaks it across the membrane
6. results in massive dopamine release without the need for stimulation of the presynaptic neuron or any depolarization to occur resulting in activation of the post synaptic

Question 15

what effects of AMPH in the brain make it unique to only amphetamines?

Answer 15

reversal of NT transporters like DAT and the release of NT into cytoplasm and then onto the synapse in the presynaptic is unique to the amphetamines

Question 16

what other pathways does amphetamines also effect besides dopaminergic?

Answer 16

noradrenergic and serotonergic pathways

Question 17

why do amphetamines have different effects on transporters compared to cocaine? what is the role of the TAAR protein?

Answer 17

methamphetamines activate an intracellular receptor called the trace-amine associated receptor or TAAR

activation of this g-protein coupled intracellular receptor results in the activation of other enzymes (kinases) that add phosphate groups to various proteins

• activation of the TAAR receptor by meth appears to result in the reversal of the DAT transporter
• experimental drugs that act at the TAAR have been shown in rats to decrease the dopamine-related effects of meth, but not natural rewards such as sucrose which means that TAAR is not involved in natural rewards

Question 18

How does meth and amphetamines cause tolerance?

Answer 18

tyrosine hydroxylase is an enzyme in synthesis pathway for dopamine and noradrenaline is INHIBITED

acutely –> a single high dose of AMPH results in DAT function decrease and ultimately less cell-surface expression which is the opposite of cocaine

also see decreases in levels of other transporters such as the one for noradrenaline

these transporter effects have been linked to TAAR activation

Question 19

How does AMPH’s cause brain damage?

Answer 19

• very damaging
• cause changes in brain structure
• dopaminergic, noradrenergic and serotenergic terminals are reduced and likely permanently
• damage seems to be due to free dopamine forming reactive O2 species when metabolized by MAO’s even though the enzyme is inhibited by the drug and leads to damage of cell membranes and proteins in the mitochondria

also excessive glutamate release causes toxic environment that leads to neuronal cell death (excitotoxicity)

Question 20

In what ways is brain damaged induced form nicotinic receptors (experiment)?

Answer 20

amphetamines could bind to nicotinic acetylcholine receptors

when they are bound with AMPH, receptors allow for calcium to pass through them and into the neuron

calcium levels increase and cause trigger of a cascade of events that lead to increased levels of reactive oxygen species (ROS)

nicotinic receptor blockers have been shown to prevent ROS increase and prevent some neuronal damage in VITRO (in the lab)

MLA and BGT are a nicotinic alpha-7 receptor antagonist and prevents activation of the alpha-7 receptors on the mitochondria and when these are combined with meth, there is a decrease in ROS

but if you block alpha 4- beta-2 nicotinic receptors you get no affect so it shows that nicotinic alpha-7 receptors also calcium into presynaptic cell and produce ROS

Question 21

In what ways is the brain damage from AMPH similar to Parkinson?

Answer 21

• long lasting changes suggest that dopaminergic neurons die which is what happens in Parkinsons disease

many animal models support the idea of dopaminergic neuron death

evidence is weaker in post mortem human studies but still significant

76% increased risk of developing Parkinsonism in meth users but not in cocaine users

from post mortem studies, some emth users had dopamine levels as low as parkinsonian patients

caudate and putamen form the ventral striatum and NA is part of the ventral striatum

Question 22

What are some psychological affects of AMPH? 5

Answer 22

same as cocaine –> euphoria, energy, alertness

at high doses

1. punding –> repetitive meaningless behaviours from too much dopamine in basal ganglia
   - basal ganglia involved in voluntary motor control and action selection which of several behaviours to engage
   - striatum is major component of basal ganglia and funding is also seen in parkinsonian patients if medicine drastically increases their dopamine levels
2. unprovoked aggression –> AMPH strongly associated with violence in the intoxication stage (43% engaged in violence while 27% attempted suicide)
3. grandiosity
4. hallucinations and paranoia
5. delusions of parsitosis (bugs under skin)
   - these get worse with prolonged use and may include homicidal and suicidal thoughts coupled with violent behaviour and extreme anxiety

Question 23

What are some physiological effects of AMPH?(5)

Answer 23

1. no local anesthesia action
2. same type of sympathetic stimulation as cocaine –> increase HR, BP and insomnia
3. tremors, headache and profuse sweating
4. meth mouth, skin disorders from picking (meth mites)
5. hyperthermia, renal and hepatic failure, strokes and seizures

Question 24

what are the withdrawal symptoms of AMPH and how Long do they last?

Answer 24

anhedonia (lack of pleasure), extreme fatigue, mood volatility, vegetative state, intense cravings

very long lasting often at least 12 months, link with degree of brain damage/dysfunction caused by drug use

if dopamingeric neurons were destroyed, unlikely to recover completely (dose response relationship)

Question 25

What is meth mouth?

Answer 25

meth mouth is characterized by profound dental decay

• could be due to contaminants in meth since they are highly corrosive (phosphorous, lithium…etc..)
• could be due to lack of saliva because more bacteria in the mouth
• or could be due to vasoconstriction in the gums

Question 26

In meth mouth, what are the effects on saliva production and vasoconstriction thought to be mediated through?

Answer 26

1. excess noradrenaline activating adrenergic alpha1 receptors on blood vessels –> NE causes vasoconstriction in blood vessels which means less oxygen getting to the gums
2. activation of inhibitory alpha-2 presynaptic receptors in salivary gland neurons which prevent saliva from forming

Question 27

what is PMA? and PMMA?

Answer 27

PMA –> paramethoxyamphetamine –> has a delay reaction but more potent and neurotoxic also a MAO inhibitor and causes increase in serotonin and Dopamine

earned the street name “death” and is linked to many fatalities

hypoglycaemia, hyperkalemia (excess potassium in blood which can lead to heart stopping) and hyperthermia

sometimes sold as ecstasy or mixed in it

PMMA (paramethyoxymethamphetmaine) is the methamphetmaine version of this and can be just as toxic

Question 28

What is legal ecstasy?

Answer 28

includes BZP and TFMPP its not really legal (schedule III drug in Canada)

Question 29

What is N-benzylpiperazine?

Answer 29

its a form of ‘legal ecstacy’

BZP is the predominant ingredient in these pills

it is synthetic from a. family used in plastics, pesticides (reworking cattle), resins

liquid free base form or pills

Question 30

what is the mechanism behind BZP action?

Answer 30

levels of synaptic dopamine, NORE and serotonin increase

dopamine and serotonin are increased n the NA

produces behaviours in animals that mostly resemble amphetamines

but do not have the serotonin effect

Question 31

what are some of the dangers of BZP?

Answer 31

19% of those admitted due to BZP had seizures and it didn’t start till 8 hours after injection

some had cardiac events and some had low blood sodium

Question 32

what is TFMPP?

Answer 32

also a ‘legal ecstasy’

3-trifluoromethylphenylpiperazine

when added TFMPP to BZP produces an effect that mostly closely mimics ecstasy

TFMPP is an agonist at 5HT and 5HT2 receptors (mood and hallucinations respected) and triggers serotonin efflux through the serotonin transporters

study of transmitters in rat brains shows this mixture produces similar effects as ecstasy and rats went into convulsions