Topic 21: Amphetamines

Question 1

What are amphetamines?

Answer 1

amphetamines are a large class of stimulants originally based on the naturally occurring ephedrine

quest for alternatives to ephedrine resulted from concerns over stability of supply

amphetamine first synthesized in 1887, brought to market in 1930s as Benzedrine as a decongestant

Question 2

What are the historical impacts of stimulant effects?

Answer 2

Benzedrine came into regular use in WWII for it’s stimulant and performance enhancing effects

popular in post-war era with truck drivers, students, and the military

use became regulated in the 60s and 70s as addictive potential emerged

remain in use in military

Question 3

What are the pharmacokinetics of amphetamines?

Answer 3

typically taken orally: also IV or smoking in cases of abuse

amphetamine and methamphetamine are used interchangeably in clinical context

methamphetamine is more potent and has higher BBB permeability and is preferred for illicit use
methamphetamine HCl is preferred for smoking (crystal meth)

as with cocaine - oral route is slowest, least susceptible for abuse: most common therapeutic route

liver metabolism

much longer half-life than cocaine: 7-30 hours

susceptible to binge use - typically IV or inhalant: often combined with depressants to limit anxiety

Question 4

What are the behavioral effects of amphetamines?

Answer 4

euphoria or exhilaration

heightened alertness

increased confidence

reduced fatigue: insomnia

improved performance on repetitive motor tasks: stereotyped behavior

enhanced athletic performance: banned in many professional leagues

Question 5

What are the psychosis effects of amphetamines?

Answer 5

drug-induced, particularly in chronic users

indistinguishable from schizophrenia

use precipitates psychosis in schizophrenia

can persist beyond periods of intoxication

Question 6

What are the punding effects of amphetamines?

Answer 6

stereotyped behaviors

useless repetitive tasks

abstain from eating, drinking, bathroom breaks

irritated or angry if interrupted

Question 7

What are the formication effects of amphetamines?

Answer 7

feeling of insects crawling on skin

common to pick at skin as a result

Question 8

What is the mechanism of action of amphetamines?

Answer 8

amphetamines act at catecholaminergic nerve terminals: dopamine, norepinephrine, lesser effects on 5-HT (exception being the enactogenic amphetamines)

like cocaine, amphetamines are reinforcing through effects on dopamine and are stimulant and sympathomimetic through effects on norepinephrine

Question 9

What are the four mechanisms through which amphetamines increase catecholamine release?

Answer 9

competitive inhibition of DAT/NET

exchange transport at VMAT

altered catecholamine transport via TAAR1 signaling

MAO inhibition

Question 10

What is the competitive inhibition of DAT/NET caused by amphetamines?

Answer 10

dopamine and amphetamine are both substrates for the dopamine transporter

at dopaminergic terminals amphetamine transport competes with dopamine transport leading to elevated synaptic dopamine

Question 11

What is the changes to the exchange transport at VMAT caused by amphetamines?

Answer 11

once inside the cell, amphetamines is a substrate for the vesicular monoamine transporters (VMAT1/VMAT2)

amphetamines are transported through VMAT by exchange with intravesicular dopamine, resulting in transport of dopamine out of vesicles into the synaptic terminal

Question 12

What is the change in the activation of TAAR1 caused by amphetamines?

Answer 12

amphetamines bind an intracellular receptor (GPCR coupled to Gs/Gq) involved in monoamine regulation - trace amino-associated receptor 1 (TAAR1)

TAAR1 signaling activates protein kinase C (PKC) which phosphorylates DAT

phosphorylated DAT reverses the direction of dopamine transport (dopamine efflux transport) and is internalized (non-competitive reuptake inhibition)

Question 13

How do amphetamines impact DAT, VMAT, TAAR1, and MAO all together?

Answer 13

amphetamine competitively inhibits reuptake through DAT

amphetamine increases cytosolic dopamine levels by exchange transport at VMAT

amphetamine increases DAT internalization and induces dopamine efflux by activating TAAR1

additionally at higher doses amphetamines inhibit MAO, decreasing intracellular dopamine breakdown

Question 14

What are the persistent effects of amphetamine abuse?

Answer 14

prolonged amphetamine use can lead to psychosis: hallucinations and paranoia resembling schizophrenia, can occur outside of intoxication in chronic users

in animals, methamphetamines doses result in long-lasting decreases in DA, tyrosine hydroxylase, and DAT in the striatum: histology shows degeneration of DA fibers, damage to 5-HT fibers in neocortex, hippocampus, and striatum

Question 15

What are the adverse effects of methamphetamines?

Answer 15

formication: feeling of insects crawling on/under skin

increases with chronic use and seen as a strong hallucination with psychosis

results in picking at bugs and lesions on skin and face

methamphetamine HCl (crystal meth) is highly acidic

smoking causes degradation of tooth enamel: “meth mouth”

exacerbated by sympathomimetic and stereotypic effects: decreased salivation, dehydration, teeth grinding

reduced self-care in heavy abusers

Question 16

What are the clinical uses of amphetamines?

Answer 16

largely discontinued as decongestants after abuse potential was discovered: pseudoephedrine in common use

still can be used to treat narcolepsy

amphetamines most common treatment for ADHD

widely used (illicit) as nootropic drugs: high use among university students to improve studying

Question 17

What is ADHD?

Answer 17

ADHD characterized by increased locomotor activity and distractibility

inattentive subtype: characterized by extreme difficulty in sustained attention

impulsive-hyperactive subtype: characterized by high impulsivity and excessive motor activity

combined subtype incorporates both inattentiveness and impulsive-hyperactivity

Question 18

What are psychomotor stimulants effective in treating ADHD?

Answer 18

ADHD is dominated by an attentional deficit: hyperactivity manifests from distractibility

ADHD may occur through excessive DAT activity resulting in dopamine insufficiency: DAT density increased in ADHD adults, genetic evidence links some cases with a polymorphism in the DAT gene

Question 19

What are enactogenic amphetamines?

Answer 19

MDMA developed in 1912 by Merck as a precursor to a coagulant drug

Alexander Shulgin synthesized MDMA in 1965 while at Dow and first tested the psychoactive effects in 1976 after hearing about recreational use from a grad student

MDMA became popular among psychotherapists in the late 70s and early 80s: MDMA cause clients to become more communicative, introspective, and empathic

criminalized in 1985 as a schedule I drug (meaning no recognized medical use)

Question 20

What are the pharmacokinetics of enactogens?

Answer 20

readily absorbed from GI

plasma levels peak after 2 hours

half-life of 8 hours

liver metabolism by CYP450 2D6

Question 21

What are the drug effects of enactogens?

Answer 21

euphoria

increased wakefulness

increased endurance

sense of well-being, sociability, and extraversion

sense of closeness, tolerance, and empathy to others

sexual arousal

Question 22

What is the mechanism of action of enactogens?

Answer 22

MDMA functions as amphetamines but has increased activity at serotonergic neurons

entactogenic effects are modulated by effects on 5-HT

sympathomimetic and stimulant effected modulated by NE

reinforcing effects modulated by DA

high affinity for TAAR1 and VMAT

affects 5-HT, NE, and DA levels at synapses

weak agonist at postsynaptic 5-HT1 and 5-HT2 receptors: MDA has more potent effects at 5-HTR

MDMA found to increase oxytocin levels in healthy volunteers: oxytocin increase correlated with subjective social effects

Question 23

What are the adverse effects of enactogens?

Answer 23

increased heart rate

tremors

sweating

hyperthermia: potentially fatal, exacerbated by physical activity (i.e. dancing)

trismus (tightening of jaw muscles)

bruxism (grinding teeth): considered a stereotyped behavior

Question 24

What is withdrawal of enactogens?

Answer 24

no medically serious withdrawal syndrome

some effects persist briefly after cessation (crash similar to cocaine)

trismus, depression, anxiety or paranoia, irritability, impulsiveness, restlessness, insomnia, memory impairment, anhedonia

Question 25

What are the persistent effects of enactogens in animals?

Answer 25

debate over long-term effects of MDMA use

drug categorization has limited exploration of legitimate uses for psychotherapy

limited effects on illicit use other than to drive manufacturing underground

evidence in animals of persistent damage to DA and 5-HT systems: drug classification is based partly on demonstrations of 5-HT damage

Question 26

What are the persistent effects of enactogens in humans?

Answer 26

studies show persistent damage in chronic, heavy users: decreased 5-HIAA in CSF, decreased 5-HT transporter binding capacity, decreased hormone response to serotonergic challenge

cognitive effects: memory, visual processing, sleep

interpretations: no demonstration of effects of causal use, confounded by coincident drug use, impurities/adulterants in illicit drugs (methamphetamine, fentanyl common)