Amphetamines

Question 1

What are amphetamines?

Answer 1

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

Question 2

When was amphetamine synthesized?

Answer 2

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

Question 3

Why is amphetamine important?

Answer 3

Parent compound to the class
of substituted
amphetamines, both
synthetic and naturally
occurring.

Question 4

Describe pharmacokinetics of amphetamines

Answer 4

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
• Much longer half-life than cocaine
• 7-30 hours

Question 5

Describe psychosis

Answer 5

• Drug-induced, particularly in chronic users
• Indistinguishable from schizophrenia
• Use precipitates psychosis in schizophrenia
• Can persist beyond periods of intoxication

Question 6

Describe punding

Answer 6

stereotyped behaviours
* Useless repetitive tasks
* Abstain from eating, drinking, bathroom breaks
* Irritated or angry if interrupted

Question 7

Describe formication

Answer 7

Feeling of insects crawling on skin
* Common to pick at skin as a result

Question 8

Describe amphetamine’s mechanism of action

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
• Amphetamines increase catecholamine release through four mechanisms

1. Competitive inhibition of DAT/NET
2. Exchange transport at VMAT
3. Altered catecholamine transport via TAAR1 signalling
4. MAO inhibition

Question 9

Describe amphetamine’s competitive inhibition at DAT/NET

Answer 9

At dopaminergic
terminals amphetamine
transport competes with
dopamine transport
leading to elevated
synaptic dopamine.

Question 10

Describe exchange transport at VMAT

Answer 10

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

Question 11

Describe the activation of TAAR1

Answer 11

Amphetamines bind an
intracellular receptor (GPCR
coupled to Gs/Gq) involved in
monoamine regulation – trace
amine-associated receptor 1
(TAAR1).

TAAR1 signalling 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 12

Describe clinical uses of amphetamines

Answer 12

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 attention-deficit/hyperactivity
  disorders (ADHD)
• Widely used (illicit) as nootropic drugs
• High use among University students to
  improve studying

Question 13

Describe the link between amphetamines and ADHD

Answer 13

• ADHD characterised by increased
  locomotor activity and distractibility
• Inattentive subtype – characterised by
  extreme difficulty in sustained attention
• Impulsive-hyperactive subtype –
  characterised by high impulsivity and
  excessive motor activity
• Why are psychomotor stimulants
  effective in treating ADHD?
• ADHD is dominated by an attentional
  deficit
• Hyperactivity manifests from distractability
• 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 14

Describe Shulgin and enactogenic amphetamines

Answer 14

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

• MDE, MDA also included

MDMA (amphetamine and hallucinogen) caused clients to become more
communicative, introspective, and empathic

Question 15

Describe the drug effects of enactogens

Answer 15

• Drug effects:
• Euphoria
• Increased wakefulness
• Increased endurance
• Sense of well-being, sociability, and
  extraversion
• Sense of closeness, tolerance, and
  empathy to others
• Sexual arousal

Question 16

Describe MDMA mechanism of action

Answer 16

• Enactogenic effects are modulated
  by effects on 5-HT
• Sympathomimetic and stimulant
  effects modulated by NE
• Reinforcing effects modulated by
  DA
• MDMA found to increase oxytocin levels in
  healthy volunteers
• Oxytocin increase correlated with
  subjective social effects

Question 17

Describe adverse effects of MDMA

Answer 17

• Hyperthermia
• Potentially fatal
• Exacerbated by physical activity (i.e.
  dancing)

Question 18

Describe persistent effects in humans

Answer 18

• Studies show persistent damage in chronic, heavy users
• Decreased 5-HIAA in CSF
• Decreased 5-HT transporter binding capacity
• Decreased hormone response to seratonergic challenge
• Interpretations
• No demonstration of effects of casual use
• Confounded by coincident drug use
• Impurities / adulterants in illicit drugs
• Methamphetamine, fentanyl common