Study Drugs

Question 1

What are ‘study drugs’? (4)

Answer 1

Typically refers to prescription-based psychostimulants used to enhance aspects of cognitive function in healthy individuals

• Psychostimulants are a broad class of psychoactive substances that can increase, for example, wakefulness and aspects of cognitive performance (e.g. attention, working memory)
• Psychostimulants also include caffeine and coca leaves, whose use for increasing wakefulness or performance enhancement dates back centuries.
• Psychostimulants include drugs of abuse (e.g. cocaine, methamphetamine) as well as prescription drugs (e.g. Ritalin®)

Question 2

‘Study drugs’ over the ages (4)

Answer 2

CAFFEINE:
* Coffee used for thousands of years (e.g.Africa/Arabian Peninsula) for stimulant effects
* Used in newer products (e.g.gum) today to improve cognitive performance

COCA:
* Coca leaves also used for thousands of years (e.g., South America) for stimulant effects
* In the West, cocaine was widely used toward latter half of the 19th century in coca wines, cigarettes, and medicines, including Coca-Cola

KHAT
* Khat usage dates back to at least the 11th century
* Khat is a social mainstay in several countries (e.g., Yemen) to assist in work, study and social cohesion

AMPHETAMINES
* Ephedra has been used in Traditional Chinese Medicine for around 500 years – used to treat asthma, although modern use associated with performance enhancement
* Benzedrine is an amphetamine synthesised as an alternative to Ephedra in early 1900s – extensively used to fight fatigue and prevent sleep deprivation-related performance in US fighter pilots

Question 3

Sigmund Freud stated:

Answer 3

“You perceive an increase of self-control and possess more vitality and capacity for
work… long intensive physical work is performed without any fatigue.”

Question 4

Who uses ‘study drugs’? - survey 2008 (5)

Answer 4

• 62% of all users reported taking Ritalin®
• 44% of all users reported taking Modafinil
• 15% of all users reported taking beta blockers (e.g., propranolol) – overlap b/w drugs
• Most common alternative ‘study drug’ was Adderall®

highest in group <25: edu + high edu

Question 5

Why take ‘study drugs’? (3)

Answer 5

Most popular reason for taking the drugs was to improve concentration

• Ranking a close second was improving focus for a specific task (although difficult to distinguish from concentration)
• A range of ‘other’ reasons also provided (e.g., managing jet-lag)

Question 6

Large-scale survey of pharmacological cognitive enhancement (PCE) among students inthe UK and Ireland (877 students):

Answer 6

lower no.’ s in this survey but still used for cognitive function

Question 7

How do ‘study drugs’ work? (2)

Answer 7

caffeine: adenosine r antagonist

psychostim based: work by interacting w/DA + NA

Question 8

affects what 2 DA pathway? (2)

Answer 8

Mesocortical +
mesolimbic

Question 9

Noradrenergic pathways and effects brain parts used

Answer 9

The locus coeruleus is a small nucleus located bilaterally in the pons –noradrenergic projections to vast parts of the central nervous system (CNS)

all 4 lobes
spinal cord

Question 10

Noradrenergic projections involved in
regulating, for example: (6)

Answer 10

 Attention
 Arousal
 Sleep and wakefulness
 Learning and memory
 Pain
 Mood

Question 11

Inverted U-shaped dose-effect curve (3)

Answer 11

• The inverted U–shaped dose- effect curve is a graphical depiction of the cognitive effects of psychostimulants – also termed the optimal arousal theory
• Moderate arousal is beneficial to cognition
• However, too much arousal leads to cognitive impairment

Question 12

Continuum of psychostimulant activation (3)

Answer 12

• As low doses, psychostimulants can initially promote cognitive enhancement
• As dose increases further, a sense of power and euphoria can ensue; these are the effects addicts seek and are accompanied by cognitive deficits
• Higher doses can result in psychosis, coma, and eventual circulatory collapse

Question 13

‘Study drug’ examples (3)

Answer 13

Ritalin (Methylpheniate)

Adderall

Modafinil

Question 14

intro to Methylphenidate (Ritalin®)-uk (4)

Answer 14

Introduced in 1957 for a number of ailments (e.g.sleepiness, nasal congestion)

Use as a treatment for narcolepsy

Used today to treat ADHD

Subject to abuse as a ‘study drug’

Question 14

Methylphenidate (Ritalin®) MoA (3)

Answer 14

• Ritalin® is a non-competitive blocker of the dopamine transporter (DAT) and the noradrenaline transporter (NET)
• This means less DA and NA are taken up into the pre- synaptic terminal
• This leads to an increase in DA and NA in the synaptic cleft, leading to increased DA and NA post-synaptic receptor activation

Question 15

Ritalin studies - human + rodent: (5)

Answer 15

Rodent studies:
* Dose-dependent increase in extracellular levels of DA and NA in prefrontal cortex
* Higher doses increase DA in nucleus accumbens

Human studies:
* PET studies support DA and NA as critical to the mechanism of action of Ritalin®
* Accordingly, Ritalin® blocks DAT and causes an increase in extracellular DA conc.
* Dose leading to 70% DAT occupancy causes more than 80% NET occupancy - supports importance of NA in therapeutic effects of the drug

Question 16

Ritalin + cog function (2)

Answer 16

• Studies have shown that lower doses improve cognitive performance, whereas higher doses impair cognitive performance – specifically Spatial working memory
• Reversed with co-administration of D1 receptor antagonist or a2-receptor antagonist – suggests drug improves performance by increasing availability of DA and NA, which stim. D1 and a2 receptors

Question 17

introduction to Adderall®-amphet (4)

Answer 17

Adderall® - combination of amphetamine and dextroamphetamine salts

Adderall® is prescribed for ADHD in the USA

However, Adderall® is not prescribed in the UK

Subject to abuse as a ‘study drug’

Question 18

Adderall® MoA (5)

Answer 18

Amphetamines are competitively re-uptaken up into the pre-synaptic nerve terminal via the dopamine transporter (DAT) and the noradrenaline transporter (NET)

• This leads to less dopamine (DA) and noradrenaline (NA) being taken up into the pre-synaptic nerve terminal as amphetamine is competitively taken up in its place
• Amphetamines are taken up into vesicles by VMAT1/2
• Amphetamines accumulate in vesicles and disrupt the pH gradient required for transporters to function – VMAT1/2 become non-functional and DA/NA accumulate in cytosol
• Amphetamines activate intracellular TAAR1 receptors, which can lead to the reversal of DAT and NET and the removal of DAT and NET from the plasma membrane
• Increase in DA and NA in the synaptic cleft, leading to increased DA and NA post-synaptic receptor activation

Question 19

Adderall® dose-dependent effects

Answer 19

• Studies have shown that lower doses of amphetamine improve cognitive performance, whereas moderate-high doses impair cognitive performance– specifically Associative memory

Question 20

introduction to Modafinil (4)

Answer 20

First used as a treatment for narcolepsy (UK)

Use for obstructive sleep apnoea and shift-work sleep disorder (USA)

Tested for other conditions including ADHD and depression

used as study drug

Question 21

Modafinil MoA (6)

Answer 21

• A clear mechanism of action for Modafinil yet to be established – primary action generally considered to be upon DA (and NA) signalling
• Supported by study showing Modafinil reduces the spontaneous firing rate of DA neurons in control mice, whilst not affecting DA neurons of mutant mice insensitive to DAT blocker cocaine
• Modafinil may directly interact with D1/D2 receptors, but current evidence suggests that its primary action is through inhibition of DAT
• In addition to DA and NA, Modafinil also has actions on a host of other neurotransmitter systems
• Modafinil has been shown to increase extracellular levels of 5-HT, glutamate, histamine and orexin and decrease extracellular levels of GABA (OREXIN INC IN NARC’S = NO AADICTION)
• Modafinil acts on subcortical structures, namely the thalamus, hypothalamus and amygdala – reinforce physiological mechanisms involved in the activation and maintenance of wakefulness

Question 22

Effectiveness of ‘study drugs’ - studies + baseline drugs (5)

Answer 22

It has been proposed that cognitive performance is at its highest based upon optimal concentrations dopamine and noradrenaline in the brain.

(a) ‘Study drug’ for an individual with a low baseline of dopamine (red circle) can improve performance

’Study drug’ for an individual with a high baseline of dopamine (green circle) can impair performance

(b) Two cognitive processes (F1 and F2) may also have differential drug sensitivity in the same individual

This is in accordance with previous studies showing that amphetamine-based ‘study drugs’ can even lead to a reduction in short-term memory in ‘high performers’

Question 23

Effectiveness of Ritalin® as a ‘study drug’ (7)

Answer 23

• Meta-analysis has shown that Ritalin® has an overall positive effect on memory performance– particularly spatial working memory
• However, no consistent evidence for other enhancing effects (e.g., attention) were found
• However, other meta-analyses have shown the effects of Ritalin® are less clear on specific aspects of cognitive performance
• Single doses improve cognitive performance in the healthy population in the domains of working memory(65% of included studies) and speed of processing (48%)
• May also improve verbal learning and memory (31%), attention and vigilance (29%) and reasoning and problem solving (18%)
• No effect reported on visual learning and memory
• Effect’s dose-dependent and differ between cognitive domains

Question 24

Effectiveness of Modafinil as a ‘study drug’ (3)

Answer 24

• Meta-analysis has shown Modafinil has an overall positive effect on attention for well-rested individuals
• Modafinil maintains wakefulness, memory and executive functions to a significantly higher degree in sleep deprived individuals than placebo
• However, repeated doses of Modafinil were unable to prevent deterioration of cognitive performance over a longer period of sleep deprivation through maintaining wakefulness

Question 25

What are the limitations of meta-analyses?

Why may findings differ between the two meta-analyses shown?

Answer 25

different studies used - biases etc