Wk 12: 'Uppers', 'downers', pharmaceuticals and their complex effects on sleep

• Some increase sleepiness: (e.g. Benzodiazepines; antihistamines (next day performance effects)
• Some promote vigilance: (e.g. Caffeine, nicotine)
• Some have sleepiness as a side-effect: • (e.g. drugs to treat cardiovascular disease, SSRIs – but not performance)

• • Sleep is an active, complex state
• • Rest & Recuperation 
• • Memory encoding and consolidation • Maintain cognition and performance

• 17 hours awake performance degraded to equivalence of 0.05 BAC: =2x chance of accident
• 24 hours awake performance degraded to equivalence of 0.10 BAC =7x chance of accident

• 20% of fatal road accidents
• Annual cost of 3 billion nationally
• 300 serious injuries
• 50 deaths each year in Victoria

• Aims: Characterise use of drugs by police (alcohol, caffeine, cigarettes, wake-promoting, sleep promoting)
• (n=4,957)
• To assess relationships between drug use and:
• • Sleep outcomes (ESS, propensity to doze)
• • Work Hours
• • Near-miss crashes
• • Errors attributed to fatigue
• • Can we predict poor outcomes based on drug use and shift work?

• Discussion:
• Sleep-promoting and wake-promoting drugs were independently associated with poorer health (e.g., stress and burnout) and performance (e.g., fatigue attributable errors and near-crashes) outcomes
• While use of caffeine in moderate levels has been recommended, exceeding these levels is associated with detrimental health and performance impacts
• • Masking effect?

• Sales data: Sales data is collected at the state level (each does differently).
• Cannot tell us anything about drinking patterns, demographic differences
• National surveys: Survey data necessary to provide more detail
• Reasonably consistent

• 1. Reducing the risk of alcohol-related harm over a lifetime: no more than 2 standard drinks per day
• 2. Reducing the risk of injury on a single occasion of drinking: no more than 4 standard drinks on a single occasion
• 3. Children and young people under 18: greatest risk and delay
• 4. Pregnancy and breastfeeding: no

• 1/6 people consume alcohol at levels placing them at lifetime risk of an alcohol-related disease or injury
• 1/7 have consumed 11 r more standard drinks at least once in the previous 12 months
• 1/4 have consumed levels that place them at risk of harm on a single occasion at least monthly
• 82% of 12-17yo reported abstaining
• 32% of drug treatment episodes in 2015-16 were primarily for alcohol, making it the most commonly treated drug in Aus.

• 4/10 had ever used illicit drugs
• 1/6 have done it recently (last 12 months)
• most common:
• Cannabis: 10%
• Misuse of painkillers: 3.6
• Cocaine: 2.5
• Ecstacy: 2.2

Prescription opioids are killing more Australians than heroin

• 1/20 misused a pharmaceutical in the last 12 months
• 

• Effects depend on:
• • Dose
• • The individual (e.g. tolerance, dependence)
• • Time of consumption relative to sleep

• Effects on sleep: sleep latency onset
• Less Fragmentation, Less SWS
• Increased rem-suppression
• Rebound: increased latency and Rem
• Less SWS, more frequent, shorter cycling REM
• Withdrawal: decreased TST
• Increased latency and relapse risk
• Daytime effects: affects motor and cognitive function.
• Affects mood
• 

• Small doses decrease sleep latency
• Tolerance rapidly develops so will need more alcohol to get the same effect
• Substantial changes in sleep architecture: suppression of REM
• Increased fragmentation 2nd half of the night
• eg. needing to go to toilet (diarhettic)
• Alcohol increases stage 4 sleep in the first part of the night
• REM rebound: alcohol increases wakefulness and lengthens REM in the second part of the night.

• Sleep commonly disturbed
• Binge can result in polyphasic sleep disturbance
• Sleep latency may be prolonged
• Changes in sleep architecture
• Bad sleep thought to contribute to relapse even up to 6 months post detox

• Aim: monitor sleep changes during the acute withdrawal period using actigraphy, sleep diaries and questionnaires.
• • Identify components of sleep that are disturbed.
• ISI: 70% mod-high
• Mood K-10: not good
• Daytime sleepiness (ESS): 40%

• Recovery: TST recovers slowly
• REM recovers slowly
• But which came first? alcohol or sleep disorder?

• Facilitation of GABA and inhibition of glutamate:
• GABA neurons involved in brainstem, RAS, thalamus, basal forebrain (generation of SWS)
• Glutamate in RAS and forebrain- plays a role in wakefulness
• Adenosine: neurotransmitter and modulator of sleepniess
• ACH: memory and rem

• Can exacerbate OSA symptoms
• Increase in snoring in men
• • Increase in periodic limb movements
• Iron and vitb12 deficiencies: seen in alcohol dependence and associated with restless legs syndrome

• Most commonly used illicit drug in Australia
• 35% lifetime use
• • 10.4 % use in past year

• Naive (never used)
• • Recreational (acute and withdrawal)
• • Medicinal Users (e.g., pain)

• Marijuana decreases the time it takes to fall asleep
• Marijuana also suppresses REM sleep through the night
• Increases SWS in first part of night
• Increases stage 2 (light) sleep throughout the night

• Limited number of studies conducted (N=37)
• Small sample sizes
• Quality of studies questioned
• Unable to control pre existing sleep issues

• Low doses of THC (4-20mg) may cause large suppression of REM
• Also in recreational users – changes in dream states
• • However some findings mixed
• TST may increase in higher doses

• • Induces Deep Sleep State
• TST not affected
• Tolerance: repeated use may result in shallow and nonrestorative sleep
• • Inconsistent effects on sleep architecture

• • 28 studies (N=~3650 participants)
• Pain; MS; anorexia; immune deficiency
• Difference in analogues studied
• • Marionol, dronabinol, nabilone, nabiximols
• Quality of trials poor (average 48%)
• • Lack of standardised measures
• • Blinding issues

• Improve subjective sleep
• • Effects inconsistent
• • NB: lack of validated tools
• Objective sleep (only 2 studies)
• • Some changes in NREM and sleep quality

• Endocannabinoids are linked to GABA can directly activate GABA receptors
• Limited knowledge of compounds and effects on sleep
• Cannabis is a complex plant with over 400 chemical entities of which more than 60 of them are cannabinoid compounds, some of them with opposing effects

Combining increases global PSQI score

• MDMA (ecstasy) is a substituted amphetamine
• • It was the first drug to be classed as an entactogen

• Acute facilitation of 5-HT and other monoamines
• 1. Promotes release of stored 5-HT from pre-synaptic neurons
• 2. Blocks the serotonin transporter (SERT), preventing uptake of 5-HT
• 3. Inhibition of tryptophan hydroxylase 
• Subsequent depletion of 5-HT central stores
• May result in deleterious changes in systems modulated by 5-HT
• -mood, aggression, pain perception,
• temperature
• – sleep and circadian rhythms

• 1) Human Studies
• > Ecstasy use associated with poor sleep quality but not excessive daytime sleepiness
• > Relationship in both ecstasy-only and in polydrug users
• > Relationship with mood disturbance
• 2) Behavioural experiments (locomotor activity)
• 3) Genetic experiments (e.g., RT-PCR)

• Ecstasy users display signs of sleep disturbance that can be corroborated by others
• This suggests ecstasy users may not be aware of these symptoms
• such as long pauses between breaths, leg twitches, disorientation

• Knocks out body clock for a few days
• Light resets it

Overnight memory consolidation was poorer

• CNS stimulant
• Doses in commercially available products have increased
• Some people sensitive to its effects
• Withdrawal associated with headaches, difficulty concentrating, fatigue, and drowsiness

• Adenosine plays a role in sleep onset (builds up during the day)
• • Caffeine is an adenosine antagonist
• Adenosine also plays a role in SWS onset
• Caffeine also causes increases in dopamine in the prefrontal cortex
• Often used as a countermeasure in shift-workers

• ↓ TST (ave 2 h) in middle aged adults and ↑ sleep latency (ave 66 min). Also ↓ Stage 3 + 4 sleep (no changes in REM)
• Effect also in adolescents. Higher caffeine intake - shorter nocturnal sleep duration, increased wake time after sleep onset, and increased daytime sleep

• Caffeine enhances performance on a wide range of tasks
• Attention, reaction time and psychomotor performance stronger than complex cognitive tasks
• • Helpful for shift workers

• Stronger effects of caffeine on daytime recovery sleep compared to nocturnal sleep
• • Increasing circadian wake propensity drive and a dissipation of homeostatic sleep pressure. We propose that the reduction of SWS by caffeine during daytime sleep increases the impact of the circadian wake signal on sleep
• Mood: Caffeine dependence associated with higher levels of psychological distress including bring prone to hypervigilence

• Caffeine is an unsafe food additive to alcoholic beverages will effectively make several “premixed” alcoholic energy drinks prohibited for sale in the United States
• Increased heavy episodic drinking
• • higher prevalence of alcohol-related consequences (think you're alert enough to drive etc)

• Eg. xanax, valium
• Primary effects are anxiolytic (anti-anxiety), sedative/hypnotic, muscle relaxant and anticonvulsant
• Primarily prescribed for treatment of insomnia, some anxiety disorders, alcohol withdrawal
• Acute administration results in sedation, drowsiness, learning impairment, psychomotor slowing, and anterograde amnesia (interaction with GABA)

• Short term use
• • Reduce onset to sleep latency
• • Increase stage 2 NREM sleep
• • Decrease in slow wave sleep
• • Prolonged REM sleep latency

• Long term use:
• ↑ microarousals compared to normal sleepers and pts with insomnia
• • ↑ Stage 2, ↓ stage 3&4 compared to normal sleepers

• Post withdrawal: Immediate subjective worsening of sleep on night after withdrawal
• After 15 days: ↑ SWS, ↓ stage 2 NREM (did not differ from controls with insomnia)
• • ↑ subjective sleep quality

• Long term use can cause dependence
• Withdrawal symptoms when reducing or ceasing are significant and can include insomnia and/or anxiety
• Note that withdrawal should be completed gradually, ideally with a withdrawal plan overseen by a GP
• Underlying cause of insomnia/anxiety is important to address
• Studies suggest that long term effects can persist after withdrawing in a small number of people (e.g. cognitive, psychomotor slowing)

• In general – antagonism of ‘wake’ receptors (e.g., histamine, monoamines) associated with sleep/sedation whilst re-uptake inhibition of these receptors is associated with wake)

• • Decreased SWS and REM sleep
• Increased arousals
• • Reduced TST and sleep efficiency
• • Increased sleepiness
• • Poorer motor responses, attention & memory
• • Act on mu-receptors in CNS- collocated in areas involved in sleep regulation
• Type of opiod is important: eg. chronic morphine use changes architecture, methadone does not

• Decreased REM
• • Frequent arousals
• • Reduced total sleep time
• • Changes may return to normal 3-6 months after abstinence
• • Neurocognitive effects remain