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Many drugs affect 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)
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Sleep
- • Sleep is an active, complex state
- • Rest & Recuperation
- • Memory encoding and consolidation • Maintain cognition and performance
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Magnitude of performance impairment
- 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
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Fatigue Related Road accidents
- 20% of fatal road accidents
- Annual cost of 3 billion nationally
- 300 serious injuries
- 50 deaths each year in Victoria
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Case study: Sleep and wake promoting drug use in shift workers
- 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?
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Population measures of alcohol and drug use
- 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
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Alcohol guidelines
- 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
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Alcohol stats
- 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.
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Illicit drug use in 2016
- 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
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Opioids
Prescription opioids are killing more Australians than heroin
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Pharmaceutical misuse
- 1/20 misused a pharmaceutical in the last 12 months

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Alcohol and sleep
- 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

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Acute effects of alcohol on sleep in non dependent sample
- 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.
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Sleep in alcohol dependent populations
- 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
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Some TP Data: Sleep during 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?
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Alcohol effect on sleep-wake neurotransmitters
- 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
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Alcohol may worsen other sleep complaints
- 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
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Cannabis and sleep
- Most commonly used illicit drug in Australia
- 35% lifetime use
- • 10.4 % use in past year
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Sleep study populations
- Naive (never used)
- • Recreational (acute and withdrawal)
- • Medicinal Users (e.g., pain)
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Marijuana's effect on sleep
- 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
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Limitations of cannabis studies
- Limited number of studies conducted (N=37)
- Small sample sizes
- Quality of studies questioned
- Unable to control pre existing sleep issues
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Naive users
- 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
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Recreational users
- • Induces Deep Sleep State
- TST not affected
- Tolerance: repeated use may result in shallow and nonrestorative sleep
- • Inconsistent effects on sleep architecture
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Medicinal users
- • 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
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Mechanism of cannabis
- 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
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Alcohol and cannabis
Combining increases global PSQI score
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MDMA
- 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
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Ecstacy studies
- 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)
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Others noted sleep disturbance
- 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
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MDMA and circadian rhythms
- Knocks out body clock for a few days
- Light resets it
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MDMA and overnight memory consolidation
Overnight memory consolidation was poorer
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Caffeine
- CNS stimulant
- Doses in commercially available products have increased
- Some people sensitive to its effects
- Withdrawal associated with headaches, difficulty concentrating, fatigue, and drowsiness
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Caffeine adenosine
- 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
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Caffeine and sleep
- ↓ 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
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Daytime alertness and Performance
- Caffeine enhances performance on a wide range of tasks
- Attention, reaction time and psychomotor performance stronger than complex cognitive tasks
- • Helpful for shift workers
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Caffeine timing and mood
- 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
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Mixing caffeine
- 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)
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Benzodiazepines (BZP)
- 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)
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Benzodiazepines and sleep
- 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
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Benzodiazepines
- 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)
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Other drugs
• 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)
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Opioids: Acute effects on sleep
- • 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
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Chronic Effects of opioids on sleep
- Decreased REM
- • Frequent arousals
- • Reduced total sleep time
- • Changes may return to normal 3-6 months after abstinence
- • Neurocognitive effects remain
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