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

  1. 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)
  2. Sleep
    • • Sleep is an active, complex state
    • • Rest & Recuperation 
    • Memory encoding and consolidation • Maintain cognition and performance
  3. 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
  4. Fatigue Related Road accidents
    • 20% of fatal road accidents
    • Annual cost of 3 billion nationally
    • 300 serious injuries
    • 50 deaths each year in Victoria
  5. 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?
  6. 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
  7. 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
  8. 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.
  9. 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
  10. Opioids
    Prescription opioids are killing more Australians than heroin
  11. Pharmaceutical misuse
    • 1/20 misused a pharmaceutical in the last 12 months
    • Image Upload 1
  12. 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
    • Image Upload 2
  13. 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.
  14. 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
  15. 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?
  16. 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
  17. 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
  18. Cannabis and sleep
    • Most commonly used illicit drug in Australia
    • 35% lifetime use
    • • 10.4 % use in past year
  19. Sleep study populations
    • Naive (never used)
    • • Recreational (acute and withdrawal)
    • • Medicinal Users (e.g., pain)
  20. 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
  21. 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
  22. 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
  23. Recreational users
    • • Induces Deep Sleep State
    • TST not affected
    • Tolerance: repeated use may result in shallow and nonrestorative sleep
    • • Inconsistent effects on sleep architecture
  24. 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
  25. 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
  26. Alcohol and cannabis
    Combining increases global PSQI score
  27. 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
  28. 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)
  29. 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
  30. MDMA and circadian rhythms
    • Knocks out body clock for a few days
    • Light resets it
  31. MDMA and overnight memory consolidation
    Overnight memory consolidation was poorer
  32. 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
  33. 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
  34. 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
  35. 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
  36. 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
  37. 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)
  38. 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)
  39. 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
  40. 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)
  41. 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)
  42. 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
  43. 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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Wk 12: 'Uppers', 'downers', pharmaceuticals and their complex effects on sleep
Wk 12: 'Uppers', 'downers', pharmaceuticals and their complex effects on sleep