#650: Dr. Matthew Walker, All Things Sleep – How To Improve Sleep, How Sleep Ties Into Alzheimer’s Disease And Weight Gain, And How Medications (Ambien, Trazodone, etc.), Caffeine, THC/CBD, Psychedelics, Exercise, Smart Drugs, Fasting, And More Affect Sleep | The Tim Ferris Show

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Key Takeaways

  • Sleep is a power cleaning for the brain: the brain has a cleansing system (called glymphatic system) which is switched on during non-REM deep sleep
    • Chronic short sleep is associated with higher amounts of beta-amyloid and tau protein, putting you at higher risk for Alzheimer’s disease because you are missing out on the glymphatic system’s power
  • The choices you make about food are controlled by your brain – when you’re short on sleep or sleep deprived, the quality of food decreases, and food cravings increase so you reach for obesogenic foods (sweets, carbs, salty snacks, ice cream, etc.)
  • Behavioral levers to pull for improved deep sleep: light exposure, stress, and anxiety, temperature, exercise
  • Though Tetrahydrocannabinol (THC) will decrease time it takes to fall asleep, the trade-off might not be worth it – you may experience an increase in tolerance, dependency on sleep, significant withdrawal rebound effect (if you stop, sleep will be worse than it was at baseline), and disrupted REM
  • Traditional sleeping pills (like Ambien) can trick you into thinking you got a good night of sleep because the duration will be longer, but sleep architecture is changed and may lead to morning grogginess and reduction in memory (but there is a time and place for use)
  • The importance of positive talk for sleep: insomnia can create negative self-talk, anxiety, and worry about going to bed – cognitive behavioral therapy can be tremendously helpful before trying pharmacology


Matthew Walker, Ph.D. (@sleepdiplomat) is a sleep expert and Professor of Neuroscience and Psychology at the University of California, Berkeley, USA. He is also the founder and director of the Center for Human Sleep Science and host of his own podcast, The Matt Walker Podcast.

In this episode of The Tim Ferris Show, Tim Ferriss and Matthew Walker take a deep dive into all things sleep: how to improve it, the relationship between sleep and disease, the impact of medications, stimulants, and food on sleep, and much more.

Host: Tim Ferriss (@tferriss)

Book: Why We Sleep by Matthew Walker, PhD

Connections Between Sleep & Alzheimer’s Disease

  • There is not a single species known that does not require sleep – this means that sleep emerged with life and has survived every evolutionary path; it must be critical to life
    • Maybe wakefulness emerged from a sleep state
  • Alzheimer’s disease is a form of dementia
  • Two proteins (at least two) proteins contribute to Alzheimer’s disease: (1) beta-amyloid and (2) tau protein
  • Individuals who reported sleeping 6 hours or less throughout life have higher amounts of beta-amyloid and tau protein
  • Two sleep disorders – insomnia and sleep apnea – are associated with higher rates of cognitive decline and Alzheimer’s disease prematurely
  • If you deprive individuals of a night of sleep for one single night, there’s a significant increase in beta-amyloid and tau protein circulating in the blood and cerebrospinal fluid
    • Even a recovery night of sleep is not enough to reverse toxins that have built up
  • The brain has a cleansing system (called glymphatic system) which is switched on during non-REM deep sleep
  • The cycle of poor sleep: if you don’t get enough sleep each night, the more build-up of beta-amyloid and tau protein; the more protein that builds up, the less the brain can generate deep sleep, the more it builds up, and so on
  • On the bright side, sleep is something we can fix! Intervene early before you have cognitive impairment – mid to late 30s is generally when poor deep sleep comes in
    • It’s unclear why but men decline in deep sleep earlier than women – could be hormones, could be brain decline

Repairing Sleep With Brain Stimulation

  • Sleep study: records electrical brainwaves of natural sleep then the clinical team develops an algorithm that understands the cycling cadence of brain waves, predicts when the next brain wave will hit and the next wave is stimulated and amplified
    • Complexity: precise placement of pads on the head, duration of stimulation, frequency of stimulation
    • Company (in the early days) working on this is StimScience
  • Goal is to develop a more useable, portable stimulation device to improve the sleep of people at home
  • Desired outcomes: (1) improved onset latency (the speed at which you fall asleep); (2) increase in deep sleep and brain waves associated with deep sleep; (3) improvements in the number of times you wake in the middle of the night and rate at which you fall back asleep  

Factors Affecting Deep Sleep

  • Light exposure, especially in the evening can decrease the amount of deep sleep
    • Light exposure in the bedroom (even though eyes are closed while sleeping) and in the last few hours before sleeping
  • Stress and anxiety disrupt sleep and negatively impact deep sleep in particular
  • Temperature makes a huge difference in deep sleep; it’s not just about keeping it cold in the bedroom – there are different stages of sleep that match better with different temperatures
    • To initiate sleep, drop core body temperature (note, people with insomnia have difficulty with thermoregulation) – take a warm bath or shower before bed or at minimum, warm the hands and feet
  • Exercise, particularly cardio will improve deep sleep but cardio and strength training will both positively impact sleep
    • Greatest effects are not dependent on the time of day – the best exercise is the one you will do consistently
  • Something about rocking motion/oscillation improves sleep and feelings of restfulness the next day (but obviously, it would be challenging to emulate in adults though companies are working on it)
    • It would also be possible for something to be placed in the inner ear to give the sensation of rocking

Pros And Cons Of Caffeine

  • Caffeine disrupts sleep and makes it harder to fall asleep while selectively depriving deep sleep
  • Caffeine is a psychoactive stimulant that competes with adenosine in the brain to block them and keep you alert
  • Cons of caffeine: it will prolong the time to fall asleep, increases anxiety, duration of action is long (half-life of 5-6 hours), changes sleep architecture (not refreshed the next day), caffeine in the evening will impair non-REM deep sleep
  • Some of the benefits of coffee are the same as the benefits of a good night of sleep
  • Coffee has strong antioxidant effects (even in decaf coffee)
  • Dose & timing make the poison: don’t drink more than 2-3 cups per day; be mindful of the time and avoid afternoon coffee (since half-life is so long)
  • Choosing the right coffee
    • Light roast has the same caffeine content as a dark roast but dark roasts degrade faster with roasting so the net effect is more caffeine in light roast
    • Fine ground coffee has higher caffeine than larger
    • Cold brews have stronger caffeine content than hot brews (likely due to the duration of the brew)
    • Ranking coffee type by antioxidant content, high to low: fine grains, cold brew, espresso, instant, drip/infusion


  • THC is the psychoactive component of CBD
  • Benefits of THC for sleep: does reduce the time it takes to fall asleep
  • Cons of THC for sleep: tolerance develops which can lead to dependency, significant withdrawal rebound effect (if you stop, sleep will be worse than it was at baseline), disrupts REM sleep amount, onset, and intensity
    • You will regain REM sleep once you stop using THC and dreams may actually be more intense
  • CBD data is mixed but does seep to assist with non-REM deep sleep in higher doses (50mg or more) – but in low doses (25mg or less) may make you more awake


  • Some psychedelics appear to impact microglia in the lymphatic system which may impact glymphatic system repair mechanisms in the brain
  • Dream sleep and REM sleep is almost like sleep therapy which provides emotional convalescence
  • Many psychedelics act on serotonergic mechanisms in the brain, the opposite of what happens in the brain during REM sleep
  • Psychedelic use instills a feeling in people like they’re not tired, and don’t feel like they need sleep but they haven’t slept
  • Some psychedelics can increase heart rate variability but there isn’t enough evidence to parse out

The Role Of Sleep In Fasting, Nutrition, Food, And Weight Gain

  • Lectin sends satiety signals to the brain; ghrelin sends signals to eat
  • When sleep is disrupted, the quality of food decreases and food cravings increase – lectin drops as much as 20%, and ghrelin increases as much as 30%
  • It’s not just that you eat more when short on sleep, it’s that the things you eat more of and crave are obesogenic (sweets, carbs, salty snacks, ice cream, etc.)
  • When you sleep deprive individuals you also increase endocannabinoids in the brain
  • Possible evolutionary explanation: it’s possible you’re trying to eat sugary foods to overcome the sleep deprivation – or the lack of sleep suggests to your brain that you’re in a condition of starvation, so you need to eat
    • On average, sleep-deprived individuals will overeat 300-600 calories
  • Sleep changes significantly during periods of fasting (even intermittent) – latency period (time to fall asleep) increases but time to fall back asleep once you wake up seems to decrease
    • The peak in melatonin decreases and shifts later in the night so bedtime drifts forward


  • Modafinil is a wake-promoting chemical used by some people after poor sleep
    • Cons: tolerance and dependence is rapid
  • Traditional sleeping pills (like Ambien) work on GABA system which induces sleep but does change architecture so you’re not getting the restoration of natural sleep
    • Don’t take sleeping pills long term but there is a time and place for use
    • Sleeping pills should not be first-line defense against insomnia
    • Sleeping pills will make sleep duration longer but you’ll still wake up groggy because of changes in sleep architecture
  • Trazodone is sleep-inducing but doesn’t work like classic sleeping pills – it targets noradrenaline in the brain and reduces serotonin and histamine
    • It tries to switch off wake-promoting features in the brain which is more naturalistic than other sleeping pill mechanisms
    • It reduces the time it takes to fall asleep, and waking up during the night, and doesn’t impair REM sleep which is surprising
    • This is particularly effective for those 60+
    • There doesn’t appear to be a tolerance buildup and benefits persist at the same dose
    • Downside: unclear what long-term health associations are
  • Be mindful of polypharmacy and interactions between medications, sleeping pills, and caffeine
  • Gabapentin and pregabalin reduce the firing propensity of neurons to reduce hyperactivity of the brain – both seem to increase non-REM deep sleep and increase light REM sleep
    • Improved sleep may be an indirect effect of reduced anxiety and muscle relaxation
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