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The Hacking of the American Mind Chapter 10. Self-Inflicted Misery The Dopamine-Cortisol-Serotonin Connection
Author: Robert H. Lustig Publisher: New York, NY: Penguin Random House. Publish Date: 2017 Review Date: 2022-11-15 Status:📚
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Highlight(pink) - Location 1913
What if we could hype up our brain serotonin? What if we ate eggs and fish all day, consuming all the tryptophan and omega-3s in sight, and dumped the sugar? What if we managed to sleep a full seven hours a night? What if we fed our microbiome so it thanked us instead of paying us back? Wouldn’t we be extremely happy? We know tryptophan is not enough: if you’ve survived even one Thanksgiving with unpleasant relatives, you know that bingeing on turkey is far from a guarantee of a blissful evening. Can you binge on contentment? Maybe our serotonin receptors would start to down-regulate, just like our dopamine receptors did (see Chapter 5), and we’d end up with less of a signal for contentment after all. If so, we’d all be doomed, striving for happiness but never quite achieving it. Is that our fate? In contrast to dopamine, serotonin neurons have certain features that protect us from descending into the abyss—but they also prevent us from ascending toward nirvana (at least without chemical enhancements).
Highlight(pink) - Location 1924
In Chapter 7 we noted that serotonin-1a receptors in the brain are low in those diagnosed with major depressive disorder (MDD) from genetic studies;1 from PET scans in live patients;2 Yet we also noted that SSRIs fight depression by making serotonin clearance less effective in the synapse and increasing the odds of any serotonin molecule binding to a receptor. But if there’s more serotonin at the synapse, shouldn’t the-1a receptors down-regulate?4 Why don’t SSRIs stop working over time? Because, in contrast to dopamine receptors, the postsynaptic serotonin-1a receptors don’t down-regulate in response to increased serotonin.5 These neurons possess two special characteristics that keep our serotonin neurons and receptors resilient, even when we’re not. Serotonin neurons in the dorsal raphe nucleus (DRN) possess an extra control system: they express a set of serotonin-1a “autoreceptors” on the presynaptic side (the neuron releasing the serotonin). What does this mean? These receptors normally serve as a feedback loop that regulates how frequently that neuron fires. It’s like the servo-mechanism of the thermostat in your house. When the temperature drops, the thermostat kicks the heat on, and when it gets too hot, the furnace turns off. The-1a autoreceptor serves as the neuron’s thermostat, causing it to fire relatively slowly and rhythmically, and silencing it before it gets into trouble. By preventing these neurons from firing too rapidly, these autoreceptors make sure the serotonin neurons don’t wear out; and there is rarely enough serotonin in the synapse to down-regulate those-1a autoreceptors. SSRIs turn those autoreceptors off; it’s like setting the temperature threshold on your servo-mechanism thermostat much higher, and those serotonin nerve terminals fire like gangbusters; thus the antidepressant effects.6
Highlight(pink) - Location 1940
Perhaps the most amazing thing about serotonin’s binding to the postsynaptic-1a receptor is that, rather than stimulation, serotonin inhibits the next neuron.7 Postsynaptic-1a agonists quiet the postsynaptic neuron, giving them a rest. Remember from Chapter 5 that neuronal death occurs from a process called excitotoxicity, when a neuron keeps firing and kills its target. But there is no such thing as inhibitotoxicity!
Highlight(pink) - Location 1944
What’s more, the serotonin system has one more trick up its sleeve: it has the capacity to tame (or excite) the dopamine system.8 How to get a balance? Serotonin agonists such as LSD and psilocybin (magic mushrooms) are being used as potential treatments for smoking, alcohol, and other drug addictions. Family and religion can serve the same purpose. Could happiness and contentment reverse addictive behavior? Could our own serotonin overcome our dopamine to our benefit? Indeed, the animal data say yes, serotonin can speed up the breakdown and disposal of dopamine,9 resulting in decreased dopamine-related reward signaling and reward-seeking behavior.10, 11, 12 In humans, we know that high levels of serotonin can decrease alcohol intake13 (although your antidepressants can’t work if you’re imbibing three bottles a day). Conversely, serotonin depletion (through experimental depletion of tryptophan) is associated with risky choice making.14
Highlight(pink) - Location 1956
Could the food deserts and overall poor nutrition in inner cities impact the crime rates? Story for another time, but they certainly don’t help. Your environment, like your genetics, can make a huge difference in the functioning of this system. Low dietary tryptophan means less serotonin gets made. Fewer-1a receptors means serotonin can’t do its job. Fast serotonin recyclers/transporters (the hungry hungry hippos) mean less of a chance for each molecule to get to the receptor in the first place. Any of these three things can lead to depression (see Chapter 7). And what if these serotonin neurons die? The serotonin system is not impervious to damage; it’s just that (unlike dopamine neurons) serotonin isn’t the likely culprit.
Highlight(pink) - Location 1963
Serotonin does not exist in a vacuum. It is both directly and indirectly impacted by different neurochemicals, including other drugs, cortisol (stress), lack of sleep, and crappy diet. All the things that negatively affect dopamine as well. Uh-oh, can’t you see what’s coming? Many illicit party drugs tap-dance on both your serotonin and dopamine systems. While onetime cocaine exposure might provide a serotonin boost, binge cocaine administration does anything but. The chronic blockade of the DAT (dopamine’s hungry hippos) also plays havoc with your dopamine receptors (due to tolerance), but it’s also knocking down the serotonin-1a receptors in key regions that matter,15 which means that the happy rush is now a pretty sad puddle.
Highlight(pink) - Location 1969
But binge cocaine use is milquetoast compared to industrial-strength methylenedioxymethamphetamine (MDMA), the recreational drug known worldwide as “Molly” or “ecstasy.” This synthetic neurotransmitter analog has been available since the 1980s and has slowly inched up the list of substances of abuse that are creating societal problems. MDMA is the ultimate club drug, because it provides the user a panoply of neural experiences all at once; it is the ultimate reuptake inhibitor. It binds up the hungry hippos of both dopamine and serotonin and puts them both out of commission. In other words, dopamine and serotonin run full tilt at the same time. It heightens excitement and sexuality and postpones fatigue and sleepiness, because the dopamine receptor is activated; it increases euphoria, because the serotonin-1a receptor is activated; and it even gives the added bonus of minor hallucinations, because the serotonin-2a receptor is activated,16 although the bonus “mystical experience” is not part of the portfolio.17
Highlight(pink) - Location 1978
long-term MDMA use kills neurons. And not just the postsynaptic cortical neurons, which are responsible for the defects in memory, decision making, and impulse control. No, MDMA can kill the DRN serotonin neurons outright, and scar the brain, by enacting the same program of cell death that cocaine does.18, 19 And the current drug of the day—methamphetamine—will also kill off the nerve terminals of both dopamine and serotonin neurons.20
Note - Location 1982
Adderall too?
Highlight(pink) - Location 1983
Yet, like LSD, whose early indiscriminate use ultimately paved the way to more controlled research and potential benefit, MDMA might be useful, and researchers are beginning to examine those scenarios. We know that people with autism, social anxiety disorder, and post-traumatic stress disorder are mentally and socially compromised. Life for these patients is extremely difficult to navigate, in part because they have trouble connecting emotionally with others. But early controlled studies administering MDMA as single doses to autistic adults in medical settings are demonstrating increased openness, introspection, and social adaptability,21 without starting the slide to addiction. The effects, like single-dosage LSD, seem to be long-lasting, and with few if any side effects. Presumably, the boost in dopamine reduces the fear of social anxiety, while the boost in serotonin increases contentment, providing the impetus to let these people participate in society.
Highlight(pink) - Location 1994 ❗️
unhappiness (exclusive of clinical depression) hovers at 43 percent of all Americans, at least those who admit it. They’re on the same spectrum as those who are clinically depressed, they’re just not as severe. What are their serotonin systems up to? In one study, the MRI findings of people who identified as being less happy had on average fewer serotonin transporters or serotonin-1a receptors.22 OK, clinical depression is roughly 7 percent of the population, drug addiction requiring rehab is about 9 percent … but everyone is stressed nowadays, and for most of them, it’s chronic stress.
Highlight(pink) - Location 1999
In Chapter 4, we learned that stress and dopamine feed each other in a “positive feedback” cycle. Remember the prefrontal cortex (PFC), the “Jiminy Cricket” part of the brain that’s supposed to inhibit impulsive behavior by turning off the amygdala? Dopamine nerve terminals reside in the PFC and are ideally kept in check. But a massive amount of stress-induced dopamine flooding the PFC will squash that Cricket, increase risky and impulsive behavior,23 and keep your cortisol elevated. As you might expect, cortisol is the anti-contentment hormone. Contentment means all is well and it’s OK to chill. If the adrenal glands are releasing cortisol, something must be wrong: Indeed, stress and cortisol are the mortal enemies of the serotonin-1a receptor, and cause down-regulation throughout most species—in the Gulf toadfish,25 in the rat,26 in the tree shrew,27 and in the human.28 Fewer-1a receptors means less serotonin signaling, and less contentment.
Highlight(pink) - Location 2013
Depressed people have problems with circadian (day-night) cortisol regulation. Normally, cortisol goes up in the morning before you wake up to help you mobilize glucose, raise your blood pressure, and get ready for the day. By the time nighttime arrives, cortisol levels are in the sewer. This circadian rhythm of cortisol is missing in depressed subjects: their cortisol is always up and you can’t even suppress it with medications, making this a tough nut to crack. One study suggests that cortisol reactivity may be a predicting factor for suicide.29 More stress means more cortisol, which plays havoc by down-regulating the-1a receptor, reducing serotonin signaling and increasing risk for depression and apparently for suicide as well. And those who are cursed with a specific genetic difference making lots of serotonin recycler/transporters (hungry hungry hippos) are at the highest risk. If your hippos are gobbling most of your serotonin in the synapse, and stress is eradicating your-1a receptor, you are totally screwed.30
Highlight(pink) - Location 2022
The worst of all chronic cortisol problems stems from adverse childhood experiences, or ACEs (better known as child trauma).31 Pick your abuse (physical, sexual) or your stress (parents’ divorce, fighting, bullying): ACEs can result in cortisol dysregulation into adulthood,32 including increased risk for addiction and depression. Kids who experienced ACEs and who also harbored a genetic difference in their serotonin recycler/transporter demonstrated a fourfold risk in depression when they hit adulthood.33
Location 2029
And what does America suffer from across the board? Chronic sleep deprivation. If you really want to make someone unhappy, deprive him or her of sleep. Given that roughly 35 percent of the adult population doesn’t get enough sleep (on average less than seven hours per night),34
Note: ADHD connected to sleep deprivation
Highlight(pink) - Location 2033
What is the relationship between sleep, eating, irritability, and serotonin? Well, like everything in the brain, it’s complicated. Chronic sleep deprivation is a hallmark of severe aggression and irritability in some people35 and suicidal depression in others.36 Those who suffer from depression generally have off-kilter sleep habits, either sleeping too much (hypersomnia) or sleeping too little (insomnia). Chronic insomnia is a major risk factor for depression.37 Whether chronic sleep deprivation affects serotonin receptors directly or indirectly through effects on cortisol is not yet known, but mouse studies would suggest that cortisol plays some role.38 In rats, lack of sleep messes with cortisol reactivity to stressful situations39 and simultaneously decreases the function of serotonin-1a receptors.40
Highlight(pink) - Location 2044 ❗️
Not only does insomnia and sleep deprivation wreak havoc on our mood and emotions, it messes with our waistlines, increasing insulin resistance, glucose intolerance, obesity, and all the other diseases of metabolic syndrome.41 One study found that sleep deprivation increased wanting of high-caloric food items (compared to when the participants had a good night’s sleep), and these changes in behavior corresponded with decreased activity in brain regions related to decision making but increased activation in the amygdala (the stress and fear center).42 And it likely goes both ways. Adults who get five or fewer hours of sleep per night consume 21 percent more sugared beverages (including energy drinks) than the general population, while those who sleep six hours or less consume 11 percent more.43 But, as in all other correlation studies, what drives what? Do sugar and caffeine cause sleep deprivation? Or does sleep deprivation drive sugar and caffeine consumption? Either way, when you’re chronically underslept, the Cricket gets stomped, and it’s time for Taco Bell’s “Fourth Meal.”
Highlight(pink) - Location 2053 ❗️
Indeed, one of the most pernicious causes of unhappiness across populations is bad food. Remember from Chapter 9 that tryptophan is low in the fast-food diet, yet the competing amino acids tyrosine and phenylalanine are abundant. More precursors for dopamine means more occupied transporters, which means less chance for tryptophan to get across into the brain to be converted to serotonin. It would seem that any pleasurable item we consume that drives dopamine up (sugar, alcohol, processed foods) can also drive serotonin down, possibly directly, or indirectly through metabolic syndrome. Conversely, weight loss that reverses metabolic syndrome can also improve symptoms of anxiety while at the same time increasing blood serotonin levels,44 although blood levels are not necessarily relevant. Depression rates started to increase after the post-1940 birth cohort reached adulthood—in the 1960s,45 at the same time processed food started its ascendency as the world’s diet staple. While this temporal relation is not causation, it’s still pretty suspect.