The Hacking of the American Mind

by Robert H. Lustig

  The pop literature surrounding omega-3s has translated into people popping fish oil capsules left and right. Full disclosure: I do too. There’s even a purified omega-3 preparation available by prescription (Lovaza), but it’s very expensive and usually not covered by insurance. In fact, I take care of children with severely elevated blood triglycerides—high enough to cause spontaneous acute pancreatitis, which is a mega disaster with life-threatening complications. Purified omega-3s are the obvious treatment of choice—and still the insurance companies won’t authorize their purchase.

  So what’s behind this miracle superfood that does so much? Omega-3s are incorporated into cell membranes throughout your body. They increase “membrane fluidity,” which means that they allow for easy cell deformation, allowing them to snap back instead of rupturing. This prevents cell aging and early cell death. They also allow nutrients and hormones to pass through the cell membrane, and allow toxins to leave the cell rapidly. Nowhere in the body is this special function more important than in the brain. For instance, omega-3s help repair the damage to the membranes exerted by glucose, and especially fructose.55

  That’s all well and good, but what do omega-3s have to do with serotonin, or with the promotion of happiness, for that matter? Turns out omega-3s impact our mental well-being in two distinct but related ways.56

  Omega-3s have an indirect effect on serotonin release from nerve terminals throughout the brain. When the area surrounding the nerve terminal releasing serotonin is inflamed, it inhibits serotonin release (keys) and even fewer are able to make their way to the receptors (locks) across the synapse. This may explain why people whose bodies and brains are undergoing inflammation tend to be so irritable,57 even if they are taking an SSRI. There is even less serotonin for them to work with. But omega-3s inhibit the formation of inflammatory cells,58 which presumably would allow for better serotonin transmission.59

  DHA, one of the omega-3s, is a precursor of a class of molecules called endocannabinoids (ECs)—the brain’s and body’s version of marijuana.60 As we discussed with rimonabant in Chapter 2, we have specific receptors for marijuana, called CB1 receptors, which are ubiquitous throughout the brain. The active compound in marijuana known as tetrahydrocannabinol (THC) binds to this CB1 receptor to heighten mood by alleviating anxiety, which explains why people are so giddy when they smoke pot. Turns out our neurons make their own marijuana-like neuromodulator called anandamide, which binds to that CB1 receptor, which is designed to alleviate our level of anxiety. Anything that inhibits anandamide synthesis or action will increase your level of anxiety severalfold, while anything that improves anandamide’s action will keep you cool as a cucumber. Most of us are prone to experience anxiety and stress; an extra boost of occupancy of your CB1 receptors by smoking pot might allay some of that anxiety, if you aren’t prone to paranoia when stoned. And, as you might expect, as our collective stress and anxiety levels have continued to increase, our level of happiness has continued to decrease. The increase in anxiety is one reason for the increasing number of potheads nationwide61 and provides a rational explanation for why recreational marijuana legislation is spreading throughout the United States. Our own anandamide clearly isn’t enough to tame the wild beast anymore. Why not?

  Omega-3s are part of the endocannabinoid signaling machinery. Deficiency of omega-3s doesn’t allow endocannabinoids to act as they normally would on the system, thus causing more anxiety and depression.62 But the converse also seems to be true: we can fix this problem with omega-3 supplementation. In one study, a Mediterranean diet improved symptoms of depression.63 Was it the omega-3s? Or less processed sugar-laden food? One study showed that omega-3s were equivalent in effect to Prozac in treating depression, and the combination was more effective than either one alone.64 In a related study, administration of omega-3s to patients with recurrent self-harm (e.g., cutting, picking, scratching, burning—the ultimate expression of anxiety) showed a reduction in suicidality, depression, and daily stress.65 A recent trial gave omega-3s along with minerals to eleven-year-old kids with conduct disorder or oppositional defiant disorder (the ones who routinely find themselves in the principal’s office), and within three months their aggression was reduced, and way better than talk therapy.66 Lastly, omega-3 consumption can help ward off depression in children67 and adults,68 and can serve as an adjunct to SSRIs in its treatment.69

  And this is the gift that keeps on giving—or should I say the punishment that keeps on punishing? What your mother ate makes a difference in who you are. Many mothers state that their child’s health and happiness are at the forefront of their own life goals. What you eat when pregnant plays a large part in determining your child’s future. Lack of omega-3s during pregnancy in rats alters the offspring’s brains in a way that messes with insulin signaling and brain growth factor levels, all of which leads to increased anxiety behaviors.70 This has immediate implications for all of us. What do we tell pregnant women not to eat? Seafood—because of the concern for mercury poisoning. Except that maternal seafood consumption predicts improved neurodevelopmental outcomes in British children.71 Are we making more trouble than we are solving? Well, maybe we can skirt this issue by giving the pregnant mom some omega-3 capsules; if we do, the kids’ neurodevelopmental outcomes and the mom’s risk for depression are improved.72 New research suggests that walnuts might also be beneficial.73

  We Are Such Stuff as Dreams Are Made On

  There you have it—the dietary trifecta of happiness: tryptophan, sugar, omega-3s. Three individual components in our diet—two of which are essential nutrients and hard to get (tryptophan and omega-3s), and the third, added sugar, which is not even a food but nonetheless has been purposefully placed in virtually everything you eat and drink. Three separate mechanisms, but with a very clear interplay among all of them. The balance of these three molecules is the difference between a healthy, happy, and agile brain and an angry, sad, and demented one. And maybe your child’s angry, sad, and cognitively compromised brain as well. The two that help alleviate depression are in short supply anyway—and even less so in processed food. Conversely, the component that destroys the brain has been added to virtually every processed food item for palatability and sales. Our Western diet has done us no favors in our ever-elusive quest for happiness. But just turn the page: the true key to our unhappiness lies in our insatiable quest for pleasure. It gets worse before it gets better.

  10.

  Self-Inflicted Misery: The Dopamine-Cortisol-Serotonin Connection

  A lifetime of happiness! No man alive could bear it—it would be hell on earth.” So says the character Tanner in George Bernard Shaw’s Man and Superman (1903). A lifetime of contentment is reserved for the Dalai Lama. The rest of us mere mortals cycle through bouts of anxiety and dysphoria, squeezing out what pleasures we can and barely pausing long enough to enjoy any contentment we might be able to muster. But, as with everything else in this book, it’s really about taming your biochemistry.

  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). In Chapter 3, we noted that dopamine down-regulate
s its postsynaptic dopamine receptors. Get a hit, get a rush over and over, and the number of receptors goes down to protect the neuron, starting the vicious cycle of tolerance and dependence, crash-landing into addiction. If you bludgeon dopamine receptors, those neurons get beaten into submission and can eventually die.

  An Emotional Thermostat?

  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 and biochemically in dead ones.3 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

  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!

  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 Of course, we need both. Personally, the idea of a life with contentment but without motivation and reward, living atop a mountain in deep meditation and pondering how much karma I have lost driving in New York for twenty-five years, just isn’t all that appealing. But neither is dopamine overload and its aftereffects. 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 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.

  “Breaking” Neurons Is “Bad”

  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. Al Pacino’s Tony Montana in Scarface (1983) was anything but Zen at the end.

  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 Three big bangs for one buck, as it were. Yes, MDMA has it all—sex, drugs, and rock ’n’ roll. Except for one additional bonus: 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

  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 improvement in mood and reduction in defensiveness is allowing treated individuals to join social structures and participate in rewarding behaviors, such as dancing. 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.

  I hear you already: like South Park’s Mr. Mackey, you’re saying, “Drugs are bad, mmmkay?” Indeed they are, when taken indiscriminately and over the long term. Everyone’s reaction is different; contrary to popular belief, your brain is actually the most sensitive part of the body. But there are way more people who wish they were happy with a nonexistent magical pill, because unhappiness (exclusive of clini
cal 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

  Stress Pushes Us over the Edge

  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. 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.