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The Hacking of the American Mind Chapter 5. The Descent into Hades
Author: Robert H. Lustig Publisher: New York, NY: Penguin Random House. Publish Date: 2017 Review Date: Status:📚
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There’s a price to pay for reward. It used to be measured in dollars, pounds, or yen, but now it’s measured in neurons. As the monetary price of reward fell, the physiological price of reward skyrocketed. Because those dopamine receptor–harboring nucleus accumbens (NA) neurons are fragile. They want to be tickled; that’s why they have dopamine receptors in the first place. But they’re very sensitive; they don’t want to be bludgeoned. If you open the dopamine floodgates repeatedly, these neurons have some fail-safe methods built in to protect themselves. The goal is to have an optimal level of dopamine receptors so that even a minuscule dopamine rush (trip to the nail salon) can find an open receptor and generate a unique pleasure from the experience. Obviously, a bigger rush (a couple of glasses of scotch or jumping out of an airplane) will occupy more receptors and generate a bigger reward. But stimulating the dopamine receptors excites that next neuron in the NA, and overstimulation with multiple rapid firings can cause those receptor-containing neurons to go into overdrive, leading to cell damage or death, termed excitotoxicity. To protect themselves from your irrational exuberance, each neuron has a built-in subcellular program that reduces the number of receptors on its surface. The more dopamine chronically released from the VTA neuron, the fewer dopamine receptors will be available on the NA neuron to transduce the signal for reward. This is the law of mass action—everything kept in check. When cells in your body die, they are usually replaced with new ones. Not so with the brain, with few exceptions (like the hippocampus, which plays a role in the depression story). Once a primitive brain cell (neuroblast) turns into a functioning neuron and starts firing, it loses the capacity to divide again.1
- Lepousez G et al., “Adult Neurogenesis and the Future of the Rejuvenating Brain Circuits.” Neuron 86, 387–401 (2015).
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Clearly, chronic stimulation of neurons, resulting in cell death with no chance for replacement, is not in your best interest. So nature developed a plan B that is semi-protective. Ligands (molecules that bind to receptors, such as dopamine or cortisol) almost uniformly down-regulate their own receptors, all over the body. In other words, nature makes it so that the locks can be rekeyed or even shut down. But it also means that the response of the cell won’t be as robust the next time around. You will need more to get less. The down-regulation of receptors is a phenomenon called tolerance; the receiving neuron is becoming tolerant to the excessive stimulus. This is both good and bad. It’s good because it means your neurons aren’t dead. It’s bad because the next time you go looking, you’re going to need more of the substance in order to get the same level of reward. Which ups the ante. Tolerance is a standard response in medicine, and occurs with virtually every chemical that binds to a receptor, whether it be in the brain, the gut, the muscle, the liver, or anywhere else for that matter. Tolerance is how cells, and you, survive.
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Simile of the leper and charcoal pit
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But when neurotransmitters bludgeon the receiving neuron en masse and without cessation, they can overstimulate and eventually kill that neuron through a process of programmed cell death called apoptosis. Chronic excitation of almost any neuron can lead to cell death. This is a common phenomenon in neuroscience, and it’s a necessary process. Apoptosis is inherent to all cells in the body; it’s the self-destruct program that keeps good cells from turning bad (e.g., cancer). There are two ways for a cell to die: necrosis (poisoning it from the outside) or apoptosis (self-destruction from the inside). Drugs can do both: they can poison the cell outright, or they can beat it into permanent submission. Apoptosis is a normal and very important process throughout the body that clears away overworked, mutated, or just plain old and decrepit cells.
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We all start out as a single cell—a zygote—and by adulthood we end up as a conglomeration of 10 trillion cells, which have differentiated into hundreds of various cell types along the way. Think of apoptosis as the human equivalent of bonsai, the Japanese art of pruning and sculpting trees to take on new and beautiful dimensions; otherwise they’re just gangly weeds. Adults appear smarter than toddlers for three reasons: they have more white matter (the fatty part of the brain that insulates neurons and helps transmit impulses faster), which increases information transmission speed; they have a more developed PFC (the executive function center, or Jiminy Cricket, of the brain); and they generally have more experience to draw on. But the number of neurons remains the same. That’s why IQ tests can be administered as early as age four. If your four-year-old self could see you now, Marlon Brando’s words from On the Waterfront (1954) would no doubt reverberate: “I coulda been somebody. Instead of a bum, which is what I am.” So keeping your neurons happy and healthy throughout your life should be part of your prime directive.
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Yet many of us spend our lives bombarding our synapses with substances and behaviors that down-regulate receptors through the law of mass action (see Chapter 3) or that act as poisons (e.g., alcohol), taking out perfectly good neurons, or with substances that provide different forms of excitation, including illicit drugs of abuse,2 or too much coffee, too much stress, and not enough sleep.3 They either rapidly necrose from the outside or, more likely, slowly apoptose from the inside. And then pleasure is strewn to the wind, because those neurons are not coming back.
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This process is different from developing tolerance. Tolerance is the down-regulation of receptors with the chance of coming back. Once a neuron is dead, it ain’t never coming back. There’s less to work with, and you can’t make more neurons. All of which comes down to the same result: you need more to get less.
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As an illustration, let’s choose a peanut butter cup, the cheapest of all thrills (but it just as easily could be a shot of espresso or vodka). In terms of the reward neuron, the initial script’s the same: Get a desire (dopamine). Get a fix. Get a temporary rush (EOPs). Yum. But, man, that peanut butter cup was so delicious. Just the right amount of peanut butter, salt, chocolate, and sugar. Specifically engineered to hit your bliss point as chronicled by Michael Moss.4 Go ahead, eat the second one—they come two to a package, after all. Get another rush; this one won’t last as long as the first one because there are fewer receptors. Tomorrow, you go get another package at Walgreens—they’re staring at you right on the counter—and dig in for your third hit, but you just can’t recapitulate that gustatory nirvana again. More should be able to do it: the next day, you buy the six-pack. And now that extra fix means your receptors are down-regulated even more. So you decide to put the pedal to the metal: the economy-size bag has now become your standard, and it’s just giving you way less response than you ever had. The cashier at Safeway now recognizes you. And now you have so few reward-transducing receptors, you hardly break a smile. You want the yum, but even after eating the Halloween-size bag and a couple of pints of ice cream while watching The Notebook (2004), you still aren’t satisfied.
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The characteristic of unsatisfactoriness
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Every substance and behavior that drives up your reward triggers will just as quickly drive down your reward receptors. Different types of rewards, chronically and in excess, all have the same effect. Why is it that alcoholics can consume so much more booze than your average drinker? Their livers have a much higher tolerance, because repeated and high exposure has increased their capacity to metabolize the alcohol. Their brains also have a higher tolerance because the alcohol has been driving those VTA neurons, which have been bombarding those receptors in the NA with dopamine for so long, they need a lot more to fly the friendly skies.
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If you stop the nosedive here before your neurons are deep-sixed, you have a fighting chance of pulling out, like a withered flower that’s waiting for rain. If the postsynaptic neurons are only damaged but still alive, your dopamine receptors can regenerate over time.5 You can bring your reward system back and start over, although dopamine receptors aren’t back to normal for at least twelve months.6 But keep nosediving and you’re sure to crash. Next on the hit parade is the snowball effect. Your VTA dopamine neurons, the drivers of the reward signal, are themselves in overdrive. They’re working their little nuclei off trying to manufacture more enzymes to make more dopamine (even though your pleasure quotient is almost negligible because those dopamine receptors are so down-regulated). Now both your dopamine neurons and their target receptors are flirting with initiating that apoptotic self-destruct sequence. At some point down the line, they’re going to give up. You now have much less of the reward pathway than you used to. You’ll never reach the same level of reward as before—ever—because you just don’t have the machinery to do so. You’re constantly trying to recapture that first high, “chasing the dragon,” but you’ll never be able to because those neurons are dead.
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Heinz A et al., “Pharmacogenetic Insights to Monoaminergic Dysfunction in Alcohol Dependence.” Psychopharmacology 174, 561–70 (2004).
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Volkow ND et al., “Loss of Dopamine Transporters in Methamphetamine Abusers Recovers with Protracted Abstinence.” J. Neurosci. 21, 9414–8 (2001).
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But wait, there’s more! A third phenomenon often comes part and parcel with tolerance. Some of our favorite rewards have extra pain built right in. Once you’ve become tolerant, and you’re spending your salary to maintain your fix, you wake up and decide it’s time to quit. But changes in those neurons have occurred. The acute cessation of many of these substances can lead to severe and extremely unpleasant experiences, known as withdrawal. They tend to cluster as symptoms of physiological withdrawal (e.g., caffeine, alcohol, narcotics, and tranquilizers) with effects on the body, such as sweating, racing heart, palpitations, muscle tension, chest tightness, difficulty breathing, tremor, and GI complaints such as nausea, vomiting, and diarrhea. Some, like delirium tremens (DTs) from alcohol withdrawal, or hallucinations from benzodiazepine (benzos) or barbiturate (downers) withdrawal, can be life-threatening. Or symptoms can cluster as manifestations of emotional withdrawal (e.g., from cocaine, marijuana, and ecstasy), with effects on the brain such as anxiety, restlessness, irritability, insomnia, headaches, poor concentration, depression, and social isolation.7 These symptoms of withdrawal can be so severe as to prevent people from even wanting to give up their drug/behavior of choice, and they often lead abusers to relapse. Tolerance and withdrawal are the classic two-headed hydra of the definition of addiction. When there is too much dopamine, there can be too much motivation to obtain your pleasure. The motivation—the wanting—becomes more of a needing. Many addicts commit a host of crimes to obtain their fix, often hurting loved ones in the process. They drive drunk, lose custody of their children, and not infrequently become destitute.
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People often say addiction is a choice—after all, Nancy Reagan argued that you could “just say no.” And despite overwhelming evidence that nicotine caused both tolerance and withdrawal, the tobacco industry used “free choice” as its cornerstone defense from the 1960s through the 1990s. In 1994, on national television, Thomas Sandefur (CEO of Brown & Williamson), William Campbell (CEO of Philip Morris), and James Johnston (CEO of R.J. Reynolds) all testified under oath “I believe that nicotine is not addictive.”8
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how did the tobacco companies get away with saying nicotine was not addictive, and for so long? What were the criteria? Well, they couldn’t deny tolerance and withdrawal, so they played down the concern by equating it with other hedonic substances. According to the tobacco companies, “Addiction is an emotive subject and it is certainly possible to define the term broadly enough to include smoking … the current definition is more colloquial … and certainly applies to the use of many common substances that have familiar pharmacological effects to cigarettes, such as coffee, tea, chocolate and cola drinks.”9 Hey, don’t pick on us, we’re no worse than Coca-Cola!
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Whether they knew it or not, they actually got it right. Individuals in society have found pleasure in all forms of reward—to each his own. Some of those are substances. And some are behaviors, which we engage in specifically because they feel good. It doesn’t matter: the final common pathway is dopamine. Some behaviors are innate, like eating and sex. Some are learned, like shopping or shoplifting or gambling or gaming or texting or bingeing on Netflix (see Chapter 14). Similar to taking drugs of abuse, overperforming each of these behaviors can also manifest the phenomenon of tolerance (i.e., performing the behavior more and more to get less and less reward). Some will be so driven by their dopamine to greater and greater extremes to get that ever-diminishing EOP rush that they will escalate up to deviant behavior, some of which are severe enough to put you face-to-face either with the law or with your maker.
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Diagnostic and Statistical Manual (DSM),
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For decades the APA said no, behaviors like gambling weren’t manifestations of addiction because the definition was tolerance plus withdrawal. Lack of withdrawal meant they didn’t meet the criteria. But after decades of discussion, policy making, and politicking, the DSM-V has removed the requirement for withdrawal as an absolute diagnostic criterion. In so doing, the APA has now changed the definition of substance-related and addictive disorders and allowed for the inclusion of addictive behaviors as well. Here is the current mix-and-match list of eleven items: Tolerance Withdrawal Craving or a strong desire to use Recurrent use resulting in a failure to fulfill major role obligations (work, school, home) Recurrent use in physically hazardous situations (e.g., driving) Use despite social or interpersonal problems caused or exacerbated by use Taking the substance or engaging in the behavior in larger amounts or over a longer period than intended Attempts to quit or cut down Time spent seeking or recovering from use Interference with life activities Use despite negative consequences
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Instead of hard-and-fast criteria, this DSM-V paradigm allows for scaling of severity. Two or three of the above symptoms indicate a mild disorder, four or five symptoms indicate a moderate disorder, and six or more symptoms indicate a severe disorder.
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One question that people always ask: Is there an addictive personality? What they really want to know is if addiction is genetic. There are a lot of children of alcoholic parents who are worried that they will suffer the same fate. Many people are exposed to alcohol and they don’t get addicted. Many people (like me) have received the narcotic meperidine (Demerol) as pre-op for a surgery, and they don’t turn into heroin addicts. They want to know: If I’m not addicted now, I’m out of the woods, right? Is addiction driven by genes or by the substances themselves? There is no doubt that there are certain genes that predispose people to alcoholism12 or smoking,13 but they all impact dopamine in some fashion. If a genetic defect or alteration reduces the number of dopamine receptors, motivation for reward will be increased (see Chapter 3). But there’s no gene identified to date that is 100 percent predictive. If you harbor a genetic variation of your dopamine receptor, you do have an increased relative risk,14 but it’s not a faît accomplit.
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Another issue that has plagued research on addiction is the question of cause and effect. Clearly dopamine neurotransmission is associated with tolerance and withdrawal, but which comes first? Is it that dopamine drives the addictive behavior, or is it the addictive behavior that results in the changes in dopamine? A recent study looked at patients with Parkinson’s disease, which occurs due to the degeneration of dopamine neurons in another brain area, the substantia nigra (SN), which controls movement. Parkinson’s disease patients experience severe rigidity and tremor, interfering with every aspect of their lives. The neurons in the SN that produce dopamine are not just dysfunctional; they’re dying. Parkinson’s patients are given drugs, such as L-DOPA/carbidopa (Sinemet) and bromocriptine (Parlodel), that increase or mimic natural dopamine signaling to restore movement.
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These are not drugs that are abused for their pleasurable properties. But these drugs are not specific for the areas that affect movement; they also interact with the dopamine receptors in regions that affect reward-related signaling. It turns out that these drugs drive a panoply of behaviors as unwanted side effects, including aggression, paranoia, and poor impulse control.15 Some patients have even become compulsive gamblers. Activation of the dopamine receptor means the motivation for reward is enacted, with all the positive and negative consequences that come with it. What these studies show is that the dopamine comes first: the drugs drive the dopamine signal, and the dopamine signal eventually drives these behaviors.
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What happens when, for one reason or another, you can’t access your favorite fix? Once your dopamine pump is primed, it’s just waiting to be fired, for something—anything. People abstaining from one substance will frequently find themselves embroiled with another drug or activity (sex, gambling) that can generate the same effect. Because once you’re addicted to one substance and your dopamine receptors are down-regulated, you can easily become addicted to other substances as well. This is known as addiction transfer. When you’re addicted to one substance and you find yourself abstaining, your dopamine’s modus operandi is to find a substitute trigger.
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Sugar just happens to be the cheapest of our many substances of abuse. But all of these substances do essentially the same thing. By driving dopamine release, they all acutely drive reward, and in the process they also drive consumption. Yet, when taken to extreme, every stimulator of reward can instead result in addiction. For heroin or cocaine, you need a dealer and a wad of cash. For alcohol or nicotine, you need an ID. But for sugar, all you need is a quarter or a grandma. Sugar is the cheap thrill, the reward everyone on the planet is exposed to, the reward everyone can afford. Everyone’s an addict, and all your relatives are pushers. And it’s only one of two addictive substances that are legal and generally available (the other one being caffeine). That’s why soda is such a big seller: it’s two addictive substances rolled into one. Everyone has become a willing consumer of the two lowest common denominators. Sugar and caffeine are diet staples for much of the world today. Coffee is the second most important commodity (behind petroleum), and sugar is fourth.19 Sugar being a primary example, substances have been purified and mainlined, straight to your dopamine receptors. If you don’t exercise caution, you’ll blow your neurons out.