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The neurotransmitter dopamine plays a crucial role in the brain's reward processing, with studies showing that it contributes more to the motivation for rewards than to the pleasure of receiving them. For a rat in a box, chocolate increases the release of dopamine by 55%, sex by 100%, nicotine by 150%, cocaine by 225%, and amphetamines, the active ingredient in speed, meth, MDMA, and Adderall (used to treat ADHD and narcolepsy) by 1000%. According to one study, abusing dopamine levels alters our ability to delay gratification, with addicts referring to their futures as only nine days long, compared to 4.7 years for the non-addicted participants.
Since the discovery of dopamine, neuroscientists have found that pleasure and pain are processed in overlapping brain regions and form opposite sides of the desired equilibrium (homeostasis). Repeated exposure to the same or similar pleasure stimulus diminishes pleasure's effects while pain increases in intensity, a process known as neuroadaptation. Tolerance arises when homeostasis is knocked out of alignment, causing the brain to enter a dopamine deficit state, where pain sensitivity elevates while the capacity to experience pleasure decreases. Correcting this balance between pleasure and pain has become more critical than ever, with modifiable behavioral factors accounting for 70% of global deaths.
To reach homeostasis, we can harness hormesis, a branch of science that shows administering small amounts of pain increases our resistance to it. Self-binding can help control pleasure by creating physical barriers between us and our drugs of choice, thus managing our exposure and, therefore, our behavior.
Note: The following are excerpts from Dopamine Nation: Finding Balance in the Age of Indulgence by Anna Lembke, MD.
Scientists rely on dopamine as a kind of universal currency for measuring the addictive potential of any experience. The more dopamine in the brain’s reward pathway, the more addictive the experience.
The main functional cells of the brain are called neurons. They communicate with each other at synapses via electrical signals and neurotransmitters. Neurotransmitters are like baseballs. The pitcher is the presynaptic neuron. The catcher is the postsynaptic neuron. The space between pitcher and catcher is the synaptic cleft. Just as the ball is thrown between pitcher and catcher, neurotransmitters bridge the distance between neurons: chemical messengers regulating electrical signals in the brain. There are many important neurotransmitters, but let’s focus on dopamine.
Dopamine was first identified as a neurotransmitter in the human brain in 1957 by two scientists working independently: Arvid Carlsson and his team in Lund, Sweden, and Kathleen Montagu, based outside of London. Carlsson went on to win the Nobel Prize in Physiology or Medicine. Dopamine is not the only neurotransmitter involved in reward processing, but most neuroscientists agree it is among the most important. Dopamine may play a bigger role in the motivation to get a reward than the pleasure of the reward itself. Wanting more than liking. Genetically engineered mice unable to make dopamine will not seek out food, and will starve to death even when food is placed just inches from their mouth. Yet if food is put directly into their mouth, they will chew and eat the food, and seem to enjoy it.
This is not to say that high-dopamine substances literally contain dopamine. Rather, they trigger the release of dopamine in our brain’s reward pathway. For a rat in a box, chocolate increases the basal output of dopamine in the brain by 55 percent, sex by 100 percent, nicotine by 150 percent, and cocaine by 225 percent. Amphetamine, the active ingredient in the street drugs “speed,” “ice,” and “shabu” as well as in medications like Adderall that are used to treat attention deficit disorder, increases the release of dopamine by 1,000 percent. By this accounting, one hit off a meth pipe is equal to ten orgasms.
In addition to the discovery of dopamine, neuroscientists have determined that pleasure and pain are processed in overlapping brain regions and work via an opponent-process mechanism. Another way to say this is that pleasure and pain work like a balance. Imagine our brains contain a balance—a scale with a fulcrum in the center. When nothing is on the balance, it’s level with the ground. When we experience pleasure, dopamine is released in our reward pathway and the balance tips to the side of pleasure. The more our balance tips, and the faster it tips, the more pleasure we feel.
But here’s the important thing about the balance: It wants to remain level, that is, in equilibrium. It does not want to be tipped for very long to one side or another. Hence, every time the balance tips toward pleasure, powerful self-regulating mechanisms kick into action to bring it level again. These self-regulating mechanisms do not require conscious thought or an act of will. They just happen, like a reflex. I tend to imagine this self-regulating system as little gremlins hopping on the pain side of the balance to counteract the weight on the pleasure side. The gremlins represent the work of homeostasis: the tendency of any living system to maintain physiologic equilibrium. Once the balance is level, it keeps going, tipping an equal and opposite amount to the side of pain.
In the 1970s, social scientists Richard Solomon and John Corbit called this reciprocal relationship between pleasure and pain the opponent-process theory: “Any prolonged or repeated departures from hedonic or affective neutrality . . . have a cost.” That cost is an “after-reaction” that is opposite in value to the stimulus. Or as the old saying goes, What goes up must come down.
In real life, pleasure and pain are more complex than the workings of a balance. What’s pleasurable for one person may not be for another. Each person has their “drug of choice. Pleasure and pain can occur simultaneously. For example, we can experience both pleasure and pain when eating spicy food. Not everyone starts out with a level balance: Those with depression, anxiety, and chronic pain start with a balance tipped to the side of pain, which may explain why people with psychiatric disorders are more vulnerable to addiction. Our sensory perception of pain (and pleasure) is heavily influenced by the meaning we ascribe to it.
The pleasure-pain balance is triggered not only by reexposure to the drug itself but also by exposure to cues associated with drug use. In Alcoholics Anonymous, the catchphrase to describe this phenomenon is people, places, and things. In the world of neuroscience, this is called cue-dependent learning, also known as classical (Pavlovian) conditioning. Ivan Pavlov, who won the Nobel Prize in Physiology or Medicine in 1904, demonstrated that dogs reflexively salivate when presented with a slab of meat. When the presentation of meat is consistently paired with the sound of a buzzer, the dogs salivate when they hear the buzzer, even if no meat is immediately forthcoming. The interpretation is that the dogs have learned to associate the slab of meat, a natural reward, with the buzzer, a conditioned cue. What’s happening in the brain? By inserting a detection probe into a rat’s brain, neuroscientists can demonstrate that dopamine is released in the brain in response to the conditioned cue (e.g., a buzzer, metronome, light) well before the reward itself is ingested (e.g., cocaine injection). The pre-reward dopamine spike in response to the conditioned cue explains the anticipatory pleasure we experience when we know good things are coming.
Right after the conditioned cue, brain dopamine firing decreases not just to baseline levels (the brain has a tonic level of dopamine firing even in the absence of rewards), but below baseline levels. This transient dopamine mini-deficit state is what motivates us to seek out our reward. Dopamine levels below baseline drive craving. Craving translates into purposeful activity to obtain the drug. My colleague Rob Malenka, an esteemed neuroscientist, once said to me that “the measure of how addicted a laboratory animal is comes down to how hard that animal is willing to work to obtain its drug—by pressing a lever, navigating a maze, climbing up a chute.” I’ve found the same to be true for humans. Not to mention that the entire cycle of anticipation and craving can occur outside the threshold of conscious awareness. Once we get the anticipated reward, brain dopamine firing increases well above tonic baseline. But if the reward we anticipated doesn’t materialize, dopamine levels fall well below baseline. Which is to say, if we get the expected reward, we get an even bigger spike. If we don’t get the expected reward, we experience an even bigger plunge.
We’ve all experienced craving in the aftermath of pleasure. Whether it’s reaching for a second potato chip or clicking the link for another round of video games, it’s natural to want to re-create those good feelings or try not to let them fade away. The simple solution is to keep eating, or playing, or watching, or reading. But there’s a problem with that. With repeated exposure to the same or similar pleasure stimulus, the initial deviation to the side of pleasure gets weaker and shorter and the after-response to the side of pain gets stronger and longer, a process scientists call neuroadaptation. That is, with repetition, our gremlins get bigger, faster, and more numerous, and we need more of our drug of choice to get the same effect. Needing more of a substance to feel pleasure, or experiencing less pleasure at a given dose, is called tolerance. Tolerance is an important factor in the development of addiction. With prolonged, heavy drug use, the pleasure-pain balance eventually gets weighted to the side of pain. Our hedonic (pleasure) set point changes as our capacity to experience pleasure goes down and our vulnerability to pain goes up. You might think of this as the gremlins camped out on the pain side of the balance, inflatable mattresses and portable barbecues in tow.
Neuroscientist Nora Volkow and colleagues have shown that heavy, prolonged consumption of high-dopamine substances eventually leads to a dopamine deficit state. Volkow examined dopamine transmission in the brains of healthy controls compared to people addicted to a variety of drugs two weeks after they stopped using. The brain images are striking. In the brain pictures of healthy controls, a kidney-bean-shaped area of the brain associated with reward and motivation lights up bright red, indicating high levels of dopamine neurotransmitter activity. In the pictures of people with addiction who stopped using two weeks prior, the same kidney-bean-shaped region of the brain contains little or no red, indicating little or no dopamine transmission. As Dr. Volkow and her colleagues wrote, “The decreases in DA D2 receptors in the drug abusers, coupled to the decreases in DA release, would result in a decreased sensitivity of reward circuits to stimulation by natural rewards.” Once this happens, nothing feels good anymore.
The paradox is that hedonism, the pursuit of pleasure for its own sake, leads to anhedonia, which is the inability to enjoy pleasure of any kind.
Science teaches us that every pleasure exacts a price, and the pain that follows is longer lasting and more intense than the pleasure that gave rise to it. With prolonged and repeated exposure to pleasurable stimuli, our capacity to tolerate pain decreases, and our threshold for experiencing pleasure increases. By imprinting instant and permanent memory, we are unable to forget the lessons of pleasure and pain even when we want to: hippocampal tattoos to last a lifetime. The phylogenetically uber-ancient neurological machinery for processing pleasure and pain has remained largely intact throughout evolution and across species. It is perfectly adapted for a world of scarcity. Without pleasure we wouldn’t eat, drink, or reproduce. Without pain we wouldn’t protect ourselves from injury and death. By raising our neural set point with repeated pleasures, we become endless strivers, never satisfied with what we have, always looking for more.
Seventy percent of world global deaths are attributable to modifiable behavioral risk factors like smoking, physical inactivity, and diet. The leading global risks for mortality are high blood pressure (13 percent), tobacco use (9 percent), high blood sugar (6 percent), physical inactivity (6 percent), and obesity (5 percent). In 2013, an estimated 2.1 billion adults were overweight, compared with 857 million in 1980. There are now more people worldwide, except in parts of sub-Saharan Africa and Asia, who are obese than who are underweight.
Princeton economists Anne Case and Angus Deaton have shown that middle-aged white Americans without a college degree are dying younger than their parents, grandparents, and great-grandparents. The top three leading causes of death in this group are drug overdoses, alcohol-related liver disease, and suicides. Case and Deaton have aptly called this phenomenon “deaths of despair."
Greater than one in ten Americans (110 people per 1,000) takes an antidepressant, followed by Iceland (106/1,000), Australia (89/1,000), Canada (86/1,000), Denmark (85/1,000), Sweden (79/1,000), and Portugal (78/1,000). Among twenty-five countries, Korea was last (13/1,000).
Prescriptions of stimulants (Adderall, Ritalin) in the United States doubled between 2006 and 2016, including in children younger than five years old. In 2011, two-thirds of American children diagnosed with ADD were prescribed a stimulant.
Prescriptions for sedative medications like benzodiazepines (Xanax, Klonopin, Valium), also addictive, are on the rise, perhaps to compensate for all those stimulants we’re taking. Between 1996 and 2013 in the United States, the number of adults who filled a benzodiazepine prescription increased by 67 percent, from 8.1 million to 13.5 million people. In 2012, enough opioids were prescribed for every American to have a bottle of pills, and opioid overdoses killed more Americans than guns or car accidents.
[Lembke's patient] David: From 2008 to 2018, I was taking up to thirty milligrams of Adderall a day, fifty milligrams of Ambien a day, and three to six milligrams of Ativan a day. I thought, I have anxiety and ADHD and I need this to function. David attributed fatigue and inattentiveness to a mental illness rather than to sleep deprivation and overstimulation, a logic he used to justify continued use of pills. I’ve seen a similar paradox in many of my patients over the years: They use drugs, prescribed or otherwise, to compensate for a basic lack of self-care, then attribute the costs to a mental illness, thus necessitating the need for more drugs. Hence poisons become vitamins.
Unlike pressing on the pleasure side, the dopamine that comes from pain is indirect and potentially more enduring. So how does it work? Pain leads to pleasure by triggering the body’s own regulating homeostatic mechanisms. In this case, the initial pain stimulus is followed by gremlins hopping on the pleasure side of the balance. The pleasure we feel is our body’s natural and reflexive physiological response to pain. Martin Luther’s mortification of the flesh through fasting and self-flagellation may have gotten him a little bit high, even if it was for religious reasons. With intermittent exposure to pain, our natural hedonic set point gets weighted to the side of pleasure, such that we become less vulnerable to pain and more able to feel pleasure over time.
The intentional application of pain to treat pain has been around since at least Hippocrates, who wrote in his Aphorisms in 400 BC: “Of two pains occurring together, not in the same part of the body, the stronger weakens the other. In 2011, in an article in a leading medical journal, Christian Sprenger and his colleagues from Germany provided empirical support for Hippocrates’s ancient ideas about pain. They used neuroimaging (pictures of the brain in real time) to study the effects of heat and other painful stimuli applied to the arms and legs of twenty healthy young men. They found that the subjective experience of pain caused by an initial painful stimulus was lessened with the application of a second painful stimulus. Further, naloxone, an opioid receptor blocker, prevented this phenomenon, suggesting that the application of pain triggers the body’s own endogenous (self-made) opioids.
Liu Xiang, a professor at the China Academy of Traditional Chinese Medicine in Beijing, published a paper in 2001 in the Chinese Science Bulletin, revisiting the centuries-old practice of acupuncture and relying on modern science to explain how it works. He argued that the efficacy of acupuncture is mediated through pain, with needle insertion as the primary mechanism: “The needling, which can injure the tissue, is a noxious stimulation inducing pain . . . inhibiting great pain with little pain!” The opioid receptor blocker naltrexone is currently being explored as a medical treatment for chronic pain. The idea is that by blocking the effects of opioids, including the ones we make (endorphins), we trick our bodies into making more opioids as an adaptive response.
The basic principle of exposure therapy is to expose people in escalating increments to the very thing—being in crowds, driving across bridges, flying in airplanes—that causes the uncomfortable emotion they’re trying to flee, and in doing so, augment their ability to tolerate that activity. In time they may even come to enjoy it. As the philosopher Friedrich Nietzsche famously said, a sentiment echoed by many before and after through the ages, “What doesn’t kill me makes me stronger.”
Hormesis is a branch of science that studies the beneficial effects of administering small to moderate doses of noxious and/or painful stimuli, such as cold, heat, gravitational changes, radiation, food restriction, and exercise. Hormesis comes from the ancient Greek hormáein: to set in motion, impel, urge on. Edward J. Calabrese, an American toxicologist and a leader in the field of hormesis, describes this phenomenon as the “adaptive responses of biological systems to moderate environmental or self-imposed challenges through which the system improves its functionality and/or tolerance to more severe challenges.
Intermittent fasting and calorie restriction extended lifespan and increased resistance to age-related diseases in rodents and monkeys, as well as reduced blood pressure and increased heart rate variability. Intermittent fasting has become somewhat popular as a way to lose weight and improve well-being. Fasting algorithms include alternate-day fasting, one-day-per-week fasting, up-to-the-ninth-hour fasting, one-meal-per-day fasting, 16:8 fasting (fasting for sixteen hours each day and doing all your eating within the other eight-hour window), and so on.
What about exercise? Exercise is immediately toxic to cells, leading to increased temperatures, noxious oxidants, and oxygen and glucose deprivation. Yet the evidence is overwhelming that exercise is health-promoting, and the absence of exercise, especially combined with chronic sedentary feeding—eating too much all day long—is deadly. Exercise increases many of the neurotransmitters involved in positive mood regulation: dopamine, serotonin, norepinephrine, epinephrine, endocannabinoids, and endogenous opioid peptides (endorphins). Exercise contributes to the birth of new neurons and supporting glial cells. Exercise even reduces the likelihood of using and getting addicted to drugs. The evidence is indisputable: Exercise has a more profound and sustained positive effect on mood, anxiety, cognition, energy, and sleep than any pill I can prescribe.
Alex Honnold, now world-famous for climbing the face of Yosemite’s El Capitan without ropes, was found to have below-normal amygdala activation during brain imaging. For most of us, the amygdala is an area of the brain that lights up in an fMRI machine when we look at scary pictures. The researchers who studied Honnold’s brain speculated that he was born with less innate fear than others, which in turn allowed him, they hypothesized, to accomplish superhuman climbing feats. But Honnold himself disagreed with their interpretation: “I’ve done so much soloing, and worked on my climbing skills so much that my comfort zone is quite large. So these things that I’m doing that look pretty outrageous, to me they seem normal. The most likely explanation for Honnold’s brain differences is the development of tolerance to fear through neuroadaptation. My guess is that Honnold’s brain started out no different from the average brain in terms of fear sensitivity. What’s different now is that he has trained his brain through years of climbing not to react to fearful stimuli. It takes a lot more to scare Honnold’s brain than the average person’s because he has incrementally exposed himself to death-defying feats. Of note, Honnold nearly had a panic attack when he went inside the fMRI machine to get pictures taken of his “fearless brain,” which also tells us that fear tolerance doesn’t necessarily translate across all experiences.
If we consume too much pain, or in too potent a form, we run the risk of compulsive, destructive overconsumption. But if we consume just the right amount, “inhibiting great pain with little pain,” we discover the path to hormetic healing, and maybe even the occasional “fit of joy.”
Of the many dangers that awaited Homer’s Odysseus on his journey home from the Trojan War, the first was the Sirens, those half-woman, half-bird creatures whose enchanted song lured sailors to their death on the rocky cliffs of nearby islands. The only way for a sailor to pass the Sirens unharmed was by not hearing them sing. Odysseus ordered his crew to put beeswax in their ears and tie him to the mast of the sailing ship, binding him even tighter if he begged to be unfastened or tried to break loose. As this famous Greek myth illustrates, one form of self-binding is to create literal physical barriers and/or geographical distance between ourselves and our drug of choice. It turns out that willpower is not an infinite human resource. It’s more like exercising a muscle, and it can get tired the more we use it. Other modern forms of physical self-binding involve anatomical changes to our bodies; for example, weight-loss surgeries such as gastric banding, sleeve gastrectomy, and gastric bypass. These surgeries effectively create a smaller stomach and/or bypass the part of the gut that absorbs calories. The gastric band puts a physical ring around the stomach, making it smaller without removing any part of the stomach or small intestine. The sleeve gastrectomy surgically removes part of the stomach to make it smaller. Gastric bypass surgery reroutes the small intestine around the stomach and duodenum, where nutrients are absorbed.
High-dopamine goods mess with our ability to delay gratification, a phenomenon called delay discounting. Delay discounting refers to the fact that the value of a reward goes down the longer we have to wait for it. Most of us would rather get twenty dollars today than a year from now. Our tendency to overvalue short-term rewards over longer-term ones can be influenced by many factors. One of those factors is consumption of addictive drugs and behaviors. Behavioral economist Anne Line Bretteville-Jensen and her colleagues investigated the discounting in active heroin and amphetamine users compared with ex-users and with matched controls (individuals matched for gender, age, education level, etc.). The investigators asked the participants to imagine they had a winning lottery ticket worth 100,000 Norwegian kroner (NOK), approximately 14,600 US dollars. They then asked participants if they would rather have less money right now (less than 100,000 NOK) or the full amount a week from now. Of active drug users, 20 percent said they wanted the money right now and would be willing to take less to get it. Only 4 percent of former users and 2 percent of matched controls would have accepted that loss. Cigarette smokers are more likely than matched controls to discount monetary rewards (that is, they value them less if they have to wait longer for them). The more they smoke, and the more nicotine they consume, the more they discount future rewards. These findings hold true for both hypothetical money and real money. Addictions researcher Warren K. Bickel and his colleagues asked people addicted to opioids and healthy controls to complete a story that started with the line: “After awakening, Bill began to think about his future. In general, he expected to . . .” Opioid-addicted study participants referred to a future that was on average nine days long. Healthy controls referred to a future that was on average 4.7 years long. This striking difference illustrates how “temporal horizons” shrink when we’re under the sway of an addictive drug.
In today’s dopamine-rich ecosystem, we’ve all become primed for immediate gratification. We want to buy something, and the next day it shows up on our doorstep. We want to know something, and the next second the answer appears on our screen. Are we losing the knack of puzzling things out, or being frustrated while we search for the answer, or having to wait for the things we want? The neuroscientist Samuel McClure and his colleagues examined what parts of the brain are involved in choosing immediate versus delayed rewards. They found that when participants chose immediate rewards, emotion- and reward-processing parts of the brain lit up. When participants delayed their reward, the prefrontal cortex—the part of the brain involved in planning and abstract thinking—became active.
The implication here is that we are all now vulnerable to prefrontal cortical atrophy as our reward pathway has become the dominant driver of our lives.
I urge you to find a way to immerse yourself fully in the life that you’ve been given. To stop running from whatever you’re trying to escape, and instead to stop, and turn, and face whatever it is. Then I dare you to walk toward it. In this way, the world may reveal itself to you as something magical and awe-inspiring that does not require escape. Instead, the world may become something worth paying attention to. The rewards of finding and maintaining balance are neither immediate nor permanent. They require patience and maintenance. We must be willing to move forward despite being uncertain of what lies ahead. We must have faith that actions today that seem to have no impact in the present moment are in fact accumulating in a positive direction, which will be revealed to us only at some unknown time in the future. Healthy practices happen day by day. My patient Maria said to me, “Recovery is like that scene in Harry Potter when Dumbledore walks down a darkened alley lighting lampposts along the way. Only when he gets to the end of the alley and stops to look back does he see the whole alley illuminated, the light of his progress. Here we are at the end, but it could be just the beginning of a new way of approaching the hypermedicated, overstimulated, pleasure-saturated world of today. Practice the lessons of the balance, so that you too can look back at the light of your progress.
The relentless pursuit of pleasure (and avoidance of pain) leads to pain.
Recovery begins with abstinence. Abstinence resets the brain’s reward pathway and with it our capacity to take joy in simpler pleasures.
Self-binding creates literal and metacognitive space between desire and consumption, a modern necessity in our dopamine-overloaded world.
Medications can restore homeostasis, but consider what we lose by medicating away our pain. Pressing on the pain side resets our balance to the side of pleasure.
Beware of getting addicted to pain.
Radical honesty promotes awareness, enhances intimacy, and fosters a plenty mindset.
Prosocial shame affirms that we belong to the human tribe. Instead of running away from the world, we can find escape by immersing ourselves in it.
Learn more about Dopamine Nation on Amazon.
Buy Dopamine Nation: Print | Kindle | Audiobook
If you enjoyed this summary, please consider buying me a coffee to caffeinate my reading sessions.