Never Enough: The Neuroscience and Experience of Addiction

by Judith Grisel

My aim in writing this book is to share these principles and thus shed light on the biological dead end that perpetuates substance use and abuse: namely, that there will never be enough drug, because the brain’s capacity to learn and adapt is basically infinite. What was once a normal state punctuated by periods of high, inexorably transforms to a state of desperation that is only temporarily subdued by drug. Understanding the mechanisms behind every addict’s experience makes it very clear that short of death or long-term sobriety there is no way to quell the screaming need between exposures. At the point where pathology determines behavior, most addicts die trying to satisfy an insatiable drive.

The first time I got drunk, at thirteen, I felt as Eve should have after tasting the apple. Or as a bird hatched in a cage would feel upon being unexpectedly set free. The drug provided physical relief and spiritual antidote for the persistent restlessness I’d been unable to identify or share. An abrupt shift of perspective coincident with guzzling half a gallon of wine in my friend’s basement somehow made me feel sure that both life and I were going to be all right. Just as light is revealed by darkness, and joy by sorrow, alcohol provided powerful subconscious recognition of my desperate strivings for self-acceptance and existential purpose and my inability to negotiate a complex world of relationships, fears, and hopes. At the same time, it seemed to deliver, on a satin pillow, the key to all my blooming angst. Abruptly relieved from an existence both harsh and lackluster, I had finally discovered ease.

A plaque I later saw posted behind a bar described my first experience precisely: “Alcohol makes you feel like you’re supposed to feel when you’re not drinking alcohol.” Among other things, I wondered why, if the drug can do this, didn’t everyone drink more, and more often?

As far back as I can remember, I felt hemmed in, frustrated by imposed limits and my own limitations. Longing for other, for something else, is at the core of my experience of self. Even today, below the persona of nurturing friend, committed partner, determined scientist, and adoring parent is a heartbreaking desire to embrace oblivion. From what or to where I seek escape, I really can’t say; I just know that the constraints of space, time, circumstances, obligations, choices (and missed opportunities) fill me with an overwhelming sense of desperation. In fact, my modal thought is that I’m squandering time, though I am quick to admit that I have no idea what to do with myself. Like in a dream, time flows by as I futilely pursue a series of inane tasks, all the while suppressing a growing sense of panic. I fantasize about disembarking at an unfamiliar exit, or pushing aside a broken gate into a foreign sanctum, somehow entering a world where we all at least agree not to pretend things are different than they seem.

If others didn’t share my horror, or at least consternation, I couldn’t understand why not, because we were all subject to the same capricious laws of existence, the same evidence for irrational forces. If they did share it, I was amazed and repulsed by their willingness nonetheless to fritter away their lives acquiring things, planning parties, cleaning up, and checking the “news.”

In the end, the very effect I loved so much about alcohol—its ability to mute existential fears—utterly betrayed me. It didn’t take all that long before the drug’s most reliable effect was to ensure the alienation, despair, and emptiness that I sought to medicate.

The next ten years were characterized by a simple philosophy and practice: I sought any opportunity to use mind-altering drugs and paid any cost. My actions only made sense in terms of that guiding principle; virtually every moment was shaped by an orientation toward escaping sober awareness.

I have a clear memory of lying in my bunk one afternoon, stoned but despairing. Students were chatting as they walked outside my window or down the hall; I had assignments due or overdue and probably plans to meet up with friends for dinner. However, I was overwhelmed by a sense of emptiness and futility even more intense than usual. I can’t think of anything in my circumstances that precipitated this crisis; even now I think of my drug use—especially in the early stages—as much cure as cause. But for whatever reason, I saw my whole life, despite blips of disaster and achievement, as an aimless trajectory of self-preservation and promotion: starting and going nowhere, and characterized by reflexive and blind occupation. Moreover, it seemed that my life was no different from anyone else’s. We were like fish schooling in circles, oblivious to the water and indifferent to anything outside our own self-serving heads. I remember the gray and formless pit in my chest and belly that these thoughts evoked. Each of us was completely alone, and our efforts were primarily directed at maintaining delusions that kept us sane, until we died.

An avid user from the start, I now was truly committed. My behavior became reckless and spiraled quickly toward a life that matched my ideas of existence in terms of heartless insanity. In other words, my response to being overwhelmed by the deep void was to leap into it. I’d traipse back from bars in East St. Louis, alone, drunk and stoned, in the early hours of the morning. Several weeks were spent in a housing project with a group of locals I had nothing in common with except an appreciation for freebase cocaine (this, in the days just before crack), while “their” women and children hung out in a windowless bedroom watching TV. I’d end up in an assortment of sordid places completely unprepared and thought testing my wit against whoever or whatever happened to be in my face was a somewhat less tedious way to pass the time as I entertained death.

Until about ten seconds before the first time I used a needle, I thought I’d never inject drugs. Like most people, I associated needles with hard-core use. That is, until I was offered a shot. I remember feeling for an instant before acquiescing as if I really could choose; I didn’t recognize crossing this line as inevitable, as it would be the second through nth time, but rather felt as if I would just like to try it. I tasted and heard the coke before I felt it: an unusual tang on the back of my tongue coupled by ringing in my ears like a fire alarm. Then I felt it! A warm wash of euphoria that was so much richer than that from snorting as my body and brain grew warm and wet and interested, and I felt gratitude for the brilliance of living. I’m not exaggerating when I say that a few minutes later I was in charge of the point, in part so I could be sure my turn wasn’t skipped. Still more than a long year away, administering cocaine in this way, precipitated my early bottom.

Johnny was a Vietnam vet who lived next door in a crappy apartment behind the high school. A gentle and hopeless guy, he was lonely enough to share his drugs. Johnny’s life dream was to be maintained in a hospital bed with a permanent line for IV drug infusions. Under different circumstances, he might have been a friend, but friendship depends on trust and supporting each other’s well-being.

I share these stories not to make readers uncomfortable (and I’m sorry if they do) or solely to qualify myself as a bona fide addict. My primary purpose in exposing my story is to illustrate the depths, as well as the breadth (in later chapters), of the addictive experience. I don’t think I was basically a good person who got mixed up with a bad crowd, for instance, or that I was somehow dealt a crummy hand in terms of genes or neurochemistry, parents, or personal history (though these all certainly had an influence). I also don’t think that I am essentially worse than or even different from others: not those spending down their allotment of days under bridges, or in prisons, or for that matter managing PTAs or running for public office. All of us face countless choices, and there is no bright line separating good and bad, order and entropy, life and death. Perhaps as a result of following rules or conventions, some live under the delusion that they are innocent, safe, or deserving of their status as well-fed citizens. But if there is a devil, it lives inside each of us. One of my greatest assets is knowing that my primary enemy is not outside me, and for this I am grateful to all my experiences. We all have the capacity for wrong; otherwise we could not, in fact, be free. The opposite of addiction, I have learned, is not sobriety but choice. For many like me, drugs act as potent tools that obscure freedom. But there are countless ways any of us might jump the rail, unwrap...

one day just after getting up (and therefore at the nadir of my internal pharmacopoeia), I had a terrifying encounter—with myself. About three inches from the mirror, I was peering into my own eyes and was met with a clear vision of the bottomless abyss inside me. I felt as though I were looking into my own soul and what I confronted was worse than the emptiness I’d been running from, much worse.

The dam was finally breached during a visit with my father. I was surprised when he offered to take me to dinner for my twenty-third birthday, because we hadn’t spoken in years. Family ties are deep, though, and below all of my self-righteous anger, I still wanted his love and approval, so when he made the offer, I readily accepted. The day we were to go out, my main concern was to manage my dosing so as to shelter my interactions with him and still remain upright. This was a legitimate worry. By this time, I had almost no relationships that involved expectations, and I knew it was impossible to sleep anything off before an “early bird” dinner, especially because I woke most days after noon. I literally had no idea what to do with four to five hours of free time if I wasn’t getting wasted. At any rate, I was only a bit toasty when I climbed into his car, and vainly hoping not obviously so. We arrived at the restaurant, which had been my choice, a tiny sushi place with a few small tables and the requisite bar, a few minutes later. I didn’t feel particularly vulnerable and also wasn’t expecting much. So I was completely caught off guard when my father strangely announced that he just wanted me to be happy. This may possibly be the very last thing I expected to hear; he might have wished me to go back to school, sit up straight, repay what I owed, or take better care of my teeth. But be happy? Where did this father come from? (To this day, he can’t recall the conversation, an...

By the time I turned twenty-three, it had been years since I’d gone even twenty-four hours without a drink, pill, fix, or joint. Though the fun and excitement were long gone, I also could not wrap my head around having a disease that necessitated a lifetime of abstinence. I know now that the drugs were still dispensing a mite of escape, and therefore offered a more appealing option than exposing myself raw and unmedicated to the elements of living. But dying slowly a day at a time was turning out to be unbearably painful. I’d finally reached the dead end where I felt I was incapable of living either with or without mind-altering substances. This bleak situation describes the condition of many, if not all, addicts and illustrates why relatively few recover. Despite being depleted, they think the cost of abstinence seems much too high: Without drugs, what is there to live for anyway?

I also think that some of the traits that facilitated my addiction have helped to make me a good scientist. Bottomless curiosity, a willingness to take risks, and perseverance that make a bulldog seem laid-back have all contributed to the successes I’ve had as a neuroscientist. More than anything else, seeking and acquiring knowledge about drugs, addiction, and the brain have given me compassion for the desperate plight of people like me. The understanding I’ve gained has helped me stay clean by informing better choices. My hope is that by illuminating the seeming insanity of colluding in habits that are not only joyless but lethal, this book will contribute to a path of freedom for others.

The idea that I am my brain still guides the efforts of thousands of neuroscientists around the world as we work to connect experience to neural structures, chemical interactions, and genes. Though plausible, I should mention that an elegant hypothesis is no substitute for definitive data. As time has passed, we have learned that everything from the bacteria in our guts to the interactions we had in middle school partly determines our behavior. In fact, it’s beginning to seem that the brain is more like a stage for our life to be acted out upon than like the director behind a curtain calling shots. Nonetheless, it’s reasonable to assume that all of our thoughts, feelings, intentions, and behaviors at least have correlates in electrical and chemical signals in the brain, because there’s not a whit of evidence to suggest otherwise.

the vast majority of us are trichromats, meaning that we perceive thousands of different colors by the combined activity in just three types of color-sensitive neurons. But some lucky individuals have a mutation that gives them a fourth type of color sensor, and even though they may not be aware of their mutant gift, they are more likely to have careers as artists or designers. The most important lesson here, though, is that our senses constrain our experience by offering us a relatively thin slice of what’s out there—a highly filtered version of our environment.

The fundamental role of the brain is to be a contrast detector. As experiences are distinguished from monotony, they spark neurochemical changes in specific brain circuits, informing us of all we care to know: opportunities for food, drink, or sex; danger or pain; beauty and pleasure, for example. The process of actively maintaining the stable baseline critical for conducting the brain’s business of contrast detection is called homeostasis, and it depends on having a set point, a comparator, and a mechanism for adjustment. It is easy to appreciate this principle in terms of body temperature, which is maintained around ninety-nine degrees Fahrenheit. If you become much warmer or colder than this, your body feels it, and there are mechanisms to return you to baseline, such as sweating or shivering. Feelings are also constrained within tight bounds under normal conditions. What we generally experience is our personal neutral okayness; otherwise we’d be incapable of detecting “good” or “bad” events. We’ll return to homeostasis later. For now we’ll consider what makes abused drugs remarkable—their ability to hijack the contrast detector for pleasure.

All drugs affect multiple brain circuits, and variation in their sites of neural action accounts for their different effects. However, all addictive drugs are addictive precisely because they share the ability to stimulate the mesolimbic dopamine system. Countless studies have demonstrated that the squirt of dopamine in the nucleus accumbens from addictive substances (including chocolate and hot sauce!) is associated with the substances’ pleasurable outcome. Some, like cocaine and amphetamine, are universally effective; others seem to have a bigger influence on mesolimbic dopamine in some individuals than in others (for example, marijuana and alcohol), and some that have been labeled addictive probably aren’t. For instance, most research suggests that the psychedelic LSD does not stimulate the mesolimbic pathway. From this and related evidence, the majority of addiction researchers would argue that LSD is not an addictive drug.

We now also understand that the opposite of pleasure is not depression but anhedonia, the inability to experience pleasure. Of course, depression and anhedonia are not mutually exclusive, because many depressed individuals also have difficulty experiencing pleasure. But in general, the mesolimbic pathway conveys a transient good time, not a stable sense of hopefulness that would truly serve as an antidote to depression.

Without dopamine in the nucleus accumbens, nothing, not a letter from a friend, an especially beautiful sunset or piece of music, or even chocolate, would alleviate a persistently bleak existence.

Things that cause a release of dopamine in the mesolimbic pathway may be something pleasurable (sexual stimulation, a bump of cocaine) but also something surprising (drama, whatever is in the package), novel (such as travel), potentially newsworthy (a lottery ticket), or really valuable (oxygen to a deprived organism). In other words, this system alerts us to the anticipation of a meaningful event, not to pleasure per se. Pleasurable stimuli happen to be meaningful, but many other things are also inherently meaningful to an organism that has evolved to survive in ever-changing conditions.

If lesions of the mesolimbic circuit lead to anhedonia, what happens if the nigrostriatal pathway is eliminated? This produces a fairly common condition, especially in the aged. Deficits of dopamine in the nigrostriatal pathway are responsible for Parkinson’s disease. Parkinson’s sufferers have extreme difficulty enacting their intentions. For instance, people with Parkinson’s describe an incredible mental effort required to do a simple motor task such as buttoning a shirt. Parkinsonian deficits occur between the desire to move and the movement circuitry, which are both intact. How does the nigrostriatal lesion in Parkinson’s patients occur? Dopamine in both pathways naturally declines with age, partly accounting for general decreases in the eagerness to explore new things and the ability to quickly move toward them. But even before we get old, there are individual differences in dopamine activity, distributed normally, as shown in a bell curve, with those on the low end generally at greater risk for Parkinson’s. Besides being slower to enact intentions, low dopamine is also associated with higher-than-average orderliness, conscientiousness, and frugality. In other words, it confers a tendency toward rigidity in areas other than movement.

In general, the more predictable and frequent the dosing, the more addictive a drug will be. Three Laws of Psychopharmacology The very definition of an addictive drug is one that stimulates the mesolimbic pathway, but there are three general axioms in psychopharmacology that also apply to all drugs: All drugs act by changing the rate of what is already going on. All drugs have side effects. The brain adapts to all drugs that affect it by counteracting the drug’s effects.

The brain is not just a passive recipient of drug actions but responds to the effects of the drugs. Repeated administration of any drug that influences brain activity leads the brain to adapt in order to compensate for the changes associated with the drug.

The terrible truth for all those who love mind-altering chemicals is that if the chemicals are used with regularity, the brain always adapts to compensate. An addict doesn’t drink coffee because she is tired; she is tired because she drinks coffee. Regular drinkers don’t have cocktails in order to relax after a rough day; their day is filled with tension and anxiety because they drink so much. Heroin produces euphoria and blocks pain in a naive user, but addicts can’t kick a heroin habit, because without it they are in excruciating pain. The brain’s response to a drug is always to facilitate the opposite state; therefore, the only way for any regular user to feel normal is to take the drug. Getting high, if it occurs at all, is increasingly short-lived, and so the purpose of using is to stave off withdrawal.

My clever undergraduates are quick to point out a flip side to Solomon and Corbit’s model: if you want to achieve a sustained positive state, you could submit yourself to negatively charged experiences. This way the opponent process would be positive. Solomon and Corbit argued that such a pattern may be at work in an activity like skydiving. Jumping out of an airplane at several thousand feet produces intense feelings of arousal and panic, even feelings associated with impending death. They would probably last for much of the air time and certainly for all of the “free fall.” As the stimulus ends and your feet are miraculously back on solid ground, not only is the panic gone, but according to hobbyists it is like being awash in feelings of extreme calm and well-being. The relief following an intensely stressful experience, if you live through the event, may make it all worthwhile. Maybe this helps explain why people push themselves to exercise or go to graduate school.

the brain is so well organized to counteract perturbations that it uses its exceptional learning skills to anticipate disruptions, rather than wait for the changes themselves, and begins to dampen drug effects before the drug has even been delivered. Suppose you enjoy a few drinks with friends at a neighborhood bar every Friday after work, as you have been doing for years. It turns out that the predictability of this routine leads to changes in your experience. First, the alcohol will have less effect on you in that particular place and time and with those particular friends than it would have elsewhere. If you changed plans and went instead to a party, you’d become more intoxicated with the same amount to drink.

The tenacity of addiction is as evident to researchers and clinicians as it is to addicts. I’ve been clean for more than thirty years, and I’m still not really interested in moderation. Often people ask whether I don’t wish I might have a glass of wine or a hit off a joint, but I don’t want just one glass or a light buzz; I want the whole bottle, the bag, and then some more of each. The Grateful Dead argued that “too much of everything is just enough,” but as it turned out for Jerry Garcia, and I’d bet is the case for many of us, too much is still not enough. In other words, if by chance someone does develop a pill to cure my addictive nature, I’d take two and use every day.

Addicts don’t use on a regular basis because they are addicted; they are addicted because they use a lot, and regularly. The lackadaisical habits of so-called normal people who leave drinks half finished, snort a few lines on a Friday night, or occasionally smoke a cigarette with friends are strikingly different from those of addicts.

I was clean for close to two years and had been volunteering in my biopsychology professor’s laboratory to get some research experience. One part of the protocol required daily administration of an experimental drug into the subjects’ (rats’) peritoneum, which is the sac that loosely constrains the abdominal organs. The standard procedure is to cup the rat gently in one hand, insert the needle with the other, and create negative pressure by pulling slightly back on the needle to be sure the injection isn’t going straight into a blood vessel. I thought I’d fully extinguished any personal associations with needles, having performed hundreds of injections by this time, but one day when I pulled back and the needle filled with blood, I heard clamorous ringing in my ears and a taste in my mouth that were characteristic of cocaine going into my vein. It was years later, in a completely different context, and I had not a whit of desire to use at that moment, but just seeing blood filling the syringe caused an instantaneous reaction. I let my colleague finish the injections and went back to my dorm sobered by the astounding power of memory.

From the first delicious bong hits of the day until the final joint, I loved the taste, the smell, and the fabulous buffering effects separating me from the messy business of interacting with other people and fulfilling my daily obligations as, at the same time, weed lent promise of something new and glittering in the midst of the unappealing present. As an antidote to boredom, the drug made everything more interesting, and time and space delightful instead of threatening. An introvert to begin with, I loved spending hours stoned on the beach searching for shells and listening to lapping waves, a thoroughly engrossing way to pass the time. Not to belabor the point, but in many ways my relationship with the drug was among the purest and most wonderful relationships of my life. From the first time I got high until long after I’d smoked my last bowl, I loved marijuana like a best friend. This is not hyperbole. Some people it makes sleepy, others paranoid (due, no doubt, to an unfortunate confluence of neurobiology and genetics), but for me it was nearly perfect. One of my favorite moments was shortly after coming to consciousness in a new day and seeing for an instant the vast bleakness of life before me and then suddenly realizing—just as newlyweds might reach in excitement and hope for a spouse beside them in bed—that I could get high. The first few hits of the day were reliably comforting as the gray dust of reality was blown away to reveal beauty and meaning in everyday e...

The influence of the endocannabinoids is still being carefully investigated, and the details are complex to say the least, but my view of the literature is that anandamide and 2-AG act as a sort of exclamation point on neural communication, indicating that whatever the message just transmitted across the synapse, it was important.

It seems that anandamide and similar compounds evolved along with the CB1 receptor to modulate normal activity, highlighting important neurotransmission. The normal activity of the brain, as we’ve discussed, mediates all of our experiences, thoughts, behaviors, and emotions. The cannabinoid system helps to sort our experiences, indicating which are the most meaningful or salient. The system activates naturally to distinguish input that might contribute to our flourishing—for instance, a good source of food, a potential mate, or other meaningful connections, information, or stimuli. Anandamide and 2-AG and their receptor are all over the brain because such input might be carried in any number of pathways, depending on the exact nature of the stimulus. For example, let’s say one day you are exploring your surroundings somewhat aimlessly, when you serendipitously begin following a route that eventually leads to something good. The millions of neurons involved in this discovery—including those involved in processing input from your senses, stimulating movement, coding memories or thoughts connecting this good thing to your plans or communicating it to others—are likely all releasing cannabinoids to turn up the volume on this information, helping to distinguish it from the other parts of your day in which interactions with the environment weren’t all that special. This should make it easy to understand why the stimuli we encounter when stoned are so intensely rich. Sights, soun...

Predictably, chronic exposure leads to substantial consequences. The brain adapts by downregulating the cannabinoid system.2 “Downregulation” is a general term describing processes that work to ensure homeostasis, which in this case translates to a dramatic reduction in the number and sensitivity of CB1 receptors. Without copious amounts of pot on board, everything is dull and uninspiring.

There’s been a long-standing debate, akin to one about the relationship between cancer and smoking in many ways, about whether regular marijuana smoking leads to an amotivational syndrome (“amotivational” means lacking motivation). For instance, does regular use lead to spending long hours on the couch watching cartoons, or does it just so happen that people who like to sit around watching television (or poring through shells at the beach) also enjoy marijuana? Because correlation doesn’t mean causation, cigarette companies argued for decades that a predisposition for cancer and the tendency to inhale cigarette smoke just coincidentally occur in the same people. In both cases, common sense and mounting evidence point to the same thing. Downregulation of CB1 receptors might make the user more suitable for jobs that don’t require creativity or innovation, exactly the effects that initial exposure seemed to stimulate.

Fortunately, after nine long years pining away, I realized one day that I didn’t crave marijuana. For the next twenty years or so, I relished my freedom! I could be around weed without feeling like the last one sitting at a dance. And then I entered perimenopause and really understood why the drug was on the planet. Though I hadn’t smoked in thirty years, I just knew it would be a perfect antidote to the irritability, hypersensitivity, and frustration with daily tasks that accompanied my transition. During the first few years of plummeting hormones, not only would I have given my left arm to smoke; I’d have cut it off myself and felt as if I’d gotten a decent deal. The craving not only came back but had somehow matured. I even fantasized I would get cancer and a doctor would deem the prescription necessary. Hmmm, a life-threatening illness, but I could toke away! The reason I didn’t start smoking despite my desire was that I knew the delicious escape it would afford me would come at a cost. The things about my life that I’d come to enjoy—my intellectual work, family, and other ambitions and hobbies—would grow pale in comparison to sitting around smoking a bowl.

if you smoke weed, remember that infrequent and intermittent use is the best way to prevent downregulation and its unfortunate effects: tolerance, dependence, and a loss of interest in the unenhanced world.

The tale of opiate users is one of such great love and such great suffering as to make Romeo and Juliet seem like a middle school melodrama. This class of drugs delivers heartbreak like no other, initially providing a sense of security and well-being that soon transmutes into something like being stranded on a barren moonscape without oxygen. In the beginning, opiates are an ideal other. As they beckon graciously, it feels entirely natural to respond with trust and gratitude. Unlike stimulants, or even alcohol, the subjective effects of these drugs seem almost perfectly subtle as they bestow utter contentment. At first the relationship is fun and easy, polishing up cloudy afternoons that might otherwise be irksome and muting broken edges of disappointment. As with requited love, the myopic sense of contentment in opiate’s embrace is like an island vacation or a trip along a golden road; everything superfluous to the relationship recedes to a distant horizon. So what that life is full of small hurts and insults, because the perfect antidote can be readily found in a pill or bag. If only it could stay this way! But, alas, for reasons that seem cruelly capricious, the drug becomes fickle just as your longing grows increasingly urgent. “Darling!” you whisper and then cry, “Please? Please, please!” What has happened? Why can’t you experience the perfect solace you once shared? Smack is all you care about as the intimacy you shared gives way to hopeful longing and then to deep g...

The truth is, we all contribute to the prevalence of these drugs in our communities by swallowing whole the illusion that suffering is avoidable by some outside “fix.” Together with our doctors, we’ve been in collective denial about the fact that these drugs are unable to provide a sustainable solution to the pains of living, and therefore the only real beneficiaries are the pushers, in this case, the pharmaceutical companies.

a young addict who was known to most of the community checked out and promptly died with a needle in his arm. It took only a few hours after the news broke for the center to empty out entirely—not to mourn, but to score. The patients recognized in their friend’s death a sign of high-quality dope. You’ve probably seen similar phenomena in your community; regional bursts in overdoses tend to occur not because most addicts don’t know what’s to be found but because they do. They are victims of the laws of pharmacology who fail to recognize that even drugs like fentanyl and carfentanil, which are thousands of times as potent as heroin, can’t deliver the desired effects to a learned brain (though, unfortunately, they remain potent enough at depressing respiration, which is how they can be lethal).

pain has two primary purposes: the first is to teach us to avoid dangerous stimuli or situations, and the second is to encourage recuperation after failing the first lesson. Another potential rationale for the existence of anti-opiates was outlined in earlier chapters: the brain’s role as contrast detector relies upon a stable baseline. Anti-opiates restore the brain to its baseline most efficiently.

In contrast to our other senses, pain is especially critical to our survival, and the sense is more like an individualistic lens that can open and close gates of sensory experience. For instance, blind, deaf, or anosmic people (the last are those with no sense of smell) are all likely to live a normal life span, but this is not the case for those who are born with a congenital insensitivity to pain who almost invariably die young, from complications following an injury. Moreover, simply snipping a pair of cranial nerves could quickly render someone blind, deaf, or anosmic—the pathways are relatively simple, discrete, and well characterized. Pain is processed redundantly and diffusely, and there is simply no surgical intervention to relieve chronic pain (as many medical doctors and their patients know too well). Instead, pain recruits overlapping pathways and circuits throughout the body and brain and, along with a rich neurochemistry of opioids and anti-opiates, portends the critical nature of pain for our survival.

Research has demonstrated that anti-opiates contribute to addiction as a major source of sickness and misery in opiate addicts. Dozens of peptides (short chains of amino acids) with anti-opiate properties have been identified. Some of the better known of these are dynorphin, orphanin FQ, cholecystokinin, and NPFF, all of which may facilitate adaptation and contribute to tolerance, dependence, and craving. Still, they don’t account for the breadth of opiate addiction on their own. Scientists have identified several other forms of adaptation that contribute: some implicate the brain’s immune system; many others involve compensatory changes inside individual brain cells. Although the number of opiate receptors isn’t dramatically decreased in a chronic narcotic user (the way CB1 receptors decrease in marijuana smokers), the ability of opiates to affect intracellular signaling is compromised with frequent use, so the receptors are downregulated in effectiveness if not in number. But the anti-opiate system is the cruelest. Because an addict’s nervous system is regularly flooded with compounds that produce euphoria, the anti-opiate system ramps up to create pain so that the net effect is something like normal sensation. This opposing anti-opiate system can be turned on by safety, or by the expectation of safety after danger passes, but it’s likely that there is no more effective way to activate anti-opiate processes than through regular exposure to opiates, which must be like a p...

The brain adapts to all exogenous chemicals that alter its activity, but the degree of tolerance, dependence, and craving in opiate users is legend—stronger than for almost every other drug. Adaptations that underlie opiate addiction, including the production of anti-opiates, begin during the very first administration (this is true of all drugs) and rapidly gain strength with use. The strength of these opponent processes may be so robust because the sensation of pain is so critical for survival.

Opiate tolerance is mind-bogglingly robust. Addicts can administer upwards of 150 times the dose that would be lethal to naive users and, even so, just feel “right” but not really high.

One way to understand the dilemma of the opiate user is to recognize that because there are no free lunches, the benefits that drugs confer will have to be paid back. In principle, moments of superb contentment demand an equal and opposite experience of distress; the benefit of euphoria will create a debt of dysphoria; and trying to avoid this unpleasant state by taking more drug will just increase what you owe.

Methadone acts as a substitute opiate—one that is orally absorbed and has an especially long half-life. Drinking a daily “cocktail” at the clinic prevents withdrawal (as well as antisocial activities that help keep withdrawal at bay, like stealing and shooting up in public places), and because the drug is so cheap, it’s been seen as of great benefit—though likely less to the addicts than to members of their communities. Recently, however, methadone has been used in younger and younger addicts. This is especially tragic, if not unethical, from both a neurobiological and a social perspective. Because methadone is such a long-lasting opiate, when prescribed with the clinical goal of keeping the brain soaked in the stuff to stave off withdrawal, it produces an immense addiction. This drug is even harder to kick than heroin; the latter is hell, but for a relatively short time. Therefore, to prescribe a drug like this to people barely out of their teens is to condone “maintenance” that is in some ways a life sentence akin to housing the mentally ill in the back wards of state institutions: they’ll be less trouble for the rest of us, but unlikely to have much of a life.

A more enlightened and democratic approach falls almost exactly in the middle of these extremes. Suboxone is a combination of a Narcan-like drug and an opiate drug called buprenorphine. Buprenorphine doesn’t have much street appeal for the same reason it’s a good choice here: although it occupies the same places in the brain as opiate drugs, it doesn’t do as good a job and therefore it is much less rewarding than its abused counterparts. However, the effects are potent enough to reduce symptoms of withdrawal, including craving, and to allow addicts to sleep. It’s less stigmatizing than methadone, but even more important, under a doctor’s supervision, it won’t make the addiction stronger. For someone motivated to get clean, this could provide a sound start. If the dose is tapered over time, it’s likely to afford the best shot at a life free from opiate addiction.