Never Enough: The Neuroscience and Experience of Addiction

by Judith Grisel

was twenty-two. I’d been on the good end of a bad drug deal. In the wee hours of some morning late in 1985, behind a nameless restaurant in South Florida, a dealer gave me and a friend the wrong bag. I was the “winner” in this deal with substantially more drug than I was obliged to pass on to a friend of a friend somewhere in the Midwest.

With what may seem like exceptional fortitude to some, especially given that I’d been kicked out of three schools by this time, I went on to get a Ph.D. in behavioral neuroscience and to become an expert in the neurobiology, chemistry, and genetics of addictive behavior. This accomplishment would seem almost unremarkable to most addicts, who know firsthand that there is nothing we would not do, no sacrifice too great, to be able to use. It ultimately took seven years to graduate from college, including about a year of dramatic change starting in a treatment center, plus another seven years of graduate school to earn that degree.

Addiction today is epidemic and catastrophic. If we are not victims ourselves, we all know someone struggling with a merciless compulsion to remodel experience by altering brain function.

In the United States, about 16 percent of the population twelve and older meet criteria for a substance use disorder, and about a quarter of all deaths are attributed to excessive drug use.

“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?

What is going on? What am I doing? Questions like these must have been among my first conscious thoughts. If I tried to speak them to anyone, I’m sure what I heard back were directives to “be good,” “work hard,” “smile,” and “don’t get caught.” 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.”

two ways of becoming an alcoholic: either being born one or drinking a lot.

The only rational response, I thought, was to kill myself, but the aesthetic of the whole thing struck me as pathetic. Despite thinking all was vanity, I was still quite vain, and leaping from my dorm window just didn’t feel like my style. Instead, that afternoon represented a turning point in my addiction. 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.

Though I ripped off stores and stole credit cards when the opportunity presented itself, I was still able to maintain, at least to myself, that I was basically a good person. To an extent, for instance, I could count on my companions, and they could count on me. I say to an extent, because we also knew and expected that we would lie, cheat, or steal from each other if something really important were at stake (that is, drugs).

The opposite of addiction, I have learned, is not sobriety but choice.

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.

Despite being depleted, they think the cost of abstinence seems much too high: Without drugs, what is there to live for anyway?

In the 1950s, two Canadian researchers conducted an experiment typical of the period.2 Under general anesthesia they implanted an electrode (a thin wire that conducts electricity) into a rat’s brain, in the location of a specific neural circuit. After the rat fully recovered, they sent mild electric currents through the electrode to mimic natural activity in order to study the effects on the rat’s behavior and identify the circuit’s function. At first James Olds and Peter Milner thought they had discovered the cells responsible for curiosity, because the rat in their experiment kept returning to the area of its cage that had been paired with the electric current. After continued experimentation, however, the researchers concluded that they had found a site for pleasure, and they called it the brain’s “reward center.” In subsequent experiments, when a rat was given the ability to press a bar to stimulate this region of its own brain, it did so with abandon and to the exclusion of virtually everything else.

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.

Early on, a few depressed patients were implanted with electrodes so that they could self-stimulate the mesolimbic circuit in an attempt to help them feel better. Unfortunately, rather than being cured of depression as their doctors had hoped, these patients just became really distracted pressing their own “bars.”

Most of the world has prohibited this sort of surgical intervention, although some nations, including China and the Soviet Union, are reportedly reducing relapse rates by employing this strategy.

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.

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.

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.

Thus, there is good rationale for arguing that despite a high BAC (blood alcohol concentration), because you are in a state of tachyphylaxis, you are really okay to drive. Good luck persuading the judge!

For some drugs, such as antidepressants, adaptation is actually the therapeutic point. Developing tolerance to selective serotonin reuptake inhibitors (SSRIs) may help to change a pathological affective “set point” so that being depressed is no longer the patient’s normal state. With abused drugs, however, such changes are a real drag.

It also explains why the states of withdrawal and craving from any drug are always exactly opposite to the drug’s effects. If a drug makes you feel relaxed, withdrawal and craving are experienced as anxiety and tension. If a drug helps you wake up, adaptation includes lethargy; if it reduces pain sensations, suffering will be your lot.

Maybe this helps explain why people push themselves to exercise or go to graduate school.

Cutting-edge treatments take almost the opposite tact from the pastoral setting strategy (unless of course your using primarily took place on the farm). Following detox and some stability in mood and physiology (usually after several weeks of clean time), the addict is purposely exposed to cues that used to coincide with using, but this time within a supportive, therapeutic context. Wads of cash, drawing fluid into a syringe, or experiencing a disappointing day at first is likely to produce profound physiological and psychological effects such as changes in heart rate, body temperature, and mood. But with repeated exposure (and no drug delivery), such responses indicative of the b process begin to dissipate and eventually disappear.

Though adaptation still occurs in “chippers,” it is virtually imperceptible because of the irregular and low-dose patterns of use.

I now know that the delay happens because of sponge-like binding proteins that are floating around in the blood, to which THC molecules are attracted like magnets; they can’t affect the brain until these proteins are fully saturated. Once all the binding sites are occupied, though, THC can finally be distributed to the brain. I’ve heard that some people don’t get any effects from the drug, and though this is theoretically possible, it’s extremely unlikely. More likely they need to smoke a little more.

So, 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.

Who’s to blame for this situation? 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.

I tried opiates only a handful of times during my using career because with few exceptions they were not readily available in my time and place. I liked the experience, which, at the low to moderate doses I enjoyed, conveyed a sense of warmth and contentment. I’m fairly certain that the story would have been different if I’d been afforded the opportunity to inject these drugs.

The patients recognized in their friend’s death a sign of high-quality dope.

Pavlov’s dogs salivated at both food and the bell associated with mealtime. But if a drug makes your mouth water, the cues associated with the drug would give you cotton mouth instead. This apparent contradiction is understood by appreciating whether or not a stimulus acts directly on the CNS and recruits homeostatic processes. A drug does. Dinner does not.

A better strategy from a neurological perspective might be to employ the opposite tack. Instead of bathing the cells in opiates for long periods, knock them over the head with a big dose of anti-opiates! Giving anti-opiates should induce the brain to maintain homeostasis by upregulating, or at least normalizing, its opioid system. This has in fact been tried and in some ways works like a charm.

In 1839, an English traveler named Frederick Marryat noted in his diary that American practice was “if you meet, you drink; if you part, you drink; if you make acquaintance, you drink; if you close a bargain, you drink; they quarrel in their drink, and they make it up with a drink. They drink, because it is hot; they drink, because it is cold.”

This incongruity is thoroughly pervasive. We always kick off the annual meeting of the Research Society on Alcoholism, where I recently received my twenty-five-year membership pin, with a reception. Free drink tickets—two per person, just right for the social drinker—are offered to everyone, and the drug flows freely (because you can pay cash when your tickets run out).

This is due to differences in the concentration of the ALDH enzyme found in the gut, mentioned above, as well as sex differences in the proportion of body fat.

It’s hard to imagine now, because things have swung so much the other way, but heading east toward the ocean, I breezed through a red light toking on a joint with a beer between my legs. As smoke billowed out the window, the policeman who pulled me over gaped briefly with a mixture of concern and surprise before admonishing me to “be careful”! Another time a girlfriend and I were flagged over as we weaved down Dixie Highway in the wee hours of the morning and were only given a warning after we assured the officer we were able to drive home safely. I doubt there are many places in the United States where this would happen today.

Worldwide annual revenue from alcohol sales is about $150 billion. Diageo and Anheuser-Busch InBev are two of the leading global producers and have net profit margins of around 25 percent as they invest more in marketing than they do in payroll.

Western brands are promoted to middle-class consumers in low-income countries as a status symbol. For example, Diageo claims its alcoholic apple drink Snapp provides African women with a beverage “more refined than beer, with cues of differentiation and sophistication.” Similarly, there seem to be efforts to secure the next generations of consumers by developing beers with fruity flavors, likely to be better tolerated by younger drinkers.

Though hardly recreational in a classic sense, these drugs have tremendous appeal for many of us because feelings can be so darn uncomfortable. How nice just to float along in a perpetual twilight, somehow above the morass of anguish that comes with consciousness.

My point is, there will always be something available to assuage the need to escape the human experience.

People’s individual differences in a drug’s rewarding effects, as well as the development of tolerance or dependence, have been associated with structural differences in the GABAA receptor.4 For example, whether or not you are able to drink others

Or even to wonder how these conditions are so common as to be statistically normal—indeed they afflict at least one in three adults in the United States—yet still are considered abnormal behaviors. One possibility is that some people are more sensitive, or more exposed, than others to environmental factors that contribute to these conditions.

”Yes! I want it” / “No! I don’t”—suggesting

Some people have a mutation in the gene that makes CYP2A6 that slows down nicotine metabolism. Because the drug hangs around longer, these people are less likely to become smokers, but if they do, they smoke fewer cigarettes than people who have normal levels of this enzyme.

However, unlike the GABAA receptor that can be either closed or open, the nAChR has three states: closed, open, and desensitized. The open state is responsible for the stimulant properties of the drug, while the desensitized state produces a cigarette’s calming effects. The rate at which the receptor moves through these states and its ability to conduct a positive current depend on the subunit composition.

(As a rule of thumb, it takes about five half-lives to get rid of about 95 percent of any drug, so this one hangs around for a couple of days.)

Psilocybin, mescaline, and DMT are natural compounds that have been used for millennia by indigenous people in sacred rituals;

Mescaline has been used for at least fifty-seven hundred years in the region of Mexico and western South America, obtained from several species of cacti including peyote, San Pedro, and Peruvian torch. Ayahuasca, which contains DMT, has long been used in Peru and other parts of South America.

Only 50 to 100 micrograms (0.00005 grams = 50 micrograms) of LSD, usually delivered through a paper tab that has been dosed with a small amount of liquid, will induce a trip that lasts for six to twelve hours.