Never Enough [Judith Grisel]

Start Date: 30 May, 2020

Finish Date: 11 June, 2020

Source: National Library Board Singapore ebook

Goodreads link.

Goodreads summary:

Addiction is epidemic and catastrophic. With more than one in every five people over the age of fourteen addicted, drug abuse has been called the most formidable health problem worldwide. If we are not victims ourselves, we all know someone struggling with the merciless compulsion to alter their experience by changing how their brain functions.

Drawing on years of research–as well as personal experience as a recovered addict–researcher and professor Judy Grisel has reached a fundamental conclusion: for the addict, there will never be enough drugs. The brain’s capacity to learn and adapt is seemingly infinite, allowing it to counteract any regular disruption, including that caused by drugs. What begins as a normal state punctuated by periods of being high transforms over time into a state of desperate craving that is only temporarily subdued by a fix, explaining why addicts are unable to live either with or without their drug. One by one, Grisel shows how different drugs act on the brain, the kind of experiential effects they generate, and the specific reasons why each is so hard to kick.

Grisel’s insights lead to a better understanding of the brain’s critical contributions to addictive behavior, and will help inform a more rational, coherent, and compassionate response to the epidemic in our homes and communities.

General Notes:

  • If I remember right, I found out about this book from a Tyler Cowen ‘What I’ve been reading’ blogpost.
  • It strongly reminded me of one of the books I’ve obsessed about recently (and I mention that obsession so that you can take my connections with a pinch of salt!), Why Buddhism is True. More on that later.
  • As the blurb mentions, Prof Grisel is a recovered addict; which means that this book has her insights as both a researcher and a user. I didn’t really pay enough attention on my first read to say which perspective I found more interesting or insightful on its own – but the combination is definitely fantastic and enlightening.
  • A lot of the meat of the book comes in the first couple of chapters, with subsequent chapters just providing either examples or contrasts. I found this helpful rather than annoying.
  • On my “4 stars for something I’ll recommend to anybody who’s interested in the subject or genre” and “5 stars for something I’ll recommend to everybody, regardless of their interest,” this falls sort of in between. It’s one of my pet topics – or fears – which I want to talk about, so I would recommend this to everybody so that we’d have a common base of understanding. But I do wish it’d have been just a little better. Don’t get me wrong, it’s very good.
  • I came to this partly out of worries that social media use is addictive; and seeing addiction in a lot of fiction (especially TV) that I’ve been reading or watching in the recent past. Quick list:
    • Crazy Ex Girlfriend: Greg is alcoholic, and Rebecca can’t break out of a cycle of bad decisions and behaviour (which isn’t necessarily addiction)
    • Sherlock Holmes and adaptations:
      • Sherlock: “I know what you could become, because I know who you really are – a junkie who solves crimes to get high, and the doctor who never came home from the war. Will you listen to me? Who you really are, it doesn’t matter. It’s all about the legend, the stories, the adventures. There is a last refuge for the desperate, the unloved, the persecuted. There is a final court of appeal for everyone. When life gets too strange, too impossible, too frightening, there is always one last hope.”
      • House: pain medication addiction and really, that “final court of appeal” description fits house so well.
      • Elementary, which leaned very hard into the actual drug use and less into the “solving cases is also addictive”
    • Doctor Who Season 9’s theme about how the Doctor and Clara got addicted to adventure and recklessness.
  • In a sense I’m using addiction as shorthand for “actions where you let your habits override your prudence,” which is not necessarily medically accurate. But it does some up where I’m coming from that I got so interested in this topic and tend to see it everywhere.
  • This is partly serious, partly tongue-in-cheek, and partly concern trolling; but I am ready to make a case that porn usage, social media usage, frequent news checking, and sports fandom are all forms of addictive behaviour. But maybe not in this post.
  • Chapter by chapter notes now.


Chapter 1: Brain Food

  • Introduces the subject of homoeostasis; which I was familiar with through its most familiar example, body temperature regulation. But this book points out that the brain attempts to stay in homoeostasis too. This is the introduction to the heart of the book. It also brings in the line “The fundamental role of the brain is to be a contrast detector.” and this is going to be important later on.

All addictive drugs are addictive precisely because they share the ability to stimulate the mesolimbic dopamine system.

  • It refers to what I had learned in Why Buddhism is True; which is that natural selection drove us into a position which would ensure our genes surviving – to anticipate food, sex, and anything else pleasurable; and its gut-punch passage:

Natural selection doesn’t “want” us to be happy, after all; it just “wants” us to be productive, in its narrow sense of productive. And the way to make us productive is to make the anticipation of pleasure very strong but the pleasure itself not very long-lasting.

  • This book expresses that thought with:

In recent years, new evidence has shown that dopamine in the mesolimbic pathway works not exactly by signaling pleasure but by signaling the anticipation of pleasure. This anticipatory state is not the same as the pleasure associated with satisfaction, contentment, or release, but rather the anxious, lip-smacking foretaste of something of import that is just around the corner.

  • And also clarifies:

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.

  • It mentions that lesioning or excising the mesolimbic brain is an effective but unethical way to prevent addiction – it does this by driving you into complete anhedonia. And also mentions that this arises naturally in patients of Parkinson’s Disease – which leads to the side effect that they find it incredibly difficult to enact their intentions; even to the point of something like buttoning their shirt. I wonder how this correlates with depression and the difficulty of getting out of bed/ having a shower/ eating.

To sum all this up, dopamine in the mesolimbic circuit leads us to appreciate opening doors, and dopamine in the nigrostriatal circuit enables us to do so. Drugs of abuse (as well as natural reinforcers like food and sex) stimulate both of these pathways, which is how drugs make us feel good and why we seek them.

  • “The brain adapts to all drugs that affect it by counteracting the drug’s effects.” – this tiny line, which is point c. in a list, is what connects to homeostasis; and which lies at the base of the rest of the book to follow. It also explains drug tolerance, which is what leads to drug addiction.

The brain’s response to a drug is always to facilitate the opposite state; therefore, the only way for any user to feel normal is to take the drug.

  • I’ve long looked at headlines that go “X has the same impact on your brain as heroin!” with some skepticism and thought “Well, won’t anything fun have the same impact on your brain as heroin?” This book doesn’t answer that directly, but it does provide the answer in bits and pieces. But I need to sit, reread and make even better notes to answer it for myself.

Chapter 2: Adaptation

  • Introduces the Solomon Corbit model, which says that “every stimulus which perturbs the way we feel is actively counteracted by the nervous system in order to return to homoeostasis.” And suggests that feeling states are at a set point, so anything which makes us feel a particular way leads to the brain compensating by feeling the opposite. As Grisel puts it: “any stimulus that alters brain functioning to affect the way we feel will elicit a response by the brain that is exactly opposite to the affect of the stimulus. As Newton might succintly put it: who goes up, must come down.”
  • In fact, it’s even worse than Newton’s third law, because the reaction isn’t equal and opposite. Some hysteresis ensures that it’ll be worse and to get the same feeling the next time around, you’ll need a higher stimulus. Ad infinitum; or ad overdosum.
  • I also have a horrid feeling – perhaps influenced by Why Buddhism is True – that the brain’s homoeostatic condition isn’t contentment but vague longing; which means that the homoeostatic condition is itself awful.
  • Solomon Corbit model calls the brain’s attempt to return to homeostasis an “opponent process,” and also call stimulus and brain response ‘a process’ and ‘b process.’ Every exposure to an a process makes the brain respond with faster, bigger, and longer-lasting b processes – the “more than equal” opposite reaction I talked about earlier.
  • It gets worse. Environmental stimuli correlated to the a process itself can elicit the b process. Which means that for an addict, just seeing a syringe could lead to the brain overcompensating before it even gets the drug.

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.


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 quote above and its strategy of making yourself miserable to elicit an opponent process of happiness sounds remarkably like Calvin’s dad.
  • Leading on from the earlier point about how correlations can also lead to a b process; earlier deaddiction programs which would place an addict in entirely new settings, away from all cues, would have high relapse rates. Better designed programs provide the addict with cues but also with someone supportive to stand between them and the cue.
  • “Addiction is a consequence of normal brain functioning” – I have more to write on this, which I will at the end of my chapter by chapter notes.

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

Chapter 3: One Salient Example: THC

Unlike cocaine, for instance, which acts in relatively few discrete spots in the brain, THC (or delta-9-tetrahydrocannabinol), the active ingredient in marijuana, acts throughout the brain, and in some regions in every single connection (of which there are trillions).

  • Prof Grisel says that this is the explanation for why marijuana effects are so inconsistent across users – you can never tell which receptors it’s going to end up in.

Much to everyone’s surprise, the THC was interacting with receptors all over the brain—on the cortex, the structure involved in information processing and other kinds of thinking and awareness, but also in many deeper subcortical structures having to do with emotion and motivation. There were differences in the density of the receptors, with some areas expressing fewer interaction sites, but others were virtually opaque with binding.

  • From personal experience, she suggests that the opponent process to marijuana use will leave you unable to appreciate everyday beauty when not high.

Chapter 4: Dream Weavers: Opiates

This horrifying quote:

However, the study was unexpectedly cut short after 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.

The book suggests that tolerance to opiate drugs evolves the quickest; and that opiate addiction is not a question of wanting to get high, but to get out of the horrors of withdrawal. Skipping ahead to the chapter’s concluding paragraph:

The bottom line for opiate users, and the bottom line of this book, is that there can never be enough drug. Because of the brain’s tremendous capacity to adapt, it’s impossible for a regular user to get high, and the best a voracious appetite for more drug can hope to accomplish is to stave off withdrawal. This situation is best recognized as a dead end.

  • I learned that the brain can generate morphine on its own; when painkillers are required.
  • But it can also release anti-opiates and anti-opiods to counteract the opiods it released earlier – homoeostasis again!

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.

And follows it up with:

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.

Methadone is still an opiate, just one which isn’t as short-lived and so doesn’t lead addicts to constantly be in craving. Prof Grisel says the benefit isn’t so much to the addicts as to the people around them who don’t want to see the consequences of their using. And proposes:

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.

  • Narcan and suboxone are such anti-opiates; but with Narcan you experience immediate and severe withdrawal; and addicts who emerge from that immediately skip hospital to score. Suboxone can be tapered down.

Chapter 5: The Sledgehammer: Alcohol

The bipolar practice of pitying addicts while at the same time greasing virtually every social interaction with an obscene amount and variety of booze seems heartless if not mindless.

  • Makes the point, and I wish it had been made earlier that drugs may be either positively reinforcing (seeking pleasure) or negatively reinforcing (avoiding pain). Opiates reduce pain, alcohol reduces anxiety, and stimulants reduce boredom.
  • In alcohol’s case, the opponent process will create anxiety.
  • An early anti-alcoholic drug, Antabuse acted through punishment and conditioning – it would make you allergic; and relies on the same process as “Asian flush” and the mutation that makes East Asians alcohol-intolerant. I’m remembering Professor Calculus’s pills in Tintin and the Picaros.
  • It doesn’t really work well.

In other words, addicts may be those who are especially charmed by the quality of carrots and immune to the beating of sticks, as any municipal court could attest.

  • I think there’s a case to be made here tying it to Adam Smith’s impartial spectator and the ability to, I don’t know, put yourself in the shoes of your future self (or best self). Maybe addicts are the people who can’t do that. But maybe my thinking about impartial spectators, theory of mind, and Pratchett’s theory of imagination and finding its absence as the root cause of all problems is my hammer looking for a nail.

Paradoxically, the simplicity of the ethanol molecule is what makes it so difficult to understand. Molecules of cocaine, THC, heroin, and ecstasy are much larger and more structurally complex, and therefore their sites of action in the brain are very specific. Alcohol is so small and wily its actions are hard to pin down.

Then, there’s:

As a rule, sedation is not as much enjoyed as stimulation, which is why, despite its popularity, alcohol is not as addictive as are some other drugs. Over 85 percent of the world’s adults drink, but only about one-tenth of these develop a problem. Also, even though the ethanol in all alcoholic beverages is the same molecule, different beverages contain different congeners or impurities from the distillation process, often connected to the source—tequila has more congeners than vodka—that can affect the experience of intoxication and withdrawal (that is, they can produce a worse hangover).

Chapter 6: The Downer Class: Tranquilizers

  • A very uninteresting chapter compared to what came before. One might even say… tranquilising.
  • Barbiturates are this class.
  • The Rolling Stones’ Mother’s Little Helper was about one such prescription tranquilizer.
  • The next class is benzodiazepines.

Chapter 7: Pick-Me-Ups: Stimulants

  • Explains that with stimulants, especially cocaine, repeated exposure leads to aversion to the drug; so that it turns into a mixture of wanting and not wanting – “measured in the lab by compulsive approach behavior as well as avoidant behaviour.” Manifests physically as rats running through a maze towards cocaine, but at the last turn, going nuts deciding whether to go for it or not – but finally succumbing.
  • I have a worry that my social media usage is similar – or at least the self-loathing with which I view it is analogous.

Caffeine is the most popular psychoactive drug in the world, although there is some debate about whether or not it is addictive. Though regular use may result in a modicum of tolerance and will likely cause dependence (that is, withdrawal upon abstinence) and craving, the drug is not considered harmful, thus skipping one of the core criterion for addiction.


The mechanism by which caffeine produces its effects is not completely understood, but we do know that it doesn’t act like cocaine, amphetamine, or MDMA to directly enhance the transmission of dopamine, norepinephrine, and/or serotonin. Instead, caffeine is an antagonist at adenosine receptors (just as Narcan is an antagonist at opiate receptors).

I need to cite this the next time Shivani calls Kopi C Kosong my crack.

  • Cigarette use in America may be falling because Americans are switching over to marijuana as it legalises or decriminalises. Physically that will be less harmful, since there is no tar in a marijuana cigarette – or in vapes. But marijuana may have psychosocial consequences.
  • Cigarettes are calming because of the opponent process, not because of nicotine’s own properties, which are stimulant:

However, unlike the GABA(A) 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.

  • Cocaine leads to a love-hate relationship which is thought to reflect the opponent process. “You hate yourself for going but end up visiting over and over.”

Coke, speed, and E all act by blocking transporters. Transporters, like receptors, are proteins embedded in the neural cell membrane, but unlike receptors the function of transporters is to transport (or recycle) released neurotransmitter back into the presynaptic neuron, where it can be repackaged and reused. Transporters are one of the two main ways that synaptic transmission is discontinued; the other is through enzymatic degradation.


Without transporters or enzymes to break apart neurotransmitters, synaptic transmission would persist much longer than it does, and therefore the signal would be quite different. When one of these drugs occupies a spot on a transporter, it prevents the monoamines from utilizing their reuptake mechanism and prolongs their effects.

  • That is, cocaine binds to the chemical which would otherwise send a packet of dopamine back to the neuron it came from; so it prevents the dopamine from going back.
  • Meth was kind of skipped over – as a sort of inferior coke that works in the same way and is too boring to go into detail about.
  • Ecstasy is a combined stimulant and hallucinogen. And because its outcome is euphoria; the opponent process will lead to depression; and seems to cause very long lasting brain damage – especially related to serotonin production.

And this warning:

Every drug that acts on the central nervous system to change the way we feel will cause an opponent process. For most drugs discussed in this book, it’s likely that with abstinence the b process will dissipate and the brain return somewhere near its nascent state. Unfortunately, it doesn’t look as if this is going to be the case with stimulants, and particularly for those abusing amphetamines or ecstasy.

Chapter 8: Seeing Clearly Now: Psychedelics

  • Makes a point that such drugs were often consumed under guidance or in a community. Quotes a doctor grumbling about white people taking them up as a fad instead of as a spiritual aid.
  • Psychedelics are probably not addictive.
  • Michael Pollan’s Econ Talk interview about psychedelics was probably more detailed about the effects of psychedelics (and got me curious about trying!).

Chapter 9: A Will and a Way: Other Abused Drugs

  • Covers the miscellania, such as sniffing glue, ketamine, PCP, ephedrine, and salvia.

Chapter 10: Why Me?

  • Talks about what leads somebody to become an addict.
  • Genetics: it goes into detail about the initial hope everyone had from the human genome project, and then the horror they had after realising that the number of genes was really tiny, and that the idea of a ‘gene for x’ completely broke down.
  • Similarly, each implicated gene has such a tiny contributory factor that there are probably hundreds of genes acting in concert which lead to an inherited propensity to addiction.
  • Early exposure definitely plays a part.

The flip side of this, also supported by strong evidence, is that the older one is when one begins getting high—on anything from alcohol to amphetamine—the less likely one’s use is to become addictive. It’s likely that if I’d begun a little later, my trajectory wouldn’t have been so precipitous. In fact, research indicates that most people with a substance use disorder started using during adolescence and met the criteria before age twenty-five.

But this is kind of futile because:

Unfortunately, this information is unlikely to prove a deterrent to young people. That is because adolescents’ general tendency to explore and experiment (or more colloquially, “engage in reckless behavior”) is partially due to underdevelopment of the prefrontal cortex. This region, right above the eyeballs, is most responsible for “adult” abilities, such as delay of reward, abstract reasoning (including statements like “if I spend the rent money on a zone bag, then…”), and impulse control. By some ill-timed developmental plan, the prefrontal cortex is the last brain region to reach its mature state. What’s more, this area of the brain is one of the regions most affected by a substance use disorder. What a pickle.

Here we go again with that link to the impartial spectator.

Chapter 11: Solving Addiction

I understand firsthand the despair that grows as drugs come to make our choices for us, deciding whom we will be with and what we will do. This gloomy cell of repetition occupied by every addict, despite variation in periodicity, strips us of our most precious commodity, the freedom to choose. This is why I’m not against drugs or drug use, but am so thoroughly opposed to addiction: it strips us of our precious freedom. And this is also why it makes no more sense to cure addiction by imposing permanent or semipermanent limits on our range of choices than it does to teach compassion through corporal punishment. How could one give rise to the other?

Sobering. Pun not intended.

  • This chapter is in a way, gloomy. It warns that neither cause nor cure for addiction are known.
  • While chemical formulations for detox are known, Prof Grisel doesn’t think that these have any long term impact without social support.
  • She makes the claim that culture and context matter and that the drug of choice in a particular time reflects the zeitgeist. Cocaine in the 1980s because it was a time of consumerism; opiates in the 2010s to deal with existential crises like climate change.

Wrap Up

In some ways, this was a book which left me despairing a little; because it made such a good case for addiction not being a sort of brain malfunction; but the outcome of the brain working as it should. In other words – and this is where the commonality with Why Buddhism is True comes in – evolution has saddled us with brains that have a fundamental design flaw.

A relevant Pratchett quote for us being well manufactured pieces of a bad design rather than defective pieces:

And of course there clearly had to be, said Koomi, a Supreme Being. But since the universe was a bit of a mess, it was obvious that the Supreme Being hadn’t in fact made it. If he had made it he would, being Supreme, have made a better job of it, with far better thought given, taking an example at random, to things like the design of the common nostril. Or, to put it another way, the existence of a badly put-together watch proved the existence of a blind watchmaker.

The mild despair I feel at evolution having led us down a path where we are filled with unquenchable longing and a propensity to addiction also brings to mind a Douglas Adams quote:

Many were increasingly of the opinion that they’d all made a big mistake in coming down from the trees in the first place. And some said that even the trees had been a bad move, and that no one should have ever left the oceans.

Michael Chabon, in Moonglow, had a line which also captures the feeling that the universe is rigged against you.

At any rate, as Uncle Ray once explained to him, if you examined the language, the concluding lines of the kaddish might have been interpreted as a wish that God and everyone else would just, for once, leave the speaker and all his fellow Jews alone.

Which brings us back to Douglas Adams.

Only his eyes bore a trace of the idea that whatever the Universe was doing to him, he would like it to stop.

That’s all, folks.

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