The Thirteenth Step: Addiction in the Age of Brain Science

2. P. Anderson et al., “Effectiveness and cost-effectiveness of policies and programmes to reduce the harm caused by alcohol.” Lancet 373, no. 9682 (2009): 2234–46.

1. “Standardized mortality rate,” or SMR, is a useful measure of how deadly a drug is. It indicates the risk of dying, within a certain timeframe, for a person who uses the drug compared with a person of the same sex, age, socioeconomic status, etc. who does not use that drug. For heroin-addicted subjects seeking methadone treatment, this measure indicates between twenty- and fiftyfold increased risk of dying.

2. Such data are important for indicating the probability of developing addiction for particular drugs; they are probably less informative when it comes to comparing the addiction liability of different drugs. The social cost of maintaining a nicotine addiction, although increasing, is still in a different league compared with that associated with cocaine addiction.

3. J. Rehm et al., “Global burden of disease and injury and economic cost attributable to alcohol use and alcohol-use disorders.” Lancet 373, no. 9682 (2009): 2223–33.

4. D. J. Nutt et al., on behalf of Independent Scientific Committee on Drugs, “Drug harms in the UK: A multicriteria decision analysis.” Lancet 376, no. 9752 (2010):1558–65. David Nutt was fired as government adviser after reaching these inconvenient conclusions.

5. J. Rehm et al., “The relationship of average volume of alcohol consumption and patterns of drinking to burden of disease: An overview.” Addiction 98, no. 9 (2003): 1209–28.

6. D. S. Hasin et al., “Prevalence, correlates, disability, and comorbidity of DSM-IV alcohol abuse and dependence in the United States: Results from the National Epidemiologic Survey on Alcohol and Related Conditions.” Archives of General Psychiatry 64, no. 7 (2007): 830–42.

1. I have not been able to establish the species of mushroom in these accounts, but from the description of symptoms, they must have contained substances that block one of the brain receptors for acetylcholin, a transmitter involved in cognition and memory.

2. Much of addiction research has been carried out without appropriate attention to this fact. Although experiments are simpler when animals have access only to the drug studied, that may well create a rather artificial situation. Illustrating this fact, the laboratory of Dr. Serge Ahmed in Bordeaux, France, has elegantly shown that when sugar is available as an alternative, the motivation of rats to obtain cocaine dramatically decreases.

3. J. Anthony et al., “Comparative epidemiology of dependence on tobacco, alcohol, controlled substances, and inhalants: Basic findings from the National Comorbidity Survey.” Experimental and Clinical Psychopharmacology 2 (1994): 244–68; National Household Survey on Drug Abuse: Main Findings, DHHS publication no. (SMA) 00–3381 (Rockville, Md.: Department of Health and Human Services, Substance Abuse and Mental Health Services Administration, 2000). The substances examined included cocaine, other stimulants such as amphetamine, heroin, painkillers, cannabis, tranquilizers, alcohol, and tobacco.

4. A new version is expected in 2017.

5. “Syndrome” comes from Greek, meaning “run together”—a set of features that frequently occur together. It is typically assumed in medicine that a common underlying mechanism causes such features.

6. The American Psychiatric Association, which publishes the Diagnostic and Statistical Manual of Mental Disorders, included a category in the fourth edition of the manual(DSM-IV) very similar to the WHO/ICD criteria. The fifth edition (DSM-V), published in October 2013, did away with the abuse/dependence dichotomy, added “craving” as an explicit criterion, and made physical dependence a characteristic of the disorder—say, “alcohol use disorder with/without tolerance/withdrawal.”

7. The exceptions are tranquilizers such as Valium and hallucinogens such as LSD.

8. V. Deroche-Gamonet et al., “Evidence for addiction-like behavior in the rat.” Science 305, no. 5686 (2004): 1014–17; L. J. Vanderschuren and B. J. Everitt, “Drug seeking becomes compulsive after prolonged cocaine self-administration.” Science 305, no. 5686 (2004): 1017–19.

9. To quote Alan Leshner, former director of NIDA and one of the most effective communicators I have ever met: “Addiction is a brain disease, and it matters.” A. Leshner, “Addiction is a brain disease, and it matters.” Science 278, no. 5335 (1997): 45–47.

10. That is an American view. Being Jewish, I could claim that what is pursued is decreased misery.

11. Although this may appear dangerously close to circular reasoning, it is not. Depression can be effectively treated in people who also have drug problems. Once treatment gets a handle on both the depression and the substance use, the desire to live is as strong as in anyone else.

12. See, e. g., S. H. Ahmed and G. F. Koob, “Transition from moderate to excessive drug intake: Change in hedonic set point.” Science 282, no. 5387 (1998): 298–300.

13. H. Kristenson et al., “Identification and intervention of heavy drinking in middle-aged men: Results and follow-up of 24–60 months of long-term study with randomized controls.” Alcoholism: Clinical and Experimental Research 7, no. 2 (1983): 203–9.

14. D. S. Hasin et al., “Prevalence, correlates, disability, and comorbidity of DSM-IV alcohol abuse and dependence in the United States: Results from the National Epidemiologic Survey on Alcohol and Related Conditions.” Archives of General Psychiatry 64, no.7 (2007): 830–42;B. F. Grant et al., “Prevalence and co-occurrence of substance use disorders and independent mood and anxiety disorders: Results from the National Epidemiologic Survey on Alcohol and Related Conditions.” Archives of General Psychiatry 61, no. 8 (2004): 807–16.

15. R. Culverhouse et al., “Long-term stability of alcohol and other substance dependence diagnoses and habitual smoking: An evaluation after 5 years.” Archives of General Psychiatry 62, no. 7 (2005): 753–60.

16. A robust cannabinoid withdrawal syndrome can be precipitated by blocking cannabinoid receptors. This withdrawal shares many similarities with that from other addictive drugs but is masked by the slow elimination.

1. When I took up the job, I discovered that one of the inpatient units prided itself in being a medication-free detox ward. I soon learned this meant that if a patient went into alcohol withdrawal seizures on the unit, the patient would be dragged out into the hall before benzodiazepines were administered to break this potentially life-threatening condition. I had to reassign the nurse manager and threaten to report a few other people to the licensing authorities before this practice stopped.

2. T. McLellan et al., “Drug dependence, a chronic medical illness: Implications for treatment, insurance, and outcomes evaluation.” JAMA 284, no. 13 (2000): 1689–95.

3. I have one complaint about this paper, and one only. Throughout, it used the term “dependence” for what should have been “addiction.” For the sake of consistency, I have used the latter.

4. And, one might add, because half the nurses decided they just don’t believe in medications, no matter what the data from controlled trials say.

1. The term “deterministic” is used here in a broad sense. Most laws of biology are probabilistic rather than truly and strictly deterministic.

2. D. Premack and G. Woodruff, “Does the chimpanzee have a theory of mind.” Behavioral and Brain Sciences 1, no. 4 (1978): 515–26.

3. At least after scientists have told the computer to assign fanciful colors to the rather boring numbers generated by statistical algorithms, in turn generated from the even more boring numbers that come off the MR equipment.

4. In Kantian terms, the processes of the brain-mind could be viewed as “the-thing-itself”—das Ding an sich.

5. S. Pinker, The Blank Slate: The Modern Denial of Human Nature (New York: Penguin, 2002).

1. FM stands for “frequency modulated,” which is how neurons encode information: a higher-intensity signal is coded by increasing the frequency of impulses, or action potentials, that get sent down the wire (the axon) that takes the signal to the synapse and through the synapse to the next cell.

2. The Nobel Prize in Medicine or Physiology was awarded to Bert Sakmann and Erwin Neher in 1991 for patch clamp electrophysiology, a way of studying electric communication between nerve cells.

3. M. A. Ungless et al., “Single cocaine exposure in vivo induces long-term potentiation in dopamine neurons.” Nature 411, no. 6837 (2001): 583–87.

4. R. Sinha et al., “Stress-induced cocaine craving and hypothalamic-pituitary-adrenal responses are predictive of cocaine relapse outcomes.” Archives of General Psychiatry 63, no. 3 (2006): 324–31; R. Sinha et al., “Effects of adrenal sensitivity, stress- and cue-induced craving, and anxiety on subsequent alcohol relapse and treatment outcomes.” Archives of General Psychiatry 68, no. 9 (2011): 942–52.

5. This statement was made famous in an essay of the same title by the Russian evolutionary biologist Theodosius Dobzhansky in American Biology Teacher 35 (1973): 125–29. Although used in the essay to reconcile the author’s Christian beliefs with a modern understanding of biology, the statement has much broader implications.

6. D. H. Ingvar, “‘Memory of the future’: An essay on the temporal organization of conscious awareness.” Human Neurobiology 4, no. 3 (1985): 127–36.

7. G. F. Koob and N. D. Volkow, “Neurocircuitry of addiction.” Neuropsychopharmacology 35, no. 1 (2010): 217–38.

1. J. A. Wilson, “Egyptian Secular Songs and Poems,” in Ancient Near Eastern Texts Relating to the Old Testament (Princeton, N. J.: Princeton University Press, 1969), 467.

2. Note that this operant conditioning is different in a fundamental way from classical, or Pavlovian, conditioning; the latter does not require the subject to exhibit a particular behavior or “operant.”

3. This term, a marriage of cognitive psychology and neuroscience, is said to have been coined by George Miller and Michael Gazzaniga in the back seat of a New York taxi. I am happy to provide that observation as experimental support for my hypothesis that being in Manhattan has a powerful influence on the probability of coming up with great ideas.

4. J. Olds and P. Milner, “Positive reinforcement produced by electrical stimulation of septal area and other regions of rat brain.” Journal of Comparative and Physiological Psychology 47, no. 6 (1954): 419–27; J. Olds, “Self-stimulation of the brain: Its use to study local effects of hunger, sex, and drugs.” Science 127, no. 3294 (1958): 315–24.

5. J. Olds, in Brain Stimulation and Reward, ed. E. S. Valenstein (Glenview, Ill.: Scott, Foresman, 1973).

6. Many hard-core behaviorists to this day do not like to talk about internal states and shrug at the notion that a rat might experience pleasure; thus they use terms such as “hedonic value.” Given that the meaning of the Greek root word for “hedonic” is “sweet” and was used to denote things that give pleasure, I find that amusing.

7. V. Deroche-Gamonet et al., “Evidence for addiction-like behavior in the rat.” Science 305, no. 5686 (2004): 1014–17; L. J. Vanderschuren and B. J. Everitt, “Drug seeking becomes compulsive after prolonged cocaine self-administration.” Science 305, no. 5686 (2004): 1017–19.

8. R. A. Wise, “Addictive drugs and brain stimulation reward.” Annual Review of Neuroscience 19 (1996): 319–40.

9. A. Carlsson et al., “3,4-Dihydroxyphenylalanine and 5-hydroxytryptophan as reserpine antagonists.” Nature 180, no. 4596 (1957): 1200. To understand why Carlsson’s discovery was met with such skepticism, one has to realize that the presence of dopamine in the brain was known at the time, but everybody thought they already knew its role there: as an intermediate step along the way to making a “real” neurotransmitter, norephinephrine.

10. Developed by two other Swedes, Bengt Falck and Nils-Åke Hillarp of Lund University, the formaldehyde fluorescence method enabled much of modern neuroscience to get started in the early 1960s. Hillarp was Carlsson’s doctoral adviser in Lund. He tragically died from melanoma at the age of forty-nine.

11. The number is much lower, perhaps around twenty-five thousand, in a mouse. It seems that the further we evolve, the more cells the ventral tegmental area contains.

12. The upper part of the basal ganglia, the dorsal striatum, is more directly involved in movement control, and its loss of dopamine input is the disease mechanism of Parkinson’s disease.

13. M. A. Bozarth and R. A. Wise, “Toxicity associated with long-term intravenous heroin and cocaine self-administration in the rat.” JAMA 254, no. 1 (1985): 81–83.

14. T. M. Tzschentke, “Measuring reward with the conditioned place preference (CPP) paradigm: Update of the last decade.” Addiction Biology 12, no. 3–4 (2007): 227–462.

15. Recently the research group of Harriet de Wit at University of Chicago and work we have done in collaboration with that group have shown that humans will also exhibit conditioned place preference. E. Childs and H. de Wit, “Amphetamineinduced place preference in humans.” Biological Psychiatry 65, no. 10 (2009):900–904; L. M. Mayo et al., “Conditioned preference to a methamphetamine-associated contextual cue in humans.” Neuropsychopharmacology 38 (2013): 921–29.

16. If this all sounds simple, it both is and is not. Conceptually, CPP indeed has an attractive simplicity to it. In practicality, it is extremely sensitive to many irrelevant factors, such as whether one of the two environments is inherently more interesting or more unpleasant for the mouse. CPP is particularly tricky with alcohol, for instance, because higher doses obviously lead to impairment that will get in the way of measuring reward based on how the mouse moves around.

17. R. A. Wise and M. A. Bozarth, “A psychomotor stimulant theory of addiction.” Psychology Review 94, no. 4 (1987): 469–92.

18. G. Di Chiara and A. Imperato, “Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats.” Proceedings of the National Academy of Science USA 85, no. 14 (1988): 5274–78.

19. E.g., N. Volkow et al., “Relationship between subjective effects of cocaine and dopamine transporter occupancy.” Nature 386, no. 6627 (1997): 827–30; N. Volkow et al., “Reinforcing effects of psychostimulants in humans are associated with increases in brain dopamine and occupancy of D(2) receptors.” Journal of Pharmacology and Experimental Therapeutics 291, no. 1 (1999): 409–15.

20. W. Schultz, “Predictive reward signal of dopamine neurons.” Journal of Neurophysiology 80 (1998): 1–27.

21. S. E. Hyman et al., “Neural mechanisms of addiction: The role of reward-related learning and memory.” Annual Review of Neuroscience 29 (2006): 565–98.

22. A. Badiani et al., “Opiate versus psychostimulant addiction: The differences do matter.” Nature Reviews Neuroscience 12, no. 11 (2011): 685–700.

23. K. Kiianmaa et al., “On the role of ascending dopamine systems in the control of voluntary ethanol intake and ethanol intoxication.” Pharmacology Biochemistry and Behavior 10, no. 4 (1979): 603–8; Z. Amit and Z. W. Brown, “Actions of drugs of abuse on brain reward systems: A reconsideration with specific attention to alcohol.” Pharmacology Biochemistry and Behavior 17, no. 2 (1982): 233–38; S. Rassnick et al., “The effects of 6-hydroxydopamine lesions of the nucleus accumbens and the mesolimbic dopamine system on oral self-administration of ethanol in the rat.” Brain Research 623, no. 1 (1993): 16–24.

24. I. Boileau et al., “Alcohol promotes dopamine release in the human nucleus accumbens.” Synapse 49, no. 4 (2003): 226–31; J. M. Gilman et al., “Why we like to drink: A functional magnetic resonance imaging study of the rewarding and anxiolytic effects of alcohol.” Journal of Neuroscience 28, no. 18 (2008): 4583–91.

25. N. B. Urban et al., “Sex differences in striatal dopamine release in young adults after oral alcohol challenge: A positron emission tomography imaging study with [¹¹C]raclopride.” Biological Psychiatry 68, no. 8 (2010): 689–96.

26. V. A. Ramchandani et al., “A genetic determinant of the striatal dopamine response to alcohol in men.” Molecular Psychiatry 16, no. 8 (2011): 809–17.

27. J. M. Gilman et al., “Subjective and neural responses to intravenous alcohol in young adults with light and heavy drinking patterns.” Neuropsychopharmacology 37, no. 2 (2012): 467–77.

28. T. Robinson and K. Berridge, “Addiction.” Annual Review of Psychology 54 (2003):25–53.

29. K. Berridge et al., “Dissecting components of reward: ‘Liking,’ ‘wanting,’ and learning.” Current Opinion in Pharmacology 9 (2009): 65–73.

30. A. J. Machin and R. I. M. Dunbar, “The brain opioid theory of social attachment: A review of the evidence.” Behaviour 148 (2011): 985–1025.

31. C. Pert and S. Snyder, “Opiate receptor: Demonstration in nervous tissue.” Science 179, no. 4077 (1973): 1011–14.

32. L. Terenius and A. Wahlstrom, “Search for an endogenous ligand for the opiate receptor.” Acta Physiologica Scandinavica 94, no. 1 (1975): 74–81.

33. J. Hughes et al., “Identification of two related pentapeptides from the brain with potent opiate agonist activity.” Nature 258, no. 5536 (1975): 577–80.

34. R. Kanigel, Apprentice to Genius: The Making of a Scientific Dynasty (Baltimore: Johns Hopkins University Press, 1993).

35. Mu-opioid receptors are of course plentiful in numerous other brain areas and are involved in many other brain functions. The ones listed are simply a selection of those most relevant for our discussion.

36. A. M. Graybiel, “Habits, rituals, and the evaluative brain.” Annual Review of Neuroscience 31 (2008): 359–87.

37. A. L. Milton and B. J. Everitt, “The persistence of maladaptive memory: Addiction, drug memories and anti-relapse treatments.” Neuroscience and Biobehavioral Reviews 36, no. 4 (2012): 1119–39.

38. Robinson and Berridge, “Addiction.”

39. D. Morgan et al., “Social dominance in monkeys: Dopamine D2 receptors and cocaine self-administration.” Nature Neuroscience 5, no. 2 (2002): 169–74.

40. N. D. Volkow et al., “Prediction of reinforcing responses to psychostimulants in humans by brain dopamine D2 receptor levels.” American Journal of Psychiatry 156, no. 9 (1999): 1440–43.

2. E. J. Khantzian et al., “Heroin use as an attempt to cope: clinical observations.” American Journal of Psychiatry 131, no. 2 (1974): 160–64; Khantzian, “The self-medication hypothesis of substance use disorders: A reconsideration and recent applications.” Harvard Review of Psychiatry 4, no. 5 (1997): 231–44.

3. D. F. Duncan, “Reinforcement of drug abuse: Implications for prevention.” Clinical Toxicology Bulletin 4, no. 2 (1974): 69–75.

4. D. A. Regier et al., “Comorbidity of mental disorders with alcohol and other drug abuse: Results from the Epidemiologic Catchment Area (ECA) Study.” JAMA 264, no. 19 (1990): 2511–18.

5. C. A. Dackis and M. S. Gold, “More on self-medication and drug abuse.” American Journal of Psychiatry 143, no. 10 (1986): 1309–10; M. A. Schuckit and V. Hesselbrock, “Alcohol dependence and anxiety disorders: What is the relationship?” American Journal of Psychiatry 151, no. 12 (1994): 1723–34; R. J. Frances, “The wrath of grapes versus the self-medication hypothesis.” Harvard Review of Psychiatry 4, no. 5 (1997): 287–89.

6. G. F. Koob and F. E. Bloom, “Cellular and molecular mechanisms of drug dependence.” Science 242, no. 4879 (1988): 715–23.

7. R. L. Solomon and J. D. Corbit, “An opponent-process theory of motivation. I. Temporal dynamics of affect.” Psychology Review 81, no. 2 (1974): 119–45.

8. P. Sterling and J. Eyer, “Allostasis: A New Paradigm to Explain Arousal Pathology.” In Handbook of Life Stress, Cognition and Health, ed. S. Fisher and J. Reason (New York: Wiley, 1988).

9. B. S. McEwen, The End of Stress as We Know It (Washington, D. C.: Joseph Henry Press, 2004).

10. D. B. Goldstein and N. Pal, “Alcohol dependence produced in mice by inhalation of ethanol: Grading the withdrawal reaction.” Science 172, no. 3980 (1971): 288–90.

11. M. Heilig and G. F. Koob, “A key role for corticotropin-releasing factor in alcohol dependence.” Trends in Neurosciences 30, no. 8 (2007): 399–406.

12. S. H. Ahmed and G. F. Koob, “Transition from moderate to excessive drug intake: Change in hedonic set point.” Science 282, no. 5387 (1998): 298–300; S. H. Ahmed et al., “Neurobiological evidence for hedonic allostasis associated with escalating cocaine use.” Nature Neuroscience 5, no. 7 (2002): 625–26.

1. Economic decision-making theory frequently refers to “utility” as an intrinsic metric of a reward; in contrast, “subjective value” is that utility, discounted by the individual for various factors such as, e. g., how long into the future the reward lies, how uncertain it may be, etc.

2. I use “light up” here in a loose sense that refers to increased activity. Most of the time we would apply different methods to follow the brain activity in the rat and the human, although advances in imaging technology actually now make it possible to apply some methods much the same way in both cases.

3. For a great review of the somatic marker theory, see A. Bechara et al., “Emotion, decision making and the orbitofrontal cortex.” Cerebral Cortex 10, no. 3 (2000):295–307. Damasio has also published a fascinating popular account of this uniquely human functionality in his book Descartes’ Error: Emotion, Reason, and the Human Brain (New York: Putnam, 1994).

4. K. R. Ridderinkhof et al., “The role of the medial frontal cortex in cognitive control.” Science 306, no. 5695 (2004): 443–47.

5. Or are at least key players in those functions; in reality, no brain structure does anything entirely on its own.

6. This seemingly simple function of the brain, how many things we can hold in memory at a given time, is in fact so important that it seems to influence academic achievement more than the global IQ measure. T. P. Alloway and R. G. Alloway, “Investigating the predictive roles of working memory and IQ in academic attainment.” Journal of Experimental Child Psychology 106, no. 1 (2010): 20–29.

7. Reviewed in W. Mischel et al., “Delay of gratification in children.” Science 244, no. 4907 (1989): 933–28.

8. A once popular hypothesis of development held that “ontogenesis recapitulates phylogenesis,” meaning that the development of the embryo follows that of the species. Although not uniformly true for all embryonic development, it is generally the rule that cognitive achievements that are the most recent in the evolutionary history of a species are also the ones to come online last during development of the individual.

9. U.S. Supreme Court, Graham v. Florida, 2010.

10. B. J. Casey et al., “Behavioral and neural correlates of delay of gratification 40 years later.” Proceedings of the National Academy of Science USA 108, no. 36 (2011): 14998–15003.

11. H. de Wit, “Impulsivity as a determinant and consequence of drug use: A review of underlying processes.” Addiction Biology 14, no. 1 (2009): 22–31.

12. T. E. Wilens et al., “Does stimulant therapy of attention-deficit/hyperactivity disorder beget later substance abuse? A meta-analytic review of the literature.” Pediatrics 111, no. 1 (2003): 179–85.

13. T. Klingberg et al., “Computerized training of working memory in children with ADHD—a randomized, controlled trial.” Journal of the American Academy of Child and Adolescent Psychiatry 44, no. 2 (2005): 177–86.

14. J. D. Jentsch and J. R. Taylor, “Impulsivity resulting from frontostriatal dysfunction in drug abuse: Implications for the control of behavior by reward-related stimuli.” Psychopharmacology (Berlin) 146, no. 4 (1999): 373–90; de Wit, “Impulsivity as a determinant and consequence of drug use”; J. M. Gilman et al., “The effect of intravenous alcohol on the neural correlates of risky decision making in healthy social drinkers.” Addiction Biology 17, no. 2 (2012): 465–78.

15. P. T. Mehlman et al., “Low CSF 5-HIAA concentrations and severe aggression and impaired impulse control in nonhuman primates.” American Journal of Psychiatry 151, no. 10 (1994): 1485–91; D. Higley and M. Linnoila, “A nonhuman primate model of excessive alcohol intake: Personality and neurobiological parallels of type I- and type II-like alcoholism.” Recent Developments in Alcoholism 13 (1997): 191–219.

16. D. Belin et al., “High impulsivity predicts the switch to compulsive cocaine-taking.” Science 320, no. 5881 (2008): 1352–55.

17. A. Damasio et al., “The return of Phineas Gage: Clues about the brain from the skull of a famous patient.” Science 264, no. 5162 (1994): 1102–5.

18. http://www.slate.com/articles/health_and_science/science/2014/05/phineas_gage_neuroscience_case_true_story_of_famous_frontal_lobe_patient.html.

1. I work obsessively with patients to reconstruct the chain of events leading up to a relapse in petty detail, which invariably requires revisiting the issue several times. It is amazing how often the initial answer to the simple question, “What happened?” is “I have no idea—all of a sudden I was drinking,” only to ultimately emerge as a logical process that the patient looks at and says, “How could I fool myself like that?” As we will see in a later chapter, behavioral analysis of that kind is a key element of relapse prevention treatment.

2. Harriet subsequently came to establish a highly successful research group at University of Chicago and remains to date at the forefront of human psychopharmacology and addiction research.

3. Y. Shaham et al., “The reinstatement model of drug relapse: History, methodology and major findings.” Psychopharmacology (Berlin) 168, nos. 1–2 (2003): 3–20; D. H. Epstein et al., “Toward a model of drug relapse: An assessment of the validity of the reinstatement procedure.” Psychopharmacology (Berlin) 189, no. 1 (2006):1–16.

4. Work by Anh Dzung Lê and colleagues at the University of Toronto suggests that in the case of alcohol, priming is less potent than other stimuli, such as stress, in triggering relapse in rats. This is not the case with other drugs when these are studied in rats or in patients. I don’t know why this is. After all, it is not too shocking that there are limits to similarities between drug-seeking behavior in rats and humans.

5. This has been studied most extensively for reinstatement of cocaine seeking and to some extent that of heroin seeking, pointing to neighboring but somewhat different parts of the frontal lobes.

6. This insight parallels critical studies on extinction of learned fear by Joseph LeDoux in the 1990s.

7. J. R. Volpicelli et al., “Naltrexone in the treatment of alcohol dependence.” Archives of General Psychiatry 49, no. 11 (1992): 876–80.

8. American as well as European studies, by Linda Sobell and Mats Berglund, respectively, have suggested that some individuals with established alcoholism may in fact be able to successfully return to controlled drinking. But these are a minority, there is no way of knowing who they are ahead of time, and the consequences of relapse to heavy drinking can be disastrous for those who find they do not belong to that group. So my advice stands. Given the stakes, it seems reasonable to err on the side of caution.

1. C. P. O’Brien et al., “Conditioned narcotic withdrawal in humans.” Science 195, no. 4282 (1977): 1000–1002. The drug was naloxone, an injectable cousin of naltrexone, both of which I will discuss later. Both these drugs effectively block the mu-opioid receptor through which heroin produces its addictive effects. Subjects were maintained on methadone, and so the administration of naloxone in an instant reproduced a situation in which the addict is coming off heroin.

2. Although to a lesser degree, opiate addiction remains an occupational hazard among physicians with easy access to these medications

3. A. Wikler, “Dynamics of drug dependence: Implications of a conditioning theory for research and treatment.” Archives of General Psychiatry 28, no. 5 (1973): 611–16.

4. The baso-lateral amygdala, or BLA for short.

5. For a hilarious and thought-provoking review of this topic, see one of the classics of modern psychology: R. E. Nisbett and T. D. Wilson, “Telling more than we can know—verbal reports on mental processes.” Psychology Review 84, no. 3 (1977): 231–59.

6. S. Grant et al., “Activation of memory circuits during cue-elicited cocaine craving.” Proceedings of the National Academy of Science USA 93, no. 21 (1996): 12040–45.

7. A PET scan does not have the resolution to reliably distinguish between different parts of this structure, so we don’t know if these are exactly the same regions as those identified in the animal studies. But they are close enough.

8. H. Myrick et al., “Differential brain activity in alcoholics and social drinkers to alcohol cues: Relationship to craving.” Neuropsychopharmacology 29, no. 2 (2004): 393–402.

9. P. W. Kalivas and N. D. Volkow, “The neural basis of addiction: A pathology of motivation and choice.” American Journal of Psychiatry 162, no. 8 (2005): 1403–13.

10. R. K. Hester and W. R. Miller, Handbook of Alcoholism Treatment Approaches: Effective Alternatives (Boston: Allyn and Bacon, 2003).

11. Over decades of work, LeDoux has made some of the most important discoveries in the understanding of the biology of emotions. He has also written the best introductory text on the topic, the informative and enjoyable The Emotional Brain: The Mysterious Underpinnings of Emotional Life (New York: Simon and Schuster,1996). Although targeting an educated lay audience, that text is required reading for all new students and postdocs in my lab.

12. K. Nader et al., “Fear memories require protein synthesis in the amygdala for reconsolidation after retrieval.” Nature 406, no. 6797 (2000): 722–26; M. H. Monfils et al., “Extinction-reconsolidation boundaries: key to persistent attenuation of fear memories.” Science 324, no. 5929 (2009): 951–55.

13. Y. X. Xue et al., “A memory retrieval-extinction procedure to prevent drug craving and relapse.” Science 336, no. 6078 (2012): 241–45.

1. The names, places, and details of this account have been altered to de-identify them. The salient facts of the experience have not.

2. R. Sinha et al., “Effects of adrenal sensitivity, stress- and cue-induced craving, and anxiety on subsequent alcohol relapse and treatment outcomes.” Archives of General Psychiatry 68, no. 9 (2011): 942–52; R. Sinha et al., “Stress-induced cocaine craving and hypothalamic-pituitary-adrenal responses are predictive of cocaine relapse outcomes.” Archives of General Psychiatry 63, no. 3 (2006): 324–31.

3. A small, initial treatment trial would typically require 150–200 subjects, each of them treated for three to six months, and cost around $10 million.

4. According to medical convention, a “factor” is a hypothetical entity that has not yet been identified. Once it is purified and its molecular nature determined, it is elevated to a real “hormone.” CRF’s discoverer Wylie Vale stuck with the label “factor.” Out of respect for his great discovery, so did many of his trainees and collaborators. As a result, both names are now used, with medical textbooks often using the term “hormone,” that is, CRH.

5. Cortisol is the main stress hormone in humans and nonhuman primates. Its chemical relative corticosterone functions in this role in commonly used laboratory animals such as rats or mice. To avoid constantly making this distinction, researchers frequently use the abbreviation “cort,” which can refer to either of these.

6. For an in-depth explanation of stress physiology combined with hilarious fun, see R. Sapolsky, Why Zebras Don’t Get Ulcers (New York: Holt, 2004). Science for nonscientists doesn’t get better than that.

7. W. Vale et al., “Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin.” Science 213, no. 4514 (1981): 1394–97.

8. N. Eisenberger et al., “Does rejection hurt? An FMRI study of social exclusion.” Science 302, no. 5643 (2003): 290–92.

9. N. H. Naqvi et al., “Damage to the insula disrupts addiction to cigarette smoking.” Science 315, no. 5811 (2007): 531–34.

10. P. Maurage et al., “Disrupted regulation of social exclusion in alcohol-dependence: An FMRI study.” Neuropsychopharmacology 37, no. 9 (2012): 2067–75.

1. This particular saying may be equally or even more important in reminding us of the role of fetal alcohol exposure in reprogramming the brain.

2. R. C. Lewontin et al., Not in Our Genes: Biology, Ideology, and Human Nature (New York: Pantheon, 1985).

3. J. Locke, “An essay concerning human understanding” (1890). Although famous for this concept in modern times, Locke is not its originator. In the first psychology textbook ever written, De Anima, Aristotle wrote about the mind literally as “an unscribed tablet.” It seems, however, that this proposition did not gain much traction for a millennium or so.

4. In his highly recommended book The Blank Slate: The Modern Denial of Human Nature (New York: Penguin, 2002), Steven Pinker traces the origins of this notion, analyzes its influence in many areas of modern thought, and picks it apart in ways that are brilliant, funny, and ultimately necessary.

5. C. R. Cloninger et al., “Inheritance of alcohol abuse: Cross-fostering analysis of adopted men.” Archives of General Psychiatry 38, no. 8 (1981): 861–68. The temperance boards have long disappeared.

6. D. W. Goodwin et al., “Drinking problems in adopted and nonadopted sons of alcoholics.” Archives of General Psychiatry 31, no. 2 (1974): 164–69.

7. S. Sigvardsson et al., “Replication of the Stockholm Adoption Study of alcoholism: Confirmatory cross-fostering analysis.” Archives of General Psychiatry 53, no. 8 (1981): 681–87.

8. This is called “the equal environment assumption” (EEA) and was for a while under some debate. Although a legitimate methodological concern, it was frequently invoked as a last-ditch effort to dismiss robust findings of a genetic risk in behavioral disorders. This was largely put to rest by Ken Kendler of Virginia Commonwealth University, using real-world data—see e. g. Kendler et al., “Parental treatment and the equal environment assumption in twin studies of psychiatric illness.” Psychological Medicine 24, no. 3 (1994): 579–90.

9. D. Goldman et al., “The genetics of addictions: uncovering the genes.” Nature Reviews Genetics 6, no. 7 (2005): 521–32.

10. T. J. Bouchard and M. McGue, “Genetic and environmental influences on human psychological differences.” Journal of Neurobiology 54, no. 1 (2003): 4–45.

11. E. Turkheimer et al., “Socioeconomic status modifies heritability of IQ in young children.” Psychological Science 14, no. 6 (2003): 623–28.

12. M. Heilig et al., “Pharmacogenetic approaches to the treatment of alcohol addiction.” Nature Reviews Neuroscience 12, no. 11 (2011): 670–84.

13. K. S. Kendler et al., “The structure of genetic and environmental risk factors for common psychiatric and substance use disorders in men and women.” Archives of General Psychiatry 60, no. 9 (2003): 929–37.

14. Schuckit was first a medical student and then a resident at Washington University, an environment shaped by several pioneers of early psychiatric genetics. He frequently speaks of the formative influence and inspiration of that environment. Great places like that are what helps great people grow.

15. M. A. Schuckit, “Low level of response to alcohol as a predictor of future alcoholism.” American Journal of Psychiatry 151, no. 2 (1994): 184–89; M. A. Schuckit, T. L. Smith, “An 8-year follow-up of 450 sons of alcoholic and control subjects.” Archives of General Psychiatry 53, no. 3 (1996): 202.

16. M. B. Stein and D. J. Stein, “Social anxiety disorder.” Lancet 371, no. 9618 (2008): 1115–25.

17. Danielle studies impulsivity and has applied this concept just to that specific domain of behavioral traits, which itself needs to be “deconstructed” into its components. But the idea applies more broadly to addiction as a concept.

18. I. I. Gottesman and T. D. Gould, “The endophenotype concept in psychiatry: Etymology and strategic intentions.” American Journal of Psychiatry 160, no. 4 (2003): 636–45.

19. See, e. g., New York Times, April 18, 1991.

20. Other examples of genetic variation are chromosome rearrangements, where pieces of a chromosome get broken off from their right place and attached somewhere else, such as in some leukemias, or where a whole chromosome is duplicated, such as in Down syndrome. These types of variation are less common and typically result in much more severe consequences.

21. H. J. Edenberg et al., “Variations in GABRA₂, encoding the alpha 2 subunit of the GABA(A) receptor, are associated with alcohol dependence and with brain oscillations.” American Journal of Human Genetics 74, no. 4 (2004): 705–14.

22. T. E. Thorgeirsson et al., “A variant associated with nicotine dependence, lung cancer and peripheral arterial disease.” Nature 452, no. 7187 (2008): 638–42.

23. L. E. Hong et al., “A genetically modulated, intrinsic cingulate circuit supports human nicotine addiction.” Proceedings of the National Academy of Science USA 107, no. 30 (2010): 13509–14.

24. L. Bevilacqua et al., “A population-specific HTR₂B stop codon predisposes to severe impulsivity.” Nature 468, no. 7327 (2010): 1061–66.

1. See, e.g., R. L. Miller, The Encyclopedia of Addictive Drugs (Westport, Conn.: Greenwood Press, 2002).

2. J. O. Josefsson and P. Johansson, “Naloxone-reversible effect of opioids on pinocytosis in Amoeba proteus.” Nature 282, no. 5734 (1979): 78–80.

3. So named by the Swedish botanist Carl Linnaeus.

4. Since the name of the plant from which the drug is extracted, Papaver somniferum, means the “sleep-giving poppy,” the new substance is named after the Greek god of sleep and dreams, Morpheus.

5. A British chemist, Charles Romley Wright, had been the first to synthesize heroin, in 1874, but does not seem to have pursued his discovery further.

6. The recovery may take longer after use of very long-lasting opioids, such as methadone.

7. The exceptions are when people in the absence of treatment lose so much fluid that they need an intravenous line to replace it, but that is still not a big deal.

8. E. L. C. Merrall et al., “Meta-analysis of drug-related deaths soon after release from prison.” Addiction 105, no. 9 (2010): 1545–54.

9. E. Poeppig, Reise in Peru, Chile und auf dem Amazonenstrohme während der Jahre 1827–32, reviewed in English in Journal of the Geographical Society of London 6 (1836): 381–85.

10. J. V. Lloyd, “Coca, divine plant of the Incas,” Bulletin of Lloyd Library, Cincinnati, Ohio, pharrn. ser. 4, bull. 18 (1911): 18–25.

11. P. Mantegazza, “On the hygienic and medicinal properties of coca and on nervine nourishment in general,” Milan, 1858.

12. H. Markel, An Anatomy of Addiction: Sigmund Freud, William Halsted and the Miracle Drug, Cocaine (New York: Pantheon, 2011).

13. B. Giros et al., “Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter.” Nature 379, no. 6566 (379): 606–12.

14. Most people think that this is what the word “paranoia” means. It isn’t. Paranoia (from Greek para: “outside,” and nous: “intellect”) literally means “delusion” in Greek. “Paranoid delusions” would be to say “delusional delusions.”

15. The effects of alcohol on GABA signals is in some ways similar to those produced by the group of antianxiety drugs called benzodiazepines, of which Valium and Librium are probably the most famous members. This explains the many similarities between alcohol and benzodiazepine actions, and also why people addicted to either of those can substitute them for each other.

1. The wording is taken from the Web version of the same ad.

2. Clinical research distinguishes between “effectiveness,” which is what we ultimately really want, and “efficacy,” which is what we can establish in a reasonable clinical trial. The former is an ability to improve a meaningful clinical outcome—say, reduce mortality from stroke—when treatment is given to regular patients under real-world conditions. The latter is an ability to improve some potentially beneficial clinical measure—say, lower blood pressure—in the people included in a clinical trial, under the rather artificial conditions of that trial.

3. J. Lind, A Treatise of the Scurvy (Edinburgh: Sands, Murray, and Cochran, 1753).

4. The NIH, often viewed as a monolith, is in fact a group of disease-oriented institutes, in this case the National Institute on Alcohol Abuse and Alcoholism and the National Institute on Drug Abuse.

5. A better but somewhat less intuitive measure is Cohen’s D. Having one of these measures and knowing a couple of other things, one can calculate the other, but the math is not obvious and would take us too far.

6. There is, of course, a whole nonmedical industry that does just that, perhaps not with cancer but certainly with hypertension, diabetes, and other fundamentally medical conditions. This industry, why you should not fall prey to it, and the history and foundations of evidence-based medicine are described in entertaining and informative ways in E. Ernst and S. Singh, Trick or Treatment: The Undeniable Facts About Alternative Medicine (New York: Norton, 2008).

7. R. K. Hester and W. R. Miller, Handbook of Alcoholism Treatment Approaches: Effective Alternatives (Boston: Allyn and Bacon, 1989).

8. See, e.g., A. T. McLellan et al., “The addiction severity index at 25: Origins, contributions, and transitions.” American Journal of Addiction 15, no. 2 (2006): 113–24.

9. A. Bandura, “Self-efficacy—toward a unifying theory of behavioral change.” Psychology Review 84, no. 2 (1977): 191–215.

1. B. L. Burke, “The efficacy of motivational interviewing: A meta-analysis of controlled clinical trials.” Journal of Consulting and Clinical Psychology 71, no. 5 (2003): 843–61.

2. J. B. Saunders et al., “Development of the Alcohol Use Disorders Identification Test (AUDIT): WHO Collaborative Project on Early Detection of Persons with Harmful Alcohol Consumption—II.” Addiction 88, no. 6 (1993): 791–804; available from the NIAAA at http://pubs.niaaa.nih.gov/publications/Practitioner/CliniciansGuide2005/clinicians_guide11.htm.

3. A. Moyer et al., “Brief interventions for alcohol problems: A meta-analytic review of controlled investigations in treatment-seeking and non-treatment-seeking populations.” Addiction 97, no. 3 (2002): 279–92.

4. M. Berglund et al., Treating Alcohol and Drug Abuse: An Evidence Based Review(Weinheim: Wiley-VCH, 2003).

5. E. V. Nunes and F. R. Levin, “Treatment of depression in patients with alcohol or other drug dependence: A meta-analysis.” JAMA 291, no. 15 (2004): 1887–96.

6. I really don’t like this term. There are no “toxins” from which the body needs to be cleansed to initiate abstinence. But the proper alternative is “medically assisted withdrawal,” which is just too long.

7. T. H. Brandon et al., “Relapse and relapse prevention.” Annual Review of Clinical Psychology 3 (2007): 257–84.

8. E. L. C. Merrall et al., “Meta-analysis of drug-related deaths soon after release from prison.” Addiction 105, no. 9 (2010): 1545–54.

9. K. Witkiewitz and G. A. Marlatt, “Relapse prevention for alcohol and drug problems: That was Zen, this is Tao.” American Psychologist 59, no. 4 (2004): 224–35.

10. Actually, it is all behavioral. Cognitions are behaviors, too. There is no difference, in principle, between sending electric impulses to muscles to initiate movement and sending them to neurons to initiate thoughts. But that is a separate discussion.

11. D. Epstein et al., “Real-time electronic diary reports of cue exposure and mood in the hours before cocaine and heroin craving and use.” Archives of General Psychiatry 66, no. 1 (2009): 88–94.

12. J. Peters et al., “Extinction circuits for fear and addiction overlap in prefrontal cortex.” Learning and Memory 16, no. 5 (2009): 279–88.

13. P. Monti, Treating Alcohol Dependence: A Coping Skills Training Guide. 2nd ed. (New York: Guilford Press, 2002).

14. M. Prendergast et al., “Contingency management for treatment of substance use disorders: A meta-analysis.” Addiction 101, no. 11 (2006): 1546–60.

15. V. Hunot et al., “‘Third wave’ cognitive and behavioural therapies versus other psychological therapies for depression.” Cochrane Database of Systematic Reviews 2013, issue 10, art. no. CD008704. DOI: 10.1002/14651858. CD008704.

1. The more standard nomenclature, which I have followed, is “opioid receptors,” that is, receptors for substances that are either opiates themselves, such as, prototypically, morphine, or similar to those, and so in Greek -oid (as in “android,” “like a human”).

2. R. P. Mattick et al., “Methadone maintenance therapy versus no opioid replacement therapy for opioid dependence.” Cochrane Database of Systematic Reviews 2009, no. 3: CD002209.

3. A. T. McLellan et al., “The effects of psychosocial services in substance abuse treatment.” JAMA 269, no. 15 (1993): 1953–59.

4. K. L. Sees et al., “Methadone maintenance vs 180-day psychosocially enriched detoxification for treatment of opioid dependence: A randomized controlled trial.” JAMA 283, no. 10 (2000): 1303–10.

5. See, e. g., L. M. Gunne et al., “Treatment characteristics and retention in methadone maintenance: High and stable retention rates in a Swedish two-phase programme.” Heroin Addiction and Related Clinical Problems 4, no. 1 (2002): 37.

6. J. Kakko et al., “A stepped care strategy using buprenorphine and methadone versus conventional methadone maintenance in heroin dependence: A randomized controlled trial.” American Journal of Psychiatry 164, no. 5 (2007): 797–803.

7. L. Gronbladh et al., “Mortality in heroin addiction: Impact of methadone treatment.” Acta Psychiatrica Scandinavica 82, no. 3 (1990): 223–27.

8. National Institute on Drug Abuse, Johns Hopkins University, and Reckitt Benckiser. Many people deserve credit, but the one I cannot leave out is Ed Johnson, the pharmacist who made much of this happen both while at Hopkins and after he transitioned to the industry.

9. R. E. Johnson et al., “A comparison of levomethadyl acetate, buprenorphine, and methadone for opioid dependence.” New England Journal of Medicine 343, no. 18 (2003): 1290–97.

10. R. P. Mattick et al., “Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence.” Cochrane Database of Systematic Reviews 2008, no. 2: CD002207.

11. J. Kakko et al., “1-year retention and social function after buprenorphine-assisted relapse prevention treatment for heroin dependence in Sweden: A randomised, placebo-controlled trial.” Lancet 361, no. 9358 (361): 662–68.

12. D. A. Fiellin et al., “Counseling plus buprenorphine-naloxone maintenance therapy for opioid dependence.” New England Journal of Medicine 355, no. 4 (2006): 365–74.

13. When taken by the mouth, naloxone will not reach the brain or other interior organs. But it will still be present in the gut, which in a way is on the “outside” of the body. The constipation I described that methadone patients experience and that is also a problem when cancer pain is treated with opioid painkillers turns out to be an effect of opioid receptor activation in the gut. When naloxone is taken by mouth, for example, as an additive to the methadone syrup, the gut receptors will still be blocked, and constipation will be less of a problem. Quite a useful application of pharmacology.

14. P. J. Fudala et al., “Office-based treatment of opiate addiction with a sublingualtablet formulation of buprenorphine and naloxone.” New England Journal of Medicine 349, no. 10 (2003): 949–58.

15. These days I don’t even have to think about it—as a U.S. government employee, I am simply not allowed to have one.

16. S. Minozzi et al., “Oral naltrexone maintenance treatment for opioid dependence.” Cochrane Database of Systematic Reviews 2011, no. 4: CD001333.

17. S. D. Comer et al., “Injectable, sustained-release naltrexone for the treatment of opioid dependence: A randomized, placebo-controlled trial.” Archives of General Psychiatry 63, no. 2 (2006): 210–18.

18. Kakko et al., “A stepped care strategy using buprenorphine and methadone versus conventional methadone maintenance in heroin dependence.”

19. L. F. Stead et al., “Nicotine replacement therapy for smoking cessation.” Cochrane Database of Systematic Reviews 2008, no. 1: CD000146.

20. K. Cahill et al., “Nicotine receptor partial agonists for smoking cessation.” Cochrane database of systematic reviews 2012, no. 4: CD006103.

21. There are different types of nicotinic receptors. One important category sends signals from nerves to muscles. These are only blocked to put people down for surgery and if blocked otherwise would make smokers quit more than their smoking.

22. R. Spanagel, “Alcoholism: A systems approach from molecular physiology to addictive behavior.” Physiological Reviews 89, no. 2 (2009): 649–705.

23. M. Heilig et al., “Pharmacogenetic approaches to the treatment of alcohol addiction.” Nature Reviews Neuroscience 12, no. 11 (2011): 670–84.

24. C. H. Jorgensen et al., “The efficacy of disulfiram for the treatment of alcohol use disorder.” Alcoholism: Clinical and Experimental Research 35, no. 10 (2011): 1749–58.

25. H. L. Altshuler et al., “Alteration of ethanol self-administration by naltrexone.” Life Sciences 26, no. 9 (1980): 679–88.

26. J. Volpicelli et al., “Naltrexone in the treatment of alcohol dependence.” Archives of General Psychiatry 49, no. 11 (1992): 876–80; S. O’Malley et al., “Naltrexone and coping skills therapy for alcohol dependence: A controlled study.” Archives of General Psychiatry 49, no. 11 (1992): 881–87.

27. S. Rosner et al., “Opioid antagonists for alcohol dependence.” Cochrane Database of Systematic Reviews 2010, no. 12: CD001867.

28. R. F. Anton et al., “Combined pharmacotherapies and behavioral interventions for alcohol dependence: The COMBINE study: A randomized controlled trial.” JAMA 295, no. 17 (2006): 2003–17.

29. It took until 2012 before release of endorphins in the brain in response to alcohol intake was directly shown in a PET study: J. M. Mitchell et al., “Alcohol consumption induces endogenous opioid release in the human orbitofrontal cortex and nucleus accumbens.” Science Translational Medicine 4, no. 116 (2012): 116ra6.

30. C. Bond et al., “Single-nucleotide polymorphism in the human mu opioid receptor gene alters beta-endorphin binding and activity: Possible implications for opiate addiction.” Proceedings of the National Academy of Sciences USA 95, no. 16 (1998): 9608–13.

31. D. W. Oslin et al., “A functional polymorphism of the mu-opioid receptor gene is associated with naltrexone response in alcohol-dependent patients.” Neuropsychopharmacology 28, no. 8 (2003): 1546–52.

32. C. S. Barr et al., “Association of a functional polymorphism in the mu-opioid receptor gene with alcohol response and consumption in male rhesus macaques.” Archives of General Psychiatry 64, no. 3 (2007): 369–76.

33. Remember, we all carry two copies of most genes. The exceptions are the few genes that are located on the sex chromosomes, X and Y. The gene for the mu-opioid receptor is not one of those; in humans it is located on chromosome 6.

34. N. B. Urban et al., “Sex differences in striatal dopamine release in young adults after oral alcohol challenge: A positron emission tomography imaging study with [11C]raclopride.” Biological Psychiatry 68, no. 8 (2010): 689–96. It has been suggested that this difference may contribute to the 2:1 ratio in alcoholism rates between men and women.

35. V. A. Ramchandani et al., “A genetic determinant of the striatal dopamine response to alcohol in men.” Molecular Psychiatry 16, no. 8 (2011): 809–17.

36. A. J. Chamorro et al., “Association of mu-opioid receptor (OPRM1) gene polymorphism with response to naltrexone in alcohol dependence: A systematic review and meta-analysis.” Addiction Biology 17, no. 3 (2012): 505–12.

37. A. B. Whitworth et al., “Comparison of acamprosate and placebo in long-term treatment of alcohol dependence.” Lancet 347, no. 9013 (1996): 1438–42; H. Sasset al., “Relapse prevention by acamprosate: Results from a placebo-controlled study on alcohol dependence.” Archives of General Psychiatry 53, no. 8 (1996): 673–80.

38. B. J. Mason and P. Lehert, “Acamprosate for alcohol dependence: A sex-specific meta-analysis based on individual patient data.” Alcoholism: Clinical and Experimental Research 36, no. 3 (2012): 497–508.

39. B. J. Mason et al., “Effect of oral acamprosate on abstinence in patients with alcohol dependence in a double-blind, placebo-controlled trial: The role of patient motivation.” Journal of Psychiatric Research 40, no. 5 (2006): 383–93.

40. R. F. Anton et al., “Combined pharmacotherapies and behavioral interventions for alcohol dependence: The COMBINE study: A randomized controlled trial.” JAMA 295, no. 17 (2006): 2003–17.

41. Rats don’t have the different genetic variants that in humans determine who will respond to naltrexone.

42. R. Rimondini et al., “Long-lasting increase in voluntary ethanol consumption and transcriptional regulation in the rat brain after intermittent exposure to alcohol.” FASEB Journal 16, no. 1 (2002): 27–35.

43. R. Spanagel et al., “The clock gene Per2 influences the glutamatergic system and modulates alcohol consumption.” Nature Medicine 11, no. 1 (2005): 35–42; J. C. Umhau et al., “Effect of acamprosate on magnetic resonance spectroscopy measures of central glutamate in detoxified alcohol-dependent individuals: A randomized controlled experimental medicine study.” Archives of General Psychiatry 67, no. 10 (2010): 1069–77.

44. B. A. Johnson et al., “Oral topiramate for treatment of alcohol dependence: A randomised controlled trial.” Lancet 361, no. 9370 (2003): 1677–85; B. A. Johnson et al., “Topiramate for treating alcohol dependence: A randomized controlled trial.” JAMA 298, no. 14 (2007): 1641–51.

45. G. Addolorato et al., “Effectiveness and safety of baclofen for maintenance of alcohol abstinence in alcohol-dependent patients with liver cirrhosis: Randomised, double-blind controlled study.” Lancet 370, no. 9603 (2007): 1915–22.

1. German: “Die Religion … ist das Opium des Volkes.” Full citation: “Religion is the sigh of the oppressed creature, the heart of a heartless world, and the soul of soulless conditions. It is the opium of the people.” Karl Marx, Deutsch-Französische Jahrbücher (1844).

2. The actual title of the book is Alcoholics Anonymous: The Story of How Many Thousands of Men and Women Have Recovered from Alcoholism.

3. Long-term follow-up studies by, for example, Linda Sobell have shown that this is not quite true. A minority of people with a formal alcoholism diagnosis are in fact able to return to controlled social drinking. These results provoked considerable controversy but have been confirmed by independent studies such as one by Berglund and colleagues in Scandinavia. The problem is, of course, that we have no way of knowing who will be in the minority that will succeed. If it were my life, I would not gamble with that kind of odds.

4. People almost never show this when they publish results of medication studies. One of the few cases where this was shown was the groundbreaking paper that evaluated Vivitrol, a depot formulation of naltrexone for alcoholism: J. C. Garbutt et al., “Efficacy and tolerability of long-acting injectable naltrexone for alcohol dependence: A randomized controlled trial.” JAMA 293, no. 13 (2005): 1617–25.

5. M. Ferri et al., “Alcoholics Anonymous and other 12-step programmes for alcohol dependence.” Cochrane Database of Systematic Reviews 2006, no. 3: CD005032.

6. As earlier chapters have discussed, methadone and buprenorphine maintenance for opioid addiction are special cases and are highly effective compared to most treatments in clinical medicine.

7. The AA Grapevine, at http://www.aagrapevine.org/content/about-us.

8. An area that remains contentious is the use of medications such as methadone and buprenorphine, with their own addictive potential. But even there some interesting developments are under way. I will return to those shortly.

9. At the time of this writing, the study is still ongoing.

10. If I understand things correctly, the original idea was to make the Old Lodge a retreat for clergy with alcoholism. This was soon broadened to include other professionals.

11. Although contracts with insurers are good in the sense that they expand access to treatment, they are not without their complications. The negotiated contract reimbursement is heavily discounted, increasing the pressure for cost savings or greater revenue elsewhere.