The Addicted Brain (22 page)

We don’t think of caffeine as a drug, but it does produce intoxication and withdrawal signs, and it is perhaps the most widely used psychoactive (mind-altering) substance in the world. It is a stimulant, but it is different from the psychostimulants like cocaine because its mechanism of action is different. It does not affect the dopamine system directly. Rather, caffeine blocks subtypes of receptors for another neurotransmitter, adenosine.

Caffeine is called a mild stimulant and is found in coffee, tea, sodas, chocolate, and some medicines. It increases alertness and wakefulness, and it produces feelings of increased energy. It improves reactions and reaction time and enhances cognitive functioning. Within reasonable limits, it is considered safe, and you wouldn’t mind if your pilot was taking it! However, if a high dose—perhaps more than three cups—is taken, unpleasant symptoms appear that include restlessness, nervousness, anxiety, insomnia, high blood pressure, frequent urination, and stomach complaints. Yet higher doses can produce muscle twitching, rapid heartbeat, abnormal heart rhythms, and a rambling thought pattern. There is some concern that the current trend among energy drinks to increase caffeine to higher levels may be somewhat dangerous.

Tolerance does occur, and, after drinking it for some time, you might need a higher dose to get the same expected effect. After becoming accustomed to as few as one or two cups per day, cessation of caffeine intake can produce withdrawal that consists mainly of feelings of fatigue and tiredness. Withdrawal can also include, particularly after higher doses, headache, nausea, and vomiting, but the latter is rare. Because few caffeine drinkers report loss of control of
intake or have a great difficulty in stopping caffeine use, it is not listed as an addicting stimulant.
¹⁰

The seven classes of abused and addicting drugs discussed in this chapter also have many additional and varying effects on the body and brain. Although addiction is a serious effect of using drugs, there are other effects of the drugs that are also serious. Because each drug class is different and because each drug in the class can be somewhat different from the others in its class, there are many different kinds of side effects. Some are subtle, such as the reduction in cognitive ability after marijuana, and some are seriously toxic, such as the increase in risk for respiratory disease and cancer after smoking. Although therapeutic medications prescribed by doctors for various illnesses also have side effects, the patient can stop taking them when trouble appears, but the addicts do not stop. They tolerate the side effects and the problems can get serious and chronic. Therefore, it is of extreme importance for everyone to recognize not only the threat of addiction, but also the other harmful and potentially life-threatening properties of these drugs.

¹
For example, see Hecht S.S. et al. “Similar Uptake of Lung Carcinogens by Smokers of Regular, Light, and Ultralight Cigarettes.”
Cancer Epidemio Biomarkers Prev
, 14: 693–698, 2005.

²
An example of a study showing withdrawal symptoms from cannabis is: Levin K.H. et al. Cannabis Withdrawal Symptoms in Nontreatment-Seeking Adult Cannabis Smokers.”
Drug Alc Dep
111: 120–127. This is an interesting topic because cannabis withdrawal is noted in the
DSM-IV-TR
, because of uncertainties about its clinical importance.

³
Han B. et al. “Associations between Duration of Illicit Drug Use and Health Conditions: Results from the 2005–2007 National Surveys on Drug Use and Health.”
Ann Epidemiol
, 20: 289–97. The National Institute on Drug Abuse has recently produced a report, “Marijuana Abuse,” which can be viewed at
www.nida.nih.gov/ResearchReports/Marijuana/default.html
, accessed on June 1, 2011.

⁴
It has been found that marijuana smoking impaired pilot performance for up to 24 hours. Nine active pilots smoked one cigarette containing 20 mg of delta-9-THC, and a placebo (no drug) cigarette. Using an aircraft simulator, seven of the nine pilots showed impairment at 24 hours after smoking the drug. There was no impairment at 48 hours after or before smoking the drug. Interestingly, only one of the seven said he felt the drug. Thus, significant impairment can be maintained for up to 24 hours after smoking marijuana, even though you might not be aware of any effect of the drug at that time. It can be argued that most users do not take that much drug or that the simulator test was especially sensitive. In any case, the negative cognitive effects of marijuana can last many hours. From Leirer, V.O. et al. “Marijuana Carry-Over Effects on Aircraft Pilot Performance.”
Aviat Space Enviro Med
, 62: 221–227, 1991.

⁵
Cocaine is addicting because it blocks the dopamine transporter. This was discovered in an experiment that compared the potency of the addicting properties of several cocaine-like drugs and in their capabilities to block transporters. The potency of the drugs in causing addiction in an animal model correlated only with their capabilities to block the dopamine transporter, not other transporters. Only cocaine-like compounds and methylphenidate that do not cause release of dopamine, but only block uptake of dopamine, were included in the study. See Ritz, M.C. et al. “Cocaine Receptors on Dopamine Transporters Are Related to Self-Administration of Cocaine.”
Science
237: 1219–1223, 1987.

⁶
The following is a brief summary of the history of the dopamine story and drug addiction. It is a personal communication from Dr. Roy Wise, a longtime, productive researcher in this field.

The earliest work was by Olds (a) who showed that nonselective drugs like chlorpromazine and reserpine (whose effects included a blunting of dopamine’s effects) antagonized electrical brain stimulation reward. Larry Stein generated a theory of reward that proposed that norepinephrine was the key neurotransmitter, but this was not supported by subsequent data (b, c). When selective dopamine antagonists became available, they, and selective destruction of dopamine-containing neurons showed effects on reward. This implicated dopamine and not norepinephrine or other neurotransmitters in brain stimulation reward (d, e). Roy Pickens and Harris were the first to suggest that the substrates of brain stimulation reward and psychostimulant reward were perhaps the same (f).

Bob Yokel and I (g) and Davis and Smith (h) were the first to show that amphetamine lost its rewarding action if the dopamine system was selectively blocked, and Harriet de Wit and I (i) and Risner and Jones (j) showed the same result with cocaine. Dave Roberts showed that selective dopamine (but not norepinephrine) lesions disrupted cocaine reward (k). These were the first studies to show that dopamine function was necessary for cocaine and amphetamine reward. Bob Yokel and I then showed that a dopamine agonist, apomorphine, (a compound that directly stimulated dopamine receptors) was self-administered (g, l), which confirmed that dopamine activation was also sufficient for drug-related reward. Ritz et al. (m) took the story further by showing that the initial site of action of cocaine and the psychostimulants—specifically for their rewarding and reinforcing actions—was the dopamine transporter rather than some other site. Initial work in knockout mice suggested that cocaine might still be rewarding in animals lacking the dopamine transporter (n), but
more recent work questions this finding and shows, rather, the opposite (o).

(a) J. Olds, K. F. Killam, P. Bach y Rita,
Science
124, 265 (1956). (b) L. Stein,
J Psychiat Res
8, 345 (1971). (c) S. K. Roll,
Science
168, 1370 (1970). (d) A. S. Lippa, S. M. Antelman, A. E. Fisher, D. R. Canfield,
Pharmacology Biochemistry and Behavior
1, 23 (1973). (e) G. Fouriezos, R. A. Wise, Brain Research 103, 377 (Feb 20, 1976). (f) R. Pickens, W. C. Harris,
Psychopharmacologia
12, 158 (1968). (g) R. A. Yokel, R. A. Wise,
Science
187, 547 (Feb 14, 1975). (h) W. M. Davis, S. G. Smith,
Journal of Pharmacy and Pharmacology
27, 540 (1975). (i) H. de Wit, R. A. Wise,
Can J Psychol
31, 195 (1977). (j) M. E. Risner, B. E. Jones,
Psychopharmacology
71, 83 (1980). (k) D. C. S. Roberts, M. E. Corcoran, H. C. Fibiger, P
harmacology Biochemistry and Behavior
6, 615 (1977). (l) R. A. Yokel, R. A. Wise,
Psychopharmacology (Berl)
58, 289 (July 19, 1978). (m) Ritz M.C. et al., 1987.
Science
237: 1219–1223. (n) B. A. Rocha et al.,
Nature Neuroscience
1, 132 (1998). (o) M. Thomsen, D. D. Han, H. H. Gu, S. B. Caine,
J Pharmacol Exp Ther
331, 204 (2009).

⁷
The
Oregonian
newspaper did a special report on methamphetamine, which is found at the site
http://www.pbs.org/wgbh/pages/frontline/meth/body/
. Deputy Brett King, from Oregon’s Multno-mah County Sheriff’s Dept, used mug shots to compare the faces of meth users before and after they used the drug. The changes in the eyes, overall expression, teeth, and body weight were astonishing. Methamphetamine, like the other most addicting drugs, can take over your life to the point when you fail to maintain your health. See also
http://www.oregonlive.com/news/oregonian/photos/gallery.ssf?cgi-bin/view_gallery.cgi/olive/view_gallery.ata?g_id=2927
, accessed on July 1, 2011.

⁸
For example, Cowan R.L. et al. “Reduced Cortical Gray Matter Density in Human MDMA (Ecstasy) Users.”
Drug Alcohol Depend
,= 72: 225–235, 2003.

⁹
See
http://www.snopes.com/horrors/drugs/facepeel.asp
for a discussion of this amazing story.

¹⁰
DSM-IV-TR
, Fourth edition, Washington DC: American Psychiatric Association, 2000.

A desperate young woman who has been addicted to crack cocaine for some years is considering entering treatment—for a second time. The last time, it just didn’t work. “Maybe I just wasn’t ready,” she said. “I have a very irrational fear of gaining back a lot of the weight that I lost when I started using crack. Extra weight has been a lifelong problem for me and I have a hard time dealing with it.” Also, there were many more men than women in her treatment group. “Whether they did or not, the men didn’t seem to have much sympathy for my problems.” She also felt her responses to issues and questions were a little different from the men’s, and she withdrew emotionally. “I never had much confidence around older men, and for personal reasons, I’m a little afraid of them.” But, this time, with the advice of friends, she has decided to ask for a treatment group or program that focuses on women. “Maybe this is petty, but I really need all the help I can get right now.”

A recent, popular book tells us that men and women are from different planets! Well, we certainly are different in many, obvious ways, and sometimes in ways that are not so obvious. Even our brain sizes are slightly different from an early age. No data has informed us whether the small difference in brain size confers any special attribute on either sex, and there is no reason to assume that it does. After all, there is evidence that the size of the Neanderthal adult brain was larger than ours.
¹
But this difference in brain size emphasizes how pervasive these sex differences, even though small, can be.

Many studies over many years have shown that there are important differences between how men and women react to drugs. Female alcoholics begin drinking later in life than men. Because they appear for treatment at about the same age, it is suggested that alcoholism progresses faster in women. Women alcoholics drink less than men at about 9 drinks per week compared to more than 16 drinks for men. They are more likely than men to report a past stressful event as a reason for drinking, and are more likely to have a second diagnosis, particularly depression. They also have a greater history of suicide attempts than either males or nonalcoholic women (about four times more frequent than nonalcoholic women).

The findings with illicit drugs are generally similar, but there are some differences. Drug dependent women enter treatment at a younger age than men. They are more likely to go voluntarily to treatment than men and are more likely to report suicide attempts. Women are more likely to say that stress and anxiety were the cause of relapse, whereas men more often seek the pleasurable effects of the drugs in relapse. Regarding adolescent women using cocaine, the National Household Survey by the National Institute on Drug Abuse found a higher rate of cocaine dependence than in men, and more symptoms with lower doses of the drug. The latter suggests that women are more sensitive than men to cocaine. Among marijuana and opiate users, women again progress to addiction faster than men. Among smokers, women have higher rates of addiction and are more sensitive to nicotine in that they show symptoms at lower doses than men. Women in treatment more often report a concern with weight gain and express a desire for all-women treatment groups.

Women also experience drugs somewhat differently than men. Women report more nervousness than men after intranasal cocaine, experience less euphoria, take more time to feel the effects of a dose of cocaine, and seem to crave more strongly than men in response to cocaine-related cues. There are also reports that they use more of the drug than men.

Because women show different behavioral patterns and responses to some drugs compared to men, there may be sex differences in the parts of the brain that cause drug addiction. Inevitably, this has raised the question of whether treatments need to be tailored specifically to women’s needs to be most effective.
²

Because of the importance of this topic, there have been many interesting laboratory studies that support the idea of sex differences. For example, female rats show greater behavioral responses than males after cocaine administration. They require lower doses than males to produce the same kind of responses, and the responses last longer than those in males. In cocaine self-administration studies, female rats take cocaine faster and more often than males. There are also sex differences in responses to opiates. Dr. Ann Z. Murphy, her colleagues, and others have noted that morphine is more effective in men than women for treating pain. Interestingly, there are corresponding sex differences in the anatomy of pain pathways in the lower brain and spinal cord.