Biosynthesis of Alkaloids
(Click on image to enlarge [1])


DRUG [3]
% who get addicted
after trying
Tobacco
31.9
Heroin
23.1
Cocaine
16.7
Alcohol
15.4
Tobacco Users Smoke Crack
Recently uncovered internal tobacco industry memos and reports reveal that industry executives knew of the addictive nature of nicotine long before they disclosed this information to the public. In this profiled document [1], industry researchers discuss the similarities between nicotine, the addictive chemical in tobacco products, and drugs like cocaine, heroin and marijuana. Although the industry knew -- more than 30 years ago -- of the highly addictive nature of modern tobacco products, few people are aware that smoking cigarettes is similar to smoking crack cocaine.

The graphic at left illustrates the biosynthesis of alkaloids. Common alkaloids are cocaine, heroin and nicotine. As seen in the expanded illustration, nicotine and cocaine are very close "cousins" [2]. The media, and our society in general, place great emphasis on the negative social aspects of illicit substances like cocaine and heroin. Yet, as this evidence shows, nicotine and cocaine are essentially the same drug.

More importatntly, the table at left highlights the superior addictiveness of nicotine. Tragically, one quarter of the U.S. population functions daily only by taking hundreds of "hits" from a highly addictive chemical. This drug alters their mental functions, corrupts rationality, and literally, takes control over lives.


"We solemnly swear..."
In 1994 tobacco industry executives stood before the U.S. Congress and testified UNDER OATH that cigarettes are not addictive. Since the 1970s, tobacco companies knew that nicotine, found naturally in tobacco plants, is highly addictive, and more importantly, that it could be manipulated to increase the popularity of their cigarettes [see Philip Morris letter, RJ Reynolds document]. In a 1977 Philip Morris document, author W.L. Dunn instructs T.S. Osdene that the Philip Morris scientists will bury the results of a study on nicotine if the outcomes prove similar to "morphine and caffein" (sic) [read document]. The tobacco industry has known for decades that nicotine is a highly addictive drug. The paragraph below comes from a RJ Reynolds document:

Most cigarette smokers begin smoking at an early age. They smoke for some period, attempt to quit, but then relapse. This sequence is similar to that for drugs of abuse. For example, both the opium and tobacco habits develop quite rapidly. Cocteau's dictum, regarding opium smoking, that "he who smoked will smoke," is equally true for tobacco smoking. In both cases, simple exposure to the substance ("experimentation") usually leads to repeated and then chronic use. To the extent that experimentation leads to chronic use, tobacco appears to have "an addictive potential" similar to that of opium. [RJ Reynolds Document p2]


America's Kids Are Crack Addicts...
Over 80% of smokers become addicted to tobacco and nicotine before they reach the age of 18 (Learn More About Nicotine). As a society, we tolerate youth smoking. We believe, falsely, there are worse problems. This myth has been perpetuated in part by the tobacco industry. The table below lists the annual death toll in the US, Britain and Australia due to addictive drugs: tobacco, alcohol and all the illicit drugs combined (powder and crack cocaine, heroin, and others) [4].


TOBACCO
ALCOHOL
ILLICIT DRUGS
Annual Death Toll
Annual Death Toll
Annual Death Toll
U.S. = 450,000
U.S. = 81,000
U.S. = 14,000
U.K. = 120,000
U.K. = 40,000
U.K. = 3,000
Australia = 19,019
Australia = 3,271
Australia = 1,023


Nicotine to the brain For a drug to be addictive, it must get to the brain quickly. Injected heroin gets to the brain in about 15 seconds, giving the user an explosive "high." Nicotine from tobacco smoke gets there even faster. It takes about seven (7) seconds to travel from the lungs to the brain -- (see special on How Tobacco Companies Free-base, or Super Charge, Nicotine).

Once in the brain, nicotine minics a chemical called acetylcholine and bonds with nerve cells scientists refer to as "nicotine receptors." These receptors are "entry gates" to the cells and the specific chemicals activate the receptors. The chemicals "fit" the receptor cells like a key sliding into a lock.

We call these chemicals neurotransmitters. They function as a postal system for the brain by delivering instructions to different cells and causing chemical reactions to occur [5].

Nicotine "hijacks" many of the receptors meant to receive acetylcholine and causes the release of other chemicals such as dopamine, serotonin and noradrenaline. These reactions create the "high" associated with smoking. The neurotransmitters make the smoker feel happy, alert or stimulated and affect the mood of the addicted user [6].


Getting "high" on Nicotine
Researchers believe smoking causes an increase in the amount of "feel good" chemicals present in the smoker's brain. As the person continues to smoke, his/her brain actually creates more nicotine receptors with which to "catch" the drug. This means that when the smoker stops smoking abruptly, all these receptors become "hungry" for their habitual dose of nicotine. This hunger is responsible for the physical cravings for a cigarette. The sudden drop in the levels of dopamine and other neurotransmitters in the smoker's brain when he/she quits result in low moods and depression that so many people experience when they try to quit [7]. The crack cocaine user goes through similar, although more intense, withdrawals upon cessation: the initial short-lived euphoria will be followed by a "crash." This involves anxiety, depression, irritability, extreme fatigue and possibly paranoia.

Exerts from: "Nicotine Addiction in Britain: A report of the Tobacco Advisory Group of the Royal College of Physicians," RCP Publications, February 2000
Cigarette smoking should be understood as a manifestation of nicotine addiction, and that the extent to which smokers are addicted to nicotine is comparable with addiction to 'hard' drugs such as heroin or cocaine. This conclusion has fundamental implications for the design and implementation of public health policy on the control and prevention of cigarette smoking.

9.1 Tobacco and nicotine addiction
The unique selling point of tobacco is its nicotine content - tobacco products without nicotine are not commercially viable. Nicotine is an addictive drug, and the primary purpose of smoking tobacco is to deliver a dose of nicotine rapidly to receptors in the brain. This generates a pleasurable sensation for the smoker which, with repeated experience, rapidly consolidates into physiological and psychological addiction reinforced by pronounced withdrawal symptoms.

The presence of nicotine is necessary, but not sufficient, for the nicotine to have a powerful psychoactive impact. To achieve the latter, nicotine must also be delivered rapidly to the brain. Tobacco smoke inhalation is the most highly optimised vehicle for nicotine administration because absorption through the lungs delivers nicotine to the brain rapidly and intensively. The potency of the nicotine effect is created by the speed of delivery, not just by the total nicotine delivered. The speed of nicotine delivery is a fundamental difference between cigarettes and nicotine replacement therapy (NRT) products which deliver nicotine at lower and slower subaddictive rates. For this reason, nicotine delivered through tobacco smoke should be regarded as a powerfully addictive drug, and smoking as the means of nicotine self-administration. The risk of addiction to NRT products is very low, but they are effective in attenuating cravings and withdrawal from tobacco-delivered nicotine dependence.

In its usual dose range, nicotine use does not cause intoxication or intense euphoria, but does have a complex physiological impact which creates dependency reinforced by withdrawal. The fact that nicotine does not intoxicate does not make it less addicting, but may explain why medical bodies and governments have not generally recognised tobacco use as a form of drug addiction or dependence. It is far from clear that benefits attributed to nicotine use such as stress relief, improved mood and enhanced cognitive performance are real. Many perceived benefits are actually attributable to the relief of nicotine withdrawal symptoms.

Although nicotine in the form of tobacco is a legal drug, it should not be regarded as pharmacologically benign. The classification of drugs as 'legal', 'soft' or 'hard' reflects public perceptions and current law enforcement practice, rather than constituting a useful pharmacological classification. In terms of addictiveness, nicotine delivered in tobacco smoke is a 'hard' drug on a par with heroin and cocaine. The status of nicotine as a seemingly innocuous legal drug, and attempts for many years by the tobacco industry to equate addiction to nicotine with addiction to substances such as coffee, colas or chocolate, have distracted attention from the highly addictive nature of nicotine in cigarettes.

9.2 Consequences of nicotine addiction
The principal adverse consequences of nicotine addiction are the morbidity and mortality caused by active and passive smoking. Nicotine addiction is the primary reason why smokers find it difficult to give up smoking. Most people begin smoking and become addicted to nicotine as teenagers. This addiction may then cause tobacco use to continue long after an informed adult choice has been made to stop smoking on the grounds of a change in attitude to health, changed circumstances such as starting work in a smoke-free office, starting a family or other reasons. This characteristic of tobacco use - an attenuation of free choice initiated in childhood - is a central plank of the case for government intervention to control tobacco use through measures such as advertising bans, tax increases, anti-smoking communications and cessation support, and to regulate the availability and safety of nicotine products.

Nicotine addiction is closely linked to socio-economic disadvantage. Smoking prevalence is higher and nicotine use heavier among poorer smokers. The socio-economic gradient in smoking behaviour accounts for about two-thirds of the excess premature mortality associated with deprivation. Nicotine addiction is therefore responsible for significant health inequalities.


An addicted brain is altered by the drugs -- it becomes physically different as well as chemically different from a normal brain. A cascade of neurobiological changes accompanies the transition from voluntary to compulsive drug use, but one of the most important is this: cocaine, heroin, nicotine, amphetamines and other addictive drugs alter the brain's pleasure circuits. Activating this circuit, also called the reward circuit, produces a feel-good sensation. Eating cheesecake or tacos or any other food you love activates it. So does sex, winning a competition, acing a test, receiving praise and other pleasurable experiences. The pleasure circuit communicates in the chemical language of dopamine: this neurotransmitter zips from neuron to neuron in the circuit like a molecular happy face, affecting the firing of other neurons and producing feelings from mild happiness to euphoria [8].

For more on nicotine addiction, see special on Why Does Smoking So Often Produce Dependence? A Somewhat Different View.


Nicotine v. Cocaine
To understand drugs like cocaine and nicotine, researchers at Massachusetts General Hospital recruited cocaine addicts who had been using for an average of seven to eight years and had used on 16 of the past 30 days. The test subjects were given a "party" dose of cocaine, up to about 40 milligrams for a 150-pound man. Using a fMRI, the researchers took snapshots of their brains every eight seconds for 18 minutes (see Illustration below). At first, during the "rush" phase, the addicts described feeling "out of control," as if they were "in a dragster" or "being dangled 10 feet off the ground by a giant hand." They also felt a high, a surge of energy and euphoria. The fMRI showed why: cocaine made a beeline for the pleasure circuit, turning on brain areas called the sublenticular extended amygdala and nucleus accumbens and keeping them on [9].

Examining the brain

"Drugs of abuse increase the concentration of dopamine in the brain's reward circuits," says Nora Volkow of Brookhaven National Lab. The drugs do that more intensely than any mere behavior, be it eating a four-star meal or winning the lottery. But each drug turns up this feel-good neurochemical in a different way: Cocaine [and nicotine] block the molecule that ordinarily mops up dopamine sloshing around neurons. When all the seats on this so-called transporter molecule are occupied by cocaine [or nicotine], there is no room for dopamine, which therefore hangs around and keeps the pleasure circuit firing. The intensity of a cocaine [or nicotine] high is directly related to how much of the drug that ties up the seats on the transporter bus [10]. Images sources: STOP! Magazine (Jan./Feb. 2001).
Nerve cells and Synapses


Tropane atom
Stimulant alkaloids such as nicotine from tobacco (Nicotiana tabacum) and cocaine from coca (Erythroxylum coca) are highly addictive and clearly alter one's mental and physical state. The starting compound of this synthesis is ornithine, methylornithine is the first intermediate. A common property of tropane alkaloids is a methylated nitrogen atom N-CH3 at one end of the molecule (see illustration at left). This chemical structure is also found in the neurotransmitter acetylcholine, which transmits impulses between nerves in the brain and neuromuscular junctions. The anesthetic properties of tropane alkaloids may relate to their interference with acetylcholine, perhaps by competing with it at the synaptic junctions, thus blocking or inhibiting nerve impulses [11].


Without getting into complicated anatomy and physiology, one nerve cell (neuron) connects to an adjacent neuron by a long extension called an axon. The axon branches into axonal endings, each of which attaches to the adjacent neuron at a synaptic knob filled with acetylcholine. The minute gap or synaptic cleft within this knob is only about 0.02 micrometers.

As a nerve impulse (wave of depolarization or action potential) reaches this gap, acetylcholine diffuses across the synaptic cleft and activates the adjacent neuron. Acetylcholine in the synaptic cleft is deactivated or broken down by the enzyme acetylcholinesterase, thus shutting off the action potential. Organophosphate insecticides, such as malathion and parathion, bind to active sites on this enzyme, thus preventing the normal shut down of nerve impulses and destroying the nervous control of insects. Nerve gasses developed during World War II have a similar effect on the nervous system. Gulf War soldiers carried an atropine syrette to counter the possible effects of nerve gas [12].

The illustration below contrasts the chemical structures for both cocaine and nicotine. Cocaine is more complex, but it begins as does nicotine with the N-CH3 methylated nitrogen atom at the end of the molecule. One way to think about the two compounds is that nicotine is like drinking a beer while cocaine is like downing a straight shot of whiskey -- both have a great potential of seriously harming the user. More importantly, smokers are unaware that the tobacco companies routinely add ammonia to cigarettes. Ammonia works to release the extra, or unused, nicotine resulting in a "free basing" effect that provides a "super-charged" kick of nicotine -- (see special on How Tobacco Companies Free-base Nicotine. The nicotine hit becomes significantly more potent, i.e., similar to free basing powder cocaine, or smoking crack cocaine, rather than just snorting powder cocaine.
Tropane atom


Cigarette Smoking Linked To Miscarriages and Other Problems, Worse Than Crack Cocaine
The similarities between smoking cigarettes and crack cociane have been available for some time, but we have been unwilling to face the truth about tobacco abuse. A study published in December 1998 confirmed the link between smoking and miscarriages, showing that 80 percent more miscarriages occur among women who smoke cigarettes.

The study, led by Dr. Roberta Ness of the University of Pittsburgh, examined the drug use of nearly 1000 Black inner-city women. The results show that smoking cocaine was responsible for eight percent of the miscarriages and smoking cigarettes caused 16 percent.

The abuse of illicit drugs like crack cocaine by pregnant women has received more attention, but experts say the common, legal drugs -- alcohol and nicotine -- present some of the greatest dangers to unborn babies. "It's our legal substances that are killing us," said Harvey Siegal, director of substance abuse treatment programs at Wright State University. "The biggest substance abuse we have to deal with is not crack, it's not cocaine, it's not alcohol -- it's smoking," said Dr. Jeffrey King, medical director for Born Free, Miami Valley Hospital's program for pregnant substance abusers. "I'll deal with the crack and the alcohol if we could get people to stop smoking." Alcohol rehab has been a solution to many abusers, but there is no cigarette rehab to be fair.

Cigarette smoking by pregnant women can cause spontaneous abortion, prematurity, sudden infant death syndrome, and asthma and other respiratory problems for babies, King noted. "We see younger and younger girls smoking and smoking regularly," he said. "Many smoke through pregnancy after pregnancy" [13].

A January 2001 study by researchers at the University of Alabama at Birmingham documented how cigarette smoke exposure in the perinatal period increases the risk of various prenatal and postnatal complications, including sudden infant death syndrome (SIDS) and persistent pulmonary hypertension of the newborn (PPHN) [14]. In a related February 2001 release of the result from a study conducted in Denmark, the researchers found maternal smoking during pregnancy and a low prepregnancy body mass index are associated with a higher risk of hospitalization with infectious disease during early childhood. These associations are independent of fetal growth indicators [15].

Shockingly, in a March 1999 study, researchers found a dose-response relationship between amount of maternal prenatal smoking and arrests for nonviolent and violent crimes. Children born to mothers who smoked during prenatal particularly related to persistent criminal behavior rather than to arrests confined to adolescence. These relationships remained significant after the resesarchers controlled for confounding potential demographic, parental and other perinatal risk [16]. The combined results from these and other studies illustrate the dramaticly similar effects between maternal crack cocaine and nicotine use and prenatal development.


Fetal Cocaine Exposure: A Comparison to Nicotine
Cocaine shares a number of key characteristics with nicotine. Both are vasoconstrictors that converge on adrenergic neurotransmission as their underlying mechanism, nicotine by evoking catecholamine release and cocaine by preventing presynaptic uptake of catecholamines, thus intensifying their activities. Therefore, cocaine, like nicotine, is capable of evoking acute episodes of fetal hypoxia-ischemia [17].

Likewise, both cocaine and nicotine are anorexic drugs and thus influence maternal nutritional state. A schematic for cocaine's impact on fetal development would resemble that of nicotine, without the participation of tobacco byproducts, but with much heavier emphasis on risky behaviors, poor prenatal care and socioeconomic status. Perhaps most importantly, co-abuse of tobacco is an invariable component in the use of crack cocaine. The illustration below highlights the variables that contribute to the adverse perinatal outcomes from maternal cigarette smoking [18].
Variables adversely affecting perinatal outcomes


Cocaine use differs from that of tobacco/nicotine, however, in that it tends to be episodic rather than continuous. An appropriate animal model for cocaine use therefore should involve repeated, acute exposure rather than continuous infusions [19]. Accordingly, we have utilized daily injections of cocaine to pregnant rats at a dose that simulates plasma levels found in crack cocaine users. This regimen has already been shown to cause CNS functional and behavioral alterations in the offspring [20].

Fetal cocaine exposure, similar to nicotine, elicits postnatal elevations in CNS ornithine decarboxylase activity, indicative of cell damage [21]. The illustration below contrasts the effects of prenatal exposure to nicotine by infusion and cocaine by injection. Although both nicotine and cocaine elicit evidence of cell damage (elevated ornithine decarboxylase, ODC), the effect of nicotine is more persistent. Nicotine, but not cocaine, produces deficits in the number of cells -- evidenced by reduced DNA content. However, the effects are smaller in magnitude than those of nicotine and do not manifest persistence into the second postnatal week. More importantly, cocaine exposure does not lead to irrevocable cell loss, as shown by maintenance of normal DNA content [22].


Prenatal exposure nicotine v. cocaine


Researchers expected were therefore surprised to find that a single injection of cocaine to neonatal rats does inhibit DNA synthesis acutely [23]. The effects differ from those of a single injection of nicotine in two regards. First, there is no regional selectivity to the effect of cocaine, whereas the effect of nicotine follows the distribution of nicotinic cholinergic receptors. Second, the effects of cocaine are extremely short-lived, disappearing within 4 hours of administration, whereas the effect of nicotine is persistent. The graphic below highlights the regional selectivity and persistence of effect from a single injection of nicotine or cocaine on DNA synthesis in neonatal rat brain. While both drugs cause acute inhibition of DNA synthesis within the first 30 minutes post injection, only the effect of nicotine is regionally selective, favoring regions that have high nicotinic receptor concentrations. Cocaine elicits uniform inhibition across all regions. The effect of nicotine persists through four hours after the administration of the drug -- whereas the effect of cocaine does not.


Prenatal exposure nicotine v. cocaine


These findings suggest a greater impact from nicotine than cocaine on cellular development. Exposure to nicotine from continued infusions results in depressed DNA synthesis for an extended period. The episodic exposure to cocaine allows the DNA synthetic rate to recover between injections, thus reducing cell loss -- although there is still evidence of cell damage, but significantly less than that observed with nicotine.

Smokers tend to maintain plasma nicotine levels at a constant value. Cocaine is used in "jags" with extended periods of non-use. Given the much shorter plasma half-life of cocaine, there is a much greater opportunity for fetal CNS recovery from mitotic suppression. These findings do not imply cocaine is without effect on the developing brain -- rather the effects are likely to be more subtle than those of nicotine. When "crack baby syndrome" first appeared in the scientific literature, the initial findings suggested extremely adverse effects [24] . During a subsequent period of retrenchment, more carefully controlled human studies had difficulty replicating the original findings and animal investigations found only subtle behavioral differences; this led to a period in which the existence of an identifiable perinatal cocaine syndrome was called into question [25]. After further study, the pendulum has swung back to the middle and it is evident that cocaine does indeed alter synaptic and behavioral performance, but without the frank damage as found with nicotine or smoking [26].


The "Selfish" Drugs
Both cocaine and nicotine cause intense pharmacological effects in the brain, generally related to the release of dopamine. Empathogens, found in other social (and illegal) drugs such as ecstasy, trigger the release of far more serotonin than dopamine. The higher levels of serotonin will typically promote empathy, trust, compassionate love and sociability. Generally, dopaminergic drugs, if taken on their own and to excess, can easily have the reverse effect, i.e., users are likely eventually to alienate family and friends. They tend to become isolated and suspicious. Simplistically, dopamine-based drugs, cocaine and nicotine, tend to be "selfish" drugs.

In the case of crack addicts, we consider users "addicted" as most of their money and time is spent thinking about how to get more of the drug. For any drug to be truly addictive, it must cause the user to demand it in a compulsive way. Need or desire for the drug makes the user lose control of the amount of time they take or the regularity with which they take it. When a person smokes a cigarette, they take an average of about ten puffs. Each puff gives them a nicotine hit, and throughout the course of the day, an average pack-a-day smoker will experience about 200 hits [27]. Taking all these hits every day adds up. There are numerous studies that have documented the loss of revenue as smokers feed their addiction. This cost the nation millions of dollars in lost productivity each year.

Think of the people we all see each day huddled in or around a sheltered doorway, battling the sometimes bitter cold and harsh elements, just to get a puff of nicotine. Puffing and getting a pay-off in the form of a "brain-reward" so often, each and every day, sets up a whole series of associations that can be extremely difficult to break when the smoker wants to quit. Essentially, everything the smoker does becomes associated with smoking, i.e., drinking, eating, talking on the telephone, driving in car, etc. Smokers develop a whole host of behaviors that are connected with smoking. The need for a nicotine fix begins to dictate who they will associate with, as they seek out other smokers who will understand their need to keep on puffing [28].


Conclusions
It is time to stop allowing tobacco companies to profit from the sale of these highly addictive products. We must recognize nicotine as the powerful, and mind-altering, drug that it is. First, smokers are addicts. We must assist these victims. Most became addicted as teens, kids or children. A recently released study shows that over 82% would like to quit -- we must help our friends and family members get the attention they need to regain control over their lives. For years the tobacco industry furthered the illusion that "people have a right to smoke." They argued that smoking is an important freedom -- yet addiction counters all principles associated with free choice. Addiction of any type results in a slavery of the mind and body. Smokers are servants to the power of nicotine.

Second, all forms of tobacco advertising and promotion must be stopped immediately. We would not conceive of allowing powder cocaine, crack cocaine or heroin to be advertised. We do not need to encourage tobacco use or smoking.

Third, we cannot consider prohibition of tobacco products. As with the War Against Drugs, prohibition does not work. This restrictive strategy did not work in our failed attempt to regulate alcohol consumption, and it is increasely clear that we have failed in our current effort against the presently illicit drugs. The solution is to focus on education. We must reduce the "demand" for addictive drugs of all types.

Lastly, David Kessler, former head of the Food and Drug Administration, proposes in his latest book, A Question of Intent, that the tobacco companies be spun away from their corporate parents and for Congress to create a tightly regulated, not-for-profit firm that would take over the manufacturing and sales. "The entity would supply tobacco products to those who want them but with no economic incentives for sales," writes Kessler. He also recommends a government buyout as "an incentive to walk away from the tobacco business." The world of Big Tobacco opened Kessler's eyes during his six-year tenure as FDA chief. We ask that America capitalize on his wisdom.
_______________________
[1] Peter v. Sengbusch at: http://www.rrz.uni-hamburg.de/biologie/b_online/e20/20a.htm.
[2] Ornithine derivatives: Ornithine is a precursor of the cyclic pyrrolidines that occur in the alkaloids of tobacco (nicotine, nornicotine) and other Solanaceae. Nicotine is a starting compound of numerous further tobacco alkaloids. During the biosynthesis of tropane are intermediates produced that are at the same time starting compounds for cocaine and hyoscamine.
[3] Sutherland, Gay, "Nicotine, Addiction & Your Brain," STOP!, Jan/Feb 2001, p.30.
[4] Ibid., p.27.
[5] Ibid., p.28.
[6] Ibid., p.28.
[7] Ibid., p.28.
[8] Begley, Sharon, "The Brain: The Origins of Dependence," Newsweek, February 12, 2001.
[9] Ibid.
[10] Ibid.
[11] Schultes, R.E. and A. Hofmann, The Botany and Chemistry of Hallucinogens, 1973; and W.H. Lewis and M.P.F. Elvin-Lewis, Medical Botany, (1977). Summarized at: http://daphne.palomar.edu/wayne/ww0703.htm.
[12] Ibid.
[13] Ness, Roberta, New England Journal of Medicine, December 1998.
[14] Waldemar F. Carlo, Arlene Bulger, Jian Shi, Joseph B. Philips III, "Effect of Cigarette Smoke Extract on Neonatal Porcine Vascular Smooth Muscle Cells." Tox & Appl Pharm, Vol. 170, No. 2, pp. 130-136, January 2001.
[15] Yuan, Wei, Olga Basso, Henrik Toft Sorensen and Jorn Olsen, "Maternal Prenatal Lifestyle Factors and Infectious Disease in Early Childhood: A Follow-Up Study of Hospitalization Within a Danish Birth Cohort," Pediatrics, Vol. 107 No. 2, pp. 357-362, February 2001
[16] Brennan, Patricia A., PhD; Emily R. Grekin; Sarnoff A. Mednick, PhD, DrMed, "Maternal Smoking During Pregnancy and Adult Male Criminal Outcomes," Archives of General Psychiatry, March 1999; 56:215-219
[17] Mahalik, M.P., Gautieri, R.F. and Mann Jr., D.E., "Mechanisms of cocaine-induced teratogenesis," Res. Comm. Subst. Abuse, 5: 279-302, 1984.
[18] Budney, A.J., Higgins, S.T., Hughes, J.R. and Bickel, W.K., "Nicotine and caffeine use in cocaine-dependent individuals," J. Subst. Abuse Treat, 5: 117-130, 1993; Higgins, S.T., Budney, A.J., Hughes, J.R., Bickel, W.K., Lynn, M. and Mortensen, A., "Influence of cocaine use on cigarette smoking," J. Amer. Med. Assoc., 272: 1724, 1994.
[19] Siegel, R.K., "Cocaine smoking," J. Psychoactive Drugs, 14: 271-359, 1982; Spear, L.P., Frambes, N.A. and Kirstein, C.L., "Fetal and maternal brain and plasma levels of cocaine and benzoylecgonine following chronic subcutaneous administration of cocaine during gestation in rats," Psychopharmacology 97: 427-431, 1989a.
[20] Dow-Edwards, D.L., "Long-term neurochemical and neurobehavioral consequences of cocaine use during pregnancy," Ann. N.Y. Acad. Sci, 562: 280-289, 1989.; Spear, L.P., Frambes, N.A. and Kirstein, C.L., "Fetal and maternal brain and plasma levels of cocaine and benzoylecgonine following chronic subcutaneous administration of cocaine during gestation in rats," Psychopharmacology 97: 427-431, 1989a
[21] Spear, L.P., Kirstein, C.L. and Frambes, N.A., "Cocaine effects on the developing nervous system: behavioral, psychopharmacological and neurochemical studies," Ann. N.Y. Acad. Sci., 562: 290-307, 1989b.; Heyser, C.J., Spear, N.E. and Spear, L.P., "Effects of prenatal exposure to cocaine on conditional discrimination learning in adult rats," Behav. Neurosci., 106: 837-845, 1992.; Spear, L.P. and Heyser, C.J., "Cocaine and the developing nervous system: laboratory findings," In Maternal Substance Abuse and the Developing Nervous System, ed. by I.S. Zagon and T.A. Slotkin, pp. 155-175, Academic Press, San Diego, 1992.; Goodwin, G.A., Moody, C.A. and Spear, L.P., "Prenatal cocaine exposure increases the behavioral sensitivity of neonatal rat pups to ligands active at opiate receptors," Neurotoxicol. Teratol., 15: 425-431, 1993.; Molina, V.A., Wagner, J.M. and Spear, L.P., "The behavioral response to stress is altered in adult rats exposed prenatally to cocaine," Physiol. Behav., 55: 941-945, 1994.
[22] Koegler, S.M., Seidler, F.J., Spencer, J.R. and Slotkin, T.A., "Ischemia contributes to adverse effects of cocaine on brain development: suppression of ornithine decarboxylase activity in neonatal rat," Brain Res. Bull., 27: 829-834, 1991.; Seidler, F.J. and Slotkin, T.A., "Prenatal cocaine and cell development in rat brain regions: effects on ornithine decarboxylase and macromolecules," Brain Res. Bull. 30: 91-99, 1993.; Slotkin, T.A., Johnson, D.J. and Seidler, F.J., "Acute effects of cocaine on ornithine decarboxylase activity in fetal and neonatal rat heart: evidence for cardiotoxicity," Biol. Neonate, 63: 290-296, 1993.; Spraggins, Y.R., Seidler, F.J. and Slotkin, T.A., "Cocaine exacerbates hypoxia-induced cell damage in developing brain: effects on ornithine decarboxylase activity and protein synthesis," Biol. Neonate, 66: 254-266, 1994.
[23] Seidler, F.J. and Slotkin, T.A., "Prenatal cocaine and cell development in rat brain regions: effects on ornithine decarboxylase and macromolecules," Brain Res. Bull. 30: 91-99, 1993.
[24] Anderson-Brown, T., Slotkin, T.A. and Seidler, F.J., "Cocaine acutely inhibits DNA synthesis in developing rat brain regions: evidence for direct actions," Brain Res. 537: 197-202, 1990.
[25] Chasnoff, I.J., Burns, K.A. and Burns, W.J., "Cocaine use in pregnancy: perinatal morbidity and mortality," Neurotoxicol. Teratol., 9: 291-293, 1987; Chasnoff, I.J., Burns, W.J., Schnoll, S.H. and Burns, K.A., "Cocaine use in pregnancy," New Engl. J. Med., 313: 666-669, 1985; Chasnoff, I.J., Lewis, D.E., Griffith, D.R. and Willey, S.; "Cocaine and pregnancy: clinical and toxicological implications for the neonate," Clin. Chem., 35: 1276-1278, 1989.
[26] Coles, C.D., "Saying goodbye to the crack baby," Neurotoxicol. Teratol., 15: 290-292, 1993.; Day, N.L. and Richardson, G.A., "Cocaine use and crack babies: science, the media, and miscommunication," Neurotoxicol. Teratol., 15: 293-294, 1993.; Koren, G., "Cocaine and the human fetus: the concept of teratophilia," Neurotoxicol. Teratol., 15: 301-304, 1993.; Neuspiel, D.R., "Cocaine and the fetus: mythology of severe risk," Neurotoxicol. Teratol., 15: 305-306, 1993.; Konkol, R.J., "Is there a cocaine baby syndrome?" J. Child Neurol. 9: 225-226, 1994.; Snodgrass, S.R., "Cocaine babies: a result of multiple teratogenic influences," J. Child Neurol., 9: 227-233, 1994.
[27] Spear, L.P. and Heyser, C.J., "Cocaine and the developing nervous system: laboratory findings." In Maternal Substance Abuse and the Developing Nervous System, ed. by I.S. Zagon and T.A. Slotkin, pp. 155-175, Academic Press, San Diego, 1992.; Zuckerman, B. and Frank, D.A., "Prenatal cocaine and marijuana exposure: research and clinical implications," In Maternal Substance Abuse and the Developing Nervous System, ed. by I.S. Zagon and T.A. Slotkin, pp. 125-153, Academic Press, San Diego, 1992; Zuckerman, B. and Frank, D.A., "Prenatal cocaine exposure: nine years later," J. Pediatr., 124: 731-733, 1994.; Meyer, J.S., Shearman, L.P. and Collins, L.M., "Monoamine transporters and the neurobehavioral teratology of cocaine," Pharmacol. Biochem. Behav., 55: 585-593, 1996.; Levitt, P., Harvey, J.A., Friedman, E., Simansky, K. and Murphy, E.H., "New evidence for neurotransmitter influences on brain development," Trends Neurosci., 20: 269-274, 1997.
[28] Sutherland, Gay, p.28.
[29] Ibid.


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