A Tentative Hypothesis On Nicotine Addiction

The Battelle scientists who conducted the Hippo projects for BAT also wrote a speculative essay about the mechanism underlying nicotine addiction. The essay, marked "Confidential" and titled "A Tentative Hypothesis on Nicotine Addiction" {1200.01}, sought to explain nicotine tolerance, withdrawal, and addiction in the context of what was then cutting-edge neuroendocrinology.

The hypothalamo-pituitary stimulation of nicotine is the beneficial mechanism which makes people smoke; in other words, nicotine helps people to cope with stress. In the beginning of nicotine consumption, relatively small doses can perform the desired action. Chronic intake of nicotine tends to restore the normal physiological functioning of the endocrine system, so that ever-increasing dose levels of nicotine are necessary to maintain the desired action. Unlike other dopings, such as morphine, the demand for increasing dose levels is relatively slow for nicotine.

In a chronic smoker the normal equilibrium in the corticotropin-releasing system can be maintained only by continuous nicotine intake. It seems that those individuals are but slightly different in their aptitude to cope with stress in comparison with a non-smoker. If nicotine intake, however, is prohibited to chronic smokers, the corticotropin-releasing ability of the hypothalamus is greatly reduced, so that these individuals are left with an unbalanced endocrine system. A body left in this unbalanced status craves for renewed drug intake in order to restore the physiological equilibrium. This unconscious desire explains the addiction of the individual to nicotine [emphasis added]. {1200.01, pp. 1–2}

The short essay includes a review of the effects of nicotine on appetite and weight control, based on experiments using animals.

It is a well-known fact that fresh smokers show loss of appetite, and therefore loss of weight. Chronic smokers gradually turn to normal food intake. If nicotine is withdrawn from these individuals, the low FFA [free fatty acid] concentration in the blood provokes increased appetite, and therefore increased food intake, or at least a permanent hunger feeling. This feeling can be satisfied either by increased food intake or by renewed smoking.

Laboratory experiments with rats confirm this mechanism: injection of nicotine induces a marked reduction in food intake in the beginning of the treatment. Chronic application of nicotine in the so-called "tolerant rats" shows after a certain time no difference in the growth curves between treated and untreated animals. Interruption of nicotine application provokes a marked increase in food intake of "tolerant rats", which increase, however, turns very rapidly to normal (in our experiments within one week). {1200.01, p. 2}

The essay concludes,

[A] tentative hypothesis for the explanation of nicotine addiction would be that of an unconscious desire to restore the normal physiological equilibrium of the corticotropin-releasing system in a body in which the normal functioning of the system has been weakened by chronic intake of nicotine. {1200.01, p. 3}

In summary, pharmacological research at Battelle sponsored by BAT in the early 1960s was based on a paradigm of addiction. It sought to elucidate "beneficial" effects of nicotine such as "tranquilising" and weight loss effects, and it also explored the extent to which other drugs might compete with cigarettes in the consumer marketplace.

The results of the Hippo projects were distributed to BAT officials around the world, including executives at Brown and Williamson. The speculative paper on nicotine addiction, however, received only limited circulation. In fact, when Sir Charles Ellis sent a copy of the essay to

Brown and Williamson's general counsel, Addison Yeaman, he attached a cover letter advising Yeaman that the essay was "a private working paper" and that it was not being circulated to the other recipients of the Hippo reports {1200.02}.