During studies of endocrine response of animals to the cold, it was found that the administration of several hormones (for various periods of time) could markedly delay the onset of hypothermia. Such hormones include catecholamines, thyroxine, mixtures of thyroxine and cortisol, and growth hormone (for a review see LeBlanc, 1975; Sellers, 1972). Although these studies were very useful to the understanding of cold-induced thermogenesis—also known as thermoregulatory thermogenesis—it is now apparent that they have little direct application to humans. For instance, the catecholamine-induced improvement in heat production is usually directly related to brown adipose tissue, the long-term use of high doses of thyroxine is not recommended in euthyroid subjects, the long-term use of high cortisol doses increases protein breakdown and is associated with Cushing's syndrome, and finally the long-term use of growth hormone leads to insulin resistance and is associated with acromegaly (for a review, see LeBlanc, 1975; Sellers, 1972). Interestingly, in parallel to the above, a wide variety of pharmacological agents have also been shown to be effective in delaying the onset of hypothermia in animals (Vallerand, 1993).

Dinitrophenol uncouples oxidative phosphorylation, and it is therefore an extremely potent thermogenic agent (Hall et al., 1948). It is rather unfortunate that this uncoupling effect happens to be generalized to virtually all body tissues. The strong thermogenic effect of dinitrophenol is even magnified in the presence of thyroxine (Frommel and Valette, 1950), but again it is difficult to find an application to humans. Other effective compounds in the cold include vitamin C, α-amino acids, strophanthin, chlorpromazine, coramine, and cardiozol (see Vallerand and Jacobs, 1992a). Of much greater interest today are methylxanthines.

Caffeine, the most well-known methylxanthine, is an established and effective thermogenic agent at comfortable ambient temperatures (Acheson et al., 1980; LeBlanc, 1987). In the cold, caffeine has been shown to improve cold tolerance since it significantly reduced the drop in rectal core temperature (T_re) in animals (Estler et al., 1978; Gennari, 1940). Another effective xanthine is theophylline. During the last decade, L. C. H. Wang has shown on numerous occasions that the acute administration of theophylline in cold-exposed rats produces significantly warmer T_re via its enhancement of thermoregulatory thermogenesis (Wang, 1981; Wang and Anholt, 1982; Wang and Lee, 1990). Other potent agents in the cold include amphetamines, the well-known central nervous system stimulants (Gilman and Goodman, 1970) that, with or without epinephrine, have been shown to markedly increase metabolic heat production (M) and to produce significantly warmer T_re in the cold (Pick, 1948). The present animal data could therefore be interpreted as indicating that sympathomimetics and methylxanthines form two classes of pharmacological agents that are likely to be useful for humans exposed to the cold.