A Conclusive Diet Pill: Slim Chances?
With obesity an American epidemic, affecting 35.7% of adults and 16.9% of children and adolescents, the demand for diet drugs rises each day (Ogden, Carroll, Kit, & Flegal, 2012). However, as of November 2013, the Food and Drug Administration has approved only three drugs as weight loss medications, all of which come with strong caution and have to be accompanied by a balanced diet and regular exercises (FDA, 2013). Historically, the FDA approved several other drugs only to remove them from the market later due to side effects. Overall, research into drugs for weight loss dated back to as far as the 1890s, yet more than 120 years have passed without the discovery of an effective and relatively safe pharmaceutical product for dieting (Cohen, Goday, & Swann, 2012). The challenges against finding diet drugs are numerous, if not insurmountable, given the convoluted nature of the brain mechanism for weight regulation and our still rudimentary knowledge of the brain and its workings.
In assessing the complexity of devising a diet pill, we first need to review the mechanisms involved in weight maintenance. Two processes contribute principally to the determination of weight: calorie intake and calorie expense. Calorie intake often depends on the initiation and cessation of eating. Researchers through the years have identified a number of brain structures and neurochemicals involved in hunger and satiety. Among these neurochemicals, the discovery of the hormone leptin in 1994 brought the most hope for drug researchers, as leptin seems to be the first hormone directly involved in obesity and holds the potential for curing obesity (Marx, 2003; Zhang et al., 1994). Through cloning and sequencing the mouse ob gene, the research team led by Friedman identified the long elusive factor that regulates between energy intake and expenditure. Further research indicated that low levels of leptin, produced by fat cells, signal the body to eat. Conversely, high levels of leptin signals satiety and increases body’s metabolism (Marx, 2003).
In the clinical investigation by Farooqi et al. (2002), three children with obesity and hyperphagia were identified to suffer from leptin deficiency. Two of these children were first cousins, while the other child had has the same ancestor but was not related for at least five generations. All these three children received subcutaneous injection of leptin, with the first dose estimated to be at the 10% level of appropriate leptin concentration in the body. This first dose was increased to 20%, 50%, 100%, and 150% in circumstances where the treatment lost its efficacy. All three children lost weight due to loss of fat (accounting for 98% of the weight loss) within two weeks of treatment. When a refractory period emerged, accompanied by regaining the fat, it was overcome through increase in dosage of leptin. The energy intake of these children also decreased, from 45% to 84%, at the test meal, two months after administration. This finding was confirmed by the general observation of parents. No change in the basal metabolic rate was observed, and all other criteria, including linear growth of children and onset of puberty, were standard for children their age.
Despite the effectiveness of this therapy in treating certain obese patients, leptin deficiency is rarely the cause of obesity. In fact, obese humans seem to already have a high level of leptins, which are produced by fat cells (Marx, 2003). Leptin appears to act more as a mechanism against weight loss, as its low level initiates eating and slows down the metabolic rates. However, the reverse, higher leptin level, does not result in satiety or higher metabolic rates. Unfortunately, this weight-loss defending tendency, which might have evolved as an adaptive feature to the long human history of epidemic starvation, not epidemic obesity, seems to be norm for most humans. In one particular case, a human weighing 207 kilogram (455.4 pounds) survived 382 days without food under monitored condition (Steward and Fleming, 1973, as cited by Freberg). A typical human’s energy regulation allows for enough storage of fat for five to six weeks of fasting, excessively unnecessary in the context of most developed countries with abundant food.
Another example of the weight-defending mechanism is the characteristics of
fat cells. Even though the number of fat cells remains relatively stable throughout adulthood of normally-weighed people, overeating in certain periods not only increases the size of fat cells but also the number of fat cells (
University of Maryland Medical Center, 2013). After losing weight, these fat cells will only shrink in size but not decline in numbers. The higher number of fat cells creates a favorable condition of weight accumulation and can explain the high likelihood of regaining fat in formerly overweighed individuals.
On the other side of weight maintenance, satiety, various drugs have also been introduced, but their usage has sometimes proven lethal, given the interconnectedness of humans’ physiology. Among the substances used for inducing satiety, amphetamine is arguably the most controversial. The anorectic effect of amphetamine was first discovered in 1930s (Cohen et al., 2012), and the first diet pills appeared in the market as Clarkotabs, produced by Clark and Clark Company. Many other players, including pharmaceutical firms and fat “doctors,” joined the market and popularized the massive use of these diet pills from the 1940s to 1970s. Reports of deaths resulting from the usage of these pills also trickled in. The adverse side effects and dubious ethical conduct of this diet pill industry became undeniable with an investigation by Susanna McBee, published in LIFE Magazine issue. The investigator exposed how, during her visits to 10 obesity clinics, she was prescribed more than 1500 diet pills after only cursory evaluation. By this time, according to an investigation by the government, at least 60 deaths and numerous cases with serious adverse effects had been linked to the usage of these diet pills.
Despite the ripple caused by these investigations and ban placed on these diet pills, pills containing amphetamine were able to return to the present US market under the guise of dietary supplements, which can even be purchased without prescription, and yet more cases of serious side effects of these supplements have been documented. This case study of the usage of amphetamine for weight loss by Cohen et al. (2012) illustrated the level of misinformation in the mainstream diet pill industry and users’ naiveté about drug usage.
More critically, the abuse of amphetamine for weight loss and the ensuing side effects exemplify the difficulties in devising a diet drug, or most psychiatric drugs. The users may only want the amphetamine to affect their satiety center; nevertheless, once amphetamine enters the system, its users are susceptible to a wide range of effects on the human body, evidenced by the cases of adverse side effects, ranging from insomnia and anxiety to amphetamine addiction and long-term cardiac problems.
The fundamental and so far insurmountable hindrance lies in how the brain is a convoluted organ, with systems intertwining and working together for various different tasks. There is no single specific part of the brain that deals with eating for drugs to target. Rather, the components involved in weight maintenance spread all over the brain, including the arcuate nucleus (in the hypothalamus) and lateral hypothalamus in initiation of eating and the pituitary to regulate metabolic activity (Freberg, 2010). Even within these components themselves, it would oversimplify the matter to classify their roles as primary dealing with only hunger or only satiety. For example, the lesion of the lateral hypothalamus of rats would not result in total cessation of eating. If the animals were force fed, they would start to initiate eating behavior again. Beyond eating, the lateral hypothalamus also participates in drinking behavior, a function just as critical to human survival.
A study by Vicentic and Jones (2007) offers a detailed demonstration of the complexity of one of the many factors involved in weight regulation, the cocaine-and-amphetamine-regulated transcript (CART). In initiating satiety, the arcuate nucleus releases CART, facilitating the rise in body metabolic rates, body temperature, and inhibition of feeding behavior (Freberg, 2010). Naturally, CART would be a target for weight-loss drug aiming to induce satiety, but this neuropeptide is responsible for numerous other functions besides satiety, including “drug reward, stress, cardiovascular function, and bone remodeling.” (Vicentic & Jones, 2007) CART is present in the pituitary and adrenal glands, pancreas, and gut. Furthermore, many studies have supported its role in drug reward and consequently addiction. These studies provided evidence of CART’s presence in reward-associated regions and synaptic connections between CART neurons to dopamine and GABA neuron (drug-related neurotransmitters). CART’s multifunction suggests that any drug attempting to influence CART may produce adverse side effects due to its involvement in other functions of the body.
These limitations of clinical psychopharmacology attest to the fact that regarding the brain and its mechanisms, our understanding remains insufficient. Contained in the brain of each human are countless structures, connected by countless neurons and pathways, and modulated by countless neurotransmitters. With the only recent advent of fMRI and the difficulty in examining humans’ brains due to practical and ethical issues, the research in neuroscience and cognitive psychology has only scratched the surface of a complete comprehension of the brain, if such a feat is possible. In examination of the multi-process nature of weight regulation, its evolutionary resistance against weight loss, and the fledging state of neuroscience in general and psychopharmacology in particular, the best course for a current obese patient remains the same as a hundred years ago: a life style change, including reduced calorie intake and increased activities.
References
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