Dimagrimento Drastico: I Rischi Biochimici e Ormonali Nascosti dietro le Diete Estreme e i Farmaci Potenti

Drastic Weight Loss: The Biochemical and Hormonal Risks Hidden Behind Extreme Diets and Powerful Drugs

Dr. Prof. Vito Traversa

Subtitle: Losing 20 or 30 kg in a few months can compromise your hormonal, psychological, and metabolic systems. A scientific guide to understanding what's happening in your body.

Introduction

Every year, thousands of people choose drastic measures to lose weight quickly: extreme low-calorie diets, appetite-inducing drugs, off-label antidepressants, and even surgery. But at what cost? The illusion of rapid weight loss hides a dangerous hormonal and metabolic imbalance that can last for years.

1. The yo-yo effect and metabolic adaptation: the body goes into alarm

During a severe diet, the body perceives a survival risk. This activates "genetic hunger" mechanisms that involve the neuroendocrine system. Studies by Leibel et al. (1995) demonstrate that, after significant weight loss, the body persistently reduces basal metabolism, even when weight is regained. This is known as thermogenic adaptation .

Source: Leibel, R.L., Rosenbaum, M., & Hirsch, J. (1995). Changes in energy expenditure resulting from altered body weight. New England Journal of Medicine , 332(10), 621–628. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4872449/

Continuing along these lines, other studies have shown that weight loss activates a neuroendocrine cascade involving the hypothalamus, the HPA axis (hypothalamic-pituitary-adrenal gland), leptin, and ghrelin. Leptin, a hormone produced by adipocytes, drops dramatically with fat loss, signaling the brain that energy is depleted. This leads to increased hunger and a reduction in sympathetic nervous system activity, impairing the ability to burn energy.

Source: Rosenbaum, M., & Leibel, R.L. (2010). Adaptive thermogenesis in humans . International Journal of Obesity, 34(S1), S47–S55. https://www.nature.com/articles/ijo201028

At the same time, ghrelin, a hormone produced by the stomach, tends to increase, further increasing the sensation of hunger. This dual mechanism—leptin decreasing, ghrelin increasing—makes it extremely difficult to maintain lost weight. This hormonal compensation is often the basis of the yo-yo effect. in classic low-calorie diets.

Source: Cummings, DE, et al. (2002). A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans . Diabetes, 50(8), 1714–1719. https://diabetesjournals.org/diabetes/article/50/8/1714/10912

Furthermore, prolonged calorie restriction also activates the stress hormone cortisol, which promotes muscle catabolism and visceral fat accumulation, worsening body composition and leading to a condition called “sarcopenic obesity.”

Source: Tomiyama, AJ, et al. (2010). Dieting and stress: An examination of stress-induced cortisol and emotional eating in women . Health Psychology, 29(4), 421–427. https://doi.org/10.1037/a0018600

In light of this evidence, it becomes clear that an approach based solely on calorie restriction is neither sustainable nor effective in the long term. Instead, it is necessary to restore neuroendocrine and metabolic balance through integrated, personalized, and progressive protocols that consider not only caloric intake, but also nutritional quality, muscle training, sleep, stress management, and liver function.

2. Ghrelin and chronic hunger after dieting

Ghrelin, known as the "hunger hormone," increases in response to weight loss. Clinical studies have shown that elevated ghrelin levels persist for up to a year after completing a low-calorie diet. The result? Chronic hunger that's difficult to control, often leading to weight regain.

Source: Sumithran, P. et al. (2011). Long-term persistence of hormonal adaptations to weight loss. New England Journal of Medicine , 365, 1597–1604. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6520897/

This persistence of ghrelin has been linked to a phenomenon called “compensatory hormonal upregulation” : even when the individual returns to a normal weight, the hypothalamus continues to receive amplified hunger signals, as if it were still in a state of energy deprivation.

At the molecular level, ghrelin is a 28-amino acid peptide which acts on GHS-R1a receptors in the arcuate hypothalamus, activating NPY/AgRP (neuropeptide Y and agouti-related peptide) neurons, potent appetite stimulators. This activation also has an inhibitory effect on anorexigenic POMC/CART neurons, reducing satiety.

Source: Müller, T.D., Nogueiras, R., Andermann, M.L., Andrews, Z.B., Anker, S.D., Argente, J., et al. (2015). Ghrelin . Molecular Metabolism, 4(6), 437–460. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4473155/

Furthermore, ghrelin interacts with the mesolimbic dopaminergic circuit , in particular with the nucleus accumbens and the ventral tegmental area (VTA) , increasing motivation and food-related gratification. This explains why those who have undergone severe food restriction tend to develop compulsive behaviors towards high-calorie foods.

Source: Abizaid, A. et al. (2006). Ghrelin modulates the activity and synaptic input organization of midbrain dopamine neurons while promoting appetite . Journal of Clinical Investigation, 116(12), 3229–3239. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1676311/

Even the active form of ghrelin – the acylated ghrelin (acyl-ghrelin) – has a short half-life but significant biological potency, and is able to cross the blood-brain barrier. It increases during prolonged fasts and remains elevated even after dietary reintroduction, slowing the return to homeostatic equilibrium.

In studies on subjects undergoing bariatric surgery or drastic protein diet, it was observed that only interventions with direct impact on the intestine (such as sleeve gastrectomy) are able to stably suppress ghrelin levels , while diet alone, although effective in the short term, does not reduce the overproduction of this hormone.

Source: Cummings, DE, et al. (2004). Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery . New England Journal of Medicine, 346(21), 1623–1630. https://www.nejm.org/doi/full/10.1056/NEJMoa012908

All this highlights how the treatment of excess weight cannot be based solely on willpower or caloric deficit. restore central hormonal regulation , modulate the activity of ghrelin receptors and intervene on deeper brain axes to avoid relapse.

3. Cortisol and the suppression of lean mass

Crash diets activate the hypothalamic-pituitary-adrenal axis, increasing levels of the stress hormone cortisol. Cortisol inhibits protein synthesis, stimulates muscle catabolism, and impairs insulin sensitivity. The result is a reduction in lean body mass and a further slowing of metabolism.

Source: Rosenbaum, M., & Leibel, R.L. (2010). Adaptive thermogenesis in humans. International Journal of Obesity , 34(Suppl 1), S47–S55. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3771367/

Cortisol exerts several metabolic effects:

  1. Stimulates muscle catabolism : promotes the breakdown of proteins in skeletal muscles to obtain amino acids to be converted into glucose (hepatic gluconeogenesis). This leads to a direct loss of lean muscle mass , essential for maintaining a high basal metabolism.
  2. Inhibits protein synthesis : blocks muscle anabolism by negatively acting on mTOR (mammalian target of rapamycin), one of the main activators of cell growth and muscle protein synthesis.
  3. Impairs insulin sensitivity : Cortisol induces hepatic and peripheral insulin resistance, promoting the accumulation of visceral fat. This effect is further exacerbated when the diet is low in complex carbohydrates and micronutrients.
  4. Reduces the conversion of active thyroid hormones : Inhibits the conversion of thyroxine (T4) to triiodothyronine (T3), further slowing metabolism and contributing to the so-called “starvation mode”.

Source: Rosenbaum, M., & Leibel, R. L. (2010) . Adaptive thermogenesis in humans . International Journal of Obesity , 34(Suppl 1), S47–S55.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3771367/

A key study that confirms the role of cortisol in lean mass loss is that of Hackney, AC et al. (1999) , who observed a significant increase in serum cortisol and a concomitant reduction in testosterone and IGF-1 (anabolic hormones) in subjects subjected to low-calorie diets combined with intense physical activity.
Source: Hackney, AC (1999). Influence of cortisol on energy regulation and testosterone responses to exercise . Current Opinion in Clinical Nutrition and Metabolic Care , 2(6), 523–526.
https://pubmed.ncbi.nlm.nih.gov/10577495/

Another important revision is that of Tomiyama et al. (2010) , who link chronic attempts to lose weight with increased basal and reactive cortisol, worsening metabolic adaptation and appetitive regulation.
Source: Tomiyama, AJ et al. (2010). Dieting: stress and weight gain . Appetite , 55(3), 681–683.
https://www.sciencedirect.com/science/article/abs/pii/S019566631000483X


The restrictive diet, increasing cortisol, not only triggers the loss of lean mass , but also predisposes to A return to initial weight with an increase in fat mass , worsening overall body composition. This cycle is known as "metabolic relapse" and represents one of the greatest obstacles in the treatment of obesity and chronic overweight.

4. Psychoactive drugs: antidepressants, antiepileptics and metabolic risk

Drugs such as fluoxetine, sertraline (SSRI), or topiramate (an antiepileptic used off-label for weight loss) can temporarily reduce appetite. However, they alter serotonin and dopamine levels, negatively impacting mood, libido, and cognitive function. Furthermore, chronic use can alter glucose metabolism and increase the risk of metabolic syndrome.

Source: Cummings, D. E., & Overduin, J. (2007). Gastrointestinal regulation of food intake. Journal of Clinical Investigation , 117(1), 13–23. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3065312/

The use of psychoactive drugs for weight control is a controversial approach, often adopted in a off-label or in unsupervised contexts. Molecules such as selective serotonin reuptake inhibitors (SSRIs) — fluoxetine, sertraline, citalopram, escitalopram — and antiepileptics such as topiramate are sometimes used for their secondary anorectic effect , that is, the ability to reduce appetite as a non-primary side effect. However, the consequences metabolic and neuroendocrine in the long term raise serious questions.

Effects on the serotoninergic and dopaminergic systems

The SSRI they work by increasing the levels of serotonin in the synaptic cleft —that is, the space between two neurons where the transmission of the nerve impulse occurs. synapses It is in fact the connection structure between two nerve cells, and neurotransmitters such as serotonin are found in the synaptic cleft.

These drugs They inhibit the reuptake of serotonin , that is, they prevent the presynaptic neuron from "reabsorbing" it after it has transmitted the signal. In other words, they leave the serotonin active in the synaptic space for longer, amplifying its effect. This mechanism can temporarily reduce appetite, but also alters the physiological regulation of the mood tone , of the sleep-wake cycle , of the libido and of the cognitive functions .

A chronic imbalance induced by these drugs can lead to:

  • Sexual dysfunctions (reduction of libido, anorgasmia), as highlighted by Serretti & Chiesa (2009).
    Source: Serretti, A., & Chiesa, A. (2009). Treatment-emergent sexual dysfunction related to antidepressants: a meta-analysis. Journal of Clinical Psychopharmacology, 29(3), 259–266.
    https://pubmed.ncbi.nlm.nih.gov/19440080/
  • Alterations of mesolimbic dopamine , i.e. of the dopaminergic system involved in motivation and reward, with manifestations of apathy and lack of motivation even in subjects without previous psychiatric pathologies.
    Source: Dunlop, B.W., & Nemeroff, C.B. (2007). The role of dopamine in the pathophysiology of depression. Archives of General Psychiatry, 64(3), 327–337.
    https://jamanetwork.com/journals/jamapsychiatry/fullarticle/210007

Effects on glucose metabolism

Numerous studies have reported that chronic use of SSRIs can induce insulin resistance , or a reduced sensitivity of cells to insulin (the hormone that regulates blood glucose levels), and alterations in sugar metabolism . This risk is particularly high in predisposed, obese, or overweight patients.

A study published in Diabetes Care showed a significant increase in the risk of type 2 diabetes in patients taking antidepressants for long periods.
Source: Andersohn, F., et al. (2009). Long-term use of antidepressants for depressive disorders and the risk of diabetes mellitus. Diabetes Care, 32(4), 602–607.
https://diabetesjournals.org/care/article/32/4/602/29220

Topiramate: neurological and metabolic effects

The topiramate , often used in combination with phentermine in clinical protocols for weight loss, it exerts an effect anorectic but it carries significant risks. Among the documented side effects:

  • Metabolic acidosis , i.e. a lowering of blood pH due to excessive systemic acidity
  • Paresthesia , or tingling or abnormal sensations in the limbs
  • Cognitive deficits (mental slowing, difficulty concentrating and recalling words)
  • Mood alterations , even in subjects without previous psychiatric vulnerability

Source: Bray, G. A., & Ryan, D. H. (2014). Update on obesity pharmacotherapy. Annals of the New York Academy of Sciences, 1311(1), 1–13.
https://nyaspubs.onlinelibrary.wiley.com/doi/10.1111/nyas.12332

Risk of metabolic syndrome

A clinically relevant, although less discussed, aspect is the increased risk of metabolic syndrome in patients undergoing chronic treatment with antidepressants And mood stabilizers . Metabolic syndrome is a clinical condition characterized by:

  • Increase in abdominal circumference
  • Fasting hyperglycemia
  • Hypertriglyceridemia
  • High blood pressure
  • Insulin resistance

This painting is the result of a combination of increased appetite , reduced physical activity , accumulation of visceral fat And dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis , which controls the stress response and the release of cortisol.

A large-scale study has confirmed that chronic use of psychotropic drugs is associated with a statistically significant increase from the waist circumference , of triglycerides and of the fasting blood sugar .
Source: Pan, A., et al. (2012). Use of antidepressant medication and risk of type 2 diabetes: results from three cohorts of US adults. Diabetology, 55, 63–72.
https://link.springer.com/article/10.1007/s00125-011-2330-0


Drugs such as fluoxetine , sertraline And topiramate They are not safe tools for sustainable body weight management. The initial effects on appetite are transient , while the neuroendocrine and metabolic alterations may persist over time or worsen. Chronic use of these drugs may contribute to the development of visceral obesity , metabolic syndrome , cognitive dysfunctions And mood disorders , compromising the patient's general health.

5. The role of adiponectin and leptin in weight regain

There leptin and adiponectin They are two hormones produced mainly by the adipose tissue (i.e. body fat) and play a crucial role in regulating metabolism, hunger, and insulin response.

Leptin: satiety hormone

There leptin It is known as the “satiety hormone” because it signals the hypothalamus — a region of the brain that regulates hunger, thirst, temperature, and metabolism — when the body has stored enough energy in the form of fat, thus reducing the feeling of hunger.

After a significant weight loss , leptin levels they drop rapidly . This drop is perceived by the brain as a threat to survival , triggering a compensatory response: increased hunger, reduced energy expenditure, and stimulation of eating behavior. In other words, the body interprets weight loss as a "famine" and attempts to regain the lost weight.

Even in subjects who have reached a healthy weight, leptin remains low for months, contributing to a persistent hunger and to a greater vulnerability to relapse .

Adiponectin: insulin-sensitizing and anti-inflammatory

Adiponectin It is another hormone released by adipose tissue, with a function insulin-sensitizing , that is, it improves the ability of insulin to lower blood sugar levels, and also has an action systemic anti-inflammatory .

During an initial phase of weight loss, adiponectin levels tend to increase , promoting improved insulin sensitivity and glycemic control. However, if the reduction in fat mass is too rapid or excessive, this balance is altered: adiponectin may be reduced or lose its effectiveness, especially if accompanied by metabolic stress or malnutrition from extreme low-calorie diets .

A adiponectin dysregulation compromises glucose management, increases low-grade inflammation (typical of visceral obesity), and may predispose to insulin resistance , making it easier to regain lost weight and more difficult to manage it in the long term.


The reduction of leptin and the alteration of adiponectin after a drastic diet create a unfavorable hormonal environment : more hunger, less satiety, worse glycemic control and greater inflammation. These mechanisms explain why the weight recovery after a restrictive diet it is not just a question of "willpower", but the result of deep biological adaptations that push the body to return to its previous weight .

Source: Blundell, JE et al. (2015). The biology of appetite control. American Journal of Clinical Nutrition, 94(1), 66–72.
https://academic.oup.com/ajcn/article/94/1/66/4412737

Marketing Diets: Pre-cooked Foods, Slimming Rewards, and the Weight Loss Business

In recent years - and with a massive advertising presence in the media - a commercial model of "remote weight loss" has spread which proposes pre-packaged meal plans And ready-made food kits , sold online or through call centers, accompanied by reward systems : the more kilos you lose, the more discounts, incentives or benefits you receive. This approach, which seems to combine comfort And quick promises , but presents serious critical issues physiological, metabolic and ethical .

A misleading narrative of weight loss

These companies build a simplified message: “You can lose 30-40 kg in a few months by eating ready-made meals, without cooking, without effort.” This is a profoundly misleading and biologically incorrect narrative.

In fact, the organism It is not a linear machine : simply introducing fewer calories is not enough to obtain a healthy and stable result. Weight loss, especially if rapid, activates a adaptive response of the body which, as explained above, involves:

  • Reduction of leptin levels (i.e. the satiety hormone): leads to increased hunger , less control, and a constant search for food.
  • Activation of the HPA (hypothalamic-pituitary-adrenal) axis : increases the cortisol , the stress hormone, which stimulates muscle loss and promotes the accumulation of visceral fat.
  • Thermogenic adaptation : slowing down of basal metabolism (i.e. resting energy expenditure), making it increasingly difficult to continue losing weight.

Precooked foods and hormonal response

Most of the industrial “diet” products sold in these home delivery packages are heavily processed , often rich in sweeteners, emulsifiers, protein isolates, and devoid of living fiber or synergistic micronutrients. These elements have poor impact on lasting satiety , they do not stimulate the intestinal receptors which regulate hunger and do not favor a physiological digestion .

For example:

  • The absence of natural fiber reduces intestinal production of GLP-1 , a hormone that signals satiety to the brain.
  • Monotonous and pre-packaged meals desensitize the enteric nervous system , the neural network that regulates the gastrointestinal tract, reducing perception of physiological hunger and instead promoting a “nervous” or disordered hunger.
  • The exclusion of pleasure and real contact with food compromises the dopamine circuit of food reward, generating craving (i.e. compulsive desires) in the long term.

The ethical-professional problem

As doctors, biologists and health professionals , our role is educate to health and not exploit the vulnerability of those suffering from obesity or physical discomfort. Encourage eating behavior with economic rewards , rankings or bonus for the thinnest It's not only incorrect, but dangerous. It promotes the idea that a person's worth is tied to the number on the scale, and it favors extreme restrictions , yo-yo effects and can lead to eating disorders (DCA).

Furthermore, the standardized and impersonal approach of these “distance diets” It completely ignores individual complexity : each patient has a unique medical history, hormonal status, metabolic response, lifestyle, and body composition.


Lose weight It is not a commercial act , nor a game with prizes. It is a complex biological and psycho-emotional process which requires time, clinical monitoring, nutritional education, personalized adjustments, and attention to mental health. Quick, pre-packaged, and marketing-driven solutions are unsustainable: they only offer apparent results , often followed by even more serious consequences .

Promote the culture of awareness , of autonomous choice and of the self-care it is an ethical duty of those who work in healthcare.

6. Psychological impact: anxiety, depression and body dysmorphic disorder

Drastic and prolonged caloric restriction, especially if followed independently or under social and media pressure, can have adverse effects profoundly destabilizing on the psyche , altering the mechanisms of mood regulation and promoting the onset of psychiatric disorders .

Neuroendocrine involvement

There serotonin and the Dopamine , two neurotransmitters essential for mood, motivation, and pleasure, are negatively affected by extreme low-calorie diets.

  • There serotonin (i.e. the neurotransmitter that regulates the sense of well-being, sleep, satiety and emotional stability) is drastically reduced in case of low intake of tryptophan , an essential amino acid found in protein foods.
  • There dopamine (involved in gratification and motivation) is lowered in response to prolonged food frustration , leading to symptoms of apathy , disinterest , and difficulty concentrating .

This imbalance leads to:

  • Increased anxiety anticipatory linked to meals,
  • Depressed or mood swings (atypical depression),
  • Reduced self-esteem and altered perception of one's body.

Body as Enemy: The Birth of Body Dysmorphic Disorder

In predisposed subjects, especially women and adolescents, rapid weight loss can trigger obsessive control mechanisms of body image. This is typical of the body dysmorphic disorder or body dysmorphic disorder, that is, a distorted perception of one's appearance, even when one is of normal weight or even underweight.

The subject, even after losing tens of kilos, He continues to see himself as "fat" or "unfit," seeking an unattainable ideal of physical perfection. This disorder can result in:

  • Compulsive behaviors (e.g. weighing yourself dozens of times a day),
  • Social avoidance (do not show yourself in a swimsuit, avoid mirrors),
  • Eating disorders such as anorexia, bulimia or binge eating (compulsive binge eating followed by feelings of guilt).

The role of social media and quick gratification

There constant exposure to unrealistic aesthetic models promoted by influencers, crash diets and motivational advertising (such as “30-day transformations”) feeds the cycle of dissatisfaction. brain develops an addiction to the visual gratification of weight loss , similar to a behavioral addiction mechanism.
When weight loss slows down - due to metabolic adaptation - or stops, frustration, panic and emotional relapse .

Clinical risk: underestimated diagnoses

Many of these conditions they are not diagnosed In weight loss programs, especially if followed online or independently, without psychological monitoring. Yet, the psychological impact can compromise:

  • There quality of life ,
  • The social and emotional relationships ,
  • There working capacity ,
  • There emotional stability in the long term.


An intervention on weight It cannot ignore mental health . Nutritional strategies must be sustainable, gradual, empathetic, and supervised by qualified professionals.
Include psychological support — including preventive support — it's not an optional , but a component fundamental to any serious treatment of overweight or obesity.

Conclusions

Lose weight It is not a simple balance between calories introduced and calories consumed , but a biologically complex process, which involves in a profound and interdependent way the endocrine system (i.e. the hormonal system), metabolism (the body's chemical reactions) and the neuropsychic network (i.e. the brain, emotions, neurotransmitters) .

Any attempt to force this balance with drastic diets, psychoactive drugs or industrialized food routes can defuse natural regulatory mechanisms , generating over time:

  • Slowing of the basal metabolism , or the amount of energy the body uses at rest;
  • Chronic hunger and appetite dysregulation linked to imbalances in ghrelin, leptin and other hormones;
  • Loss of lean mass , with muscle weakening and worsening of body composition;
  • Mental changes and dependence on rapid weight loss strategies , with risk of body dysmorphic disorder, anxiety and depression.

The scientific evidence cited demonstrates that Any serious approach to overweight and obesity must be based on gradualness, clinical expertise and personalization , taking into account the biological complexity of each individual.

There is no such thing as a miracle food , a universal program or a curative drug . Instead, there is a need for educate the body and mind to a new metabolic normality , sustainable over time, respectful of physiological needs, emotions, and biological rhythms.

True success in the nutritional and clinical fields It's not how fast you lose weight , but the quality with which lasting health is built .

Dr. Vito Traversa
Biochemist, Nutritionist, Kinesiologist, Functional Rehabilitation Therapist

Back to blog