Instalab ResearchBy the end of the first day without food, liver glycogen is largely depleted and the body begins to rely more heavily on fat for fuel. By the second day, ketone levels rise significantly, providing an alternative energy source for the brain. At around 72 hours, these metabolic shifts become fully established.
Clinical studies in healthy volunteers have shown that during this stage insulin levels fall dramatically while counterregulatory hormones such as glucagon, cortisol, and growth hormone rise. This hormonal pattern helps preserve blood glucose for critical tissues while encouraging fat breakdown and ketone production.
Researchers have documented selective increases in norepinephrine spillover from fat tissue after 72 hours, suggesting that the sympathetic nervous system is directly mobilizing fat stores for fuel. In simple terms, the body has switched into survival mode, burning fat at high efficiency while sparing protein as much as possible.
One of the fascinating findings from clinical research is how a prolonged fast alters cortisol patterns. In patients with rheumatoid arthritis, a 72 hour water-only fast increased both free and total cortisol concentrations by up to 260% at night. This rise in nocturnal cortisol may help explain why fasting protocols have been linked to temporary improvements in autoimmune symptoms. Cortisol is a powerful anti-inflammatory hormone, and its surge during fasting may provide the body with a built-in anti-inflammatory reset.
This observation, although tested in a small clinical study, provides a clue into why longer fasting protocols may influence immune-mediated diseases. Instead of simply starving, the body is actively adapting, boosting its internal stress defenses and rebalancing inflammatory responses.
The brain is highly dependent on glucose, but during prolonged fasting it learns to adapt. Clinical imaging research in healthy women found that after a 72 hour fast, there were measurable shifts in brain metabolites. Levels of glutamine and glutamate dropped across multiple brain regions, suggesting changes in neurotransmitter and energy metabolism. Participants also reported improved mood scores following the fast.
Another study using advanced magnetic resonance spectroscopy confirmed that glial cells, which support neurons, increased their acetate metabolism after 72 hours without food. This adaptation was closely tied to how well participants tolerated hypoglycemia during the fast. In effect, the brain was reprogramming itself to rely less on glucose and more on alternative fuels.
These findings help explain why prolonged fasting does not necessarily impair cognition despite very low blood sugar. Instead, the brain undergoes an adaptive shift that may actually protect its function under metabolic stress.
One of the most direct human studies on 72 hour fasting examined patients with type 2 diabetes. Researchers tested whether starting a time-restricted eating plan with a three-day fast made any difference compared to simply starting the diet alone. Interestingly, those who began with the 72 hour fast experienced a significant reduction in systolic blood pressure, while those who skipped the induction fast saw more improvements in weight and body mass index. This suggests that the three-day fast may act as a short-term intervention to lower blood pressure, even if it does not outperform other strategies for weight loss.
Another well-controlled study in healthy men revealed that a 72 hour fast caused a sharp increase in norepinephrine release specifically from fat tissue, while overall energy expenditure did not change. This selective response means the body prioritizes fat breakdown during prolonged fasting without unnecessarily accelerating total metabolism. It is a targeted survival strategy that ensures energy supply without wasting reserves too quickly.
The story is less clear when it comes to insulin sensitivity. A landmark study using glucose clamps in healthy volunteers found that after a 72 hour fast, skeletal muscle became resistant to insulin. Glucose uptake was impaired, and muscle tissue showed accumulation of both fat and glycogen. At the same time, overall insulin levels in the body were lower, and fat burning was dominant.
These findings reveal an important paradox: while fasting lowers insulin levels systemically, muscle cells themselves temporarily resist insulin action. For healthy individuals this adaptation may not matter, but for those with diabetes or metabolic instability, it could pose risks.
Beyond metabolism and cardiovascular health, fasting has been investigated as an adjunct to cancer treatment. A systematic review of clinical trials found that fasting periods of 24 to 72 hours before chemotherapy appeared safe and in some cases reduced toxicity to healthy cells while leaving cancer cells more vulnerable. While the studies reviewed were small and had risk of bias, the consistent observation was that fasting did not worsen side effects and may offer protective benefits.
Building on this, glioblastoma patients in a prospective trial completed a 72 hour water-only fast before surgery. Researchers observed shifts in lipid metabolism, including reductions in phospholipids and increases in free fatty acids, suggesting that fasting had a real impact on the metabolic environment of the tumor. Although it is too early to say whether this improves clinical outcomes, these results add weight to the idea that fasting could be paired with therapy as a metabolic stress strategy against cancer.
While the science points to potential benefits, it is equally important to acknowledge the risks of a 72 hour fast. Clinical studies have repeatedly shown that prolonged fasting induces insulin resistance in skeletal muscle, alters protein metabolism, and increases markers of muscle breakdown. For example, fasting increased net release of phenylalanine from muscle, indicating protein loss, and reduced activation of the mTOR pathway, which is critical for cell growth and repair.
For older adults, the picture is even more concerning. Large cohort studies of prolonged nightly fasting found no consistent benefits for cardiovascular or inflammatory biomarkers. In fact, some results suggested possible harm, such as reduced HDL cholesterol. While these studies involved habitual fasting windows rather than a single 72 hour fast, they raise the possibility that prolonged fasting may not be beneficial for all populations, especially the elderly.
Another consideration is safety in people with diabetes. Clinical crossover trials have shown that patients with type 1 diabetes can tolerate fasting up to 36 hours under careful supervision without major complications, but the risk of hypoglycemia increases with time. Extending to 72 hours without medical oversight could be dangerous for such individuals.
Taken together, the science shows that a 72 hour fast is a powerful physiological intervention. It lowers insulin levels, increases fat mobilization, raises counterregulatory hormones, and reprograms the brain’s metabolism. Clinical studies suggest it can reduce blood pressure, potentially protect against chemotherapy toxicity, and may even influence tumor metabolism.
At the same time, it carries risks. Skeletal muscle insulin resistance, protein breakdown, and unclear long-term cardiovascular effects highlight why such fasts should not be undertaken lightly. They are best approached occasionally, under medical guidance, and likely not appropriate for everyone.
The 72 hour fast is neither a miracle cure nor an outright danger. It is a reset button for the human body that, when pressed in the right context, may offer unique benefits. But as with all powerful tools, timing, supervision, and individual health status matter more than the hype.
