Is Intermittent Fasting Safe and Beneficial?

Practiced for centuries as a ritual in many religions, intermittent fasting (IF) is rapidly growing in popularity as a weight loss and health-improvement tool. A 2024 survey found that as many as 13% of Americans followed an IF regimen during the previous year. But does it really offer health benefits? And are there any downsides?

“Switching between time periods of negative energy balance — short fasts and/or exercise — and positive energy balance — eating and resting — can optimize general health and brain health, too,” Mark Mattson, PhD, adjunct professor of neuroscience, Johns Hopkins University School of Medicine, Baltimore, told Medscape Medical News.

IF is not a diet but rather a pattern of eating, said Mattson, former chief of the Laboratory of Neurosciences at the National Institute on Aging. “A diet is defined by what is eaten and how much of those particular foods are eaten, while IF concerns when and how often food is eaten.”

One type of IF is daily time-restricted eating (TRE), in which the individual limits the time window for eating to 6-8 hours and fasts about 18 hours each day, said Mattson, author of The Intermittent Fasting Revolution. The exact window of eating/fasting isn’t important, although “it’s not good to eat right before going to bed,” he added.

TRE is a more “precise and scientific” description of this eating pattern rather than IF because the fasting period can be as little as 12-13 hours per day, Valter Longo, PhD, director of the Longevity Institute, USC Leonard Davis School of Gerontology, Los Angeles, told Medscape Medical News. “The key is that it should take place around the same time each day,” he said.

Another IF pattern is the 5:2 diet, in which the individual eats as usual for 5 d/wk but eats only one moderate-sized meal (500-700 calories) the other 2 days, Mattson said. Other patterns include alternate-day fasting (ADF) and fast-mimicking diet (FMD) as shown in the Table below.

Different Metabolic State

Humans evolved in conditions of relative food scarcity, making IF a common occurrence.

“Our ancestors had to forage or hunt. Food was available only intermittently. When they weren’t eating, they were food-deprived but needed physical energy to search for and obtain their next meal,” Mattson noted. Those who developed adaptations that allowed them to function optimally in the fasting state survived, passing their genes down through the generations.

Our modern-day eating pattern — three meals plus snacks — is a relatively recent development in terms of human evolution, Mattson explained. This pattern can lead to food overconsumption and result in overweight or obesity, particularly when combined with a sedentary lifestyle. It also can cause metabolic morbidities, such as insulin resistance.

So how might adopting an IF regimen prevent or ameliorate these problems?

One way it addresses overweight is by limiting calorie intake. “The estimate is that by eating only during 11 hours a day, the person will consume 7000-15,000 fewer calories per month,” said Longo, author of The Longevity Diet.

But IF also appears to tap into the adaptations that enabled our human ancestors to survive periods food scarcity.

“There seem to be changes in the breakdown of fats, which can promote fat loss instead of fat storage, as well as changes in insulin sensitivity, which we’re only beginning to understand,” Longo said.

During a fast, the body receives no energy intake and uses glucose stored in the liver for fuel, Mattson noted. Humans have evolved to burn fat once the liver’s store of glucose, which lasts no more than 12 hours, has been depleted. The body then uses ketones, which are derived from fat, as an alternative energy source. It is known that sustained negative energy balance (in which energy intake is less than energy expenditure) can lead to weight loss. Negative energy balance together with increased fat oxidation should lead to weight loss through the reduction in fat mass.

The period of IF must be long enough to trigger that switch, Mattson said. At that point, the body is in a metabolic state called ketosis, defined as elevated ketones in the blood and urine. Ketones provide fuel for cells, particularly nerve and muscle, by stimulating them, promoting resistance to stress and combating disease.

The most important ketone in this process is beta-hydroxybutyrate. It “provides an alternative energy source and activates signaling pathways involved in neuroplasticity,” Mattson said.

Ido Goldstein, PhD, assistant professor, Institute of Biochemistry, Food Science and Nutrition, Hebrew University of Jerusalem, Jerusalem, Israel, explained that repeated fasting “triggers a cellular memory mechanism in the liver, enhancing the liver’s response to subsequent fasting events.”

This was demonstrated in a study in which Goldstein and colleagues randomized mice to an unrestricted or an ADF diet. Mice in the ADF group underwent 15 cycles of fasting-refeeding over 30 days. On day 31, all mice fasted for 24 hours. Half were then euthanized. The remaining mice were refed and euthanized 24 hours later.

“We found that the liver ‘remembered’ past fasting events. Mice that underwent IF responded more efficiently to the next fasting bout compared to mice that underwent fasting for the first time,” Goldstein said. “This ‘memory’ was made possible by a transcription factor termed PPARa [peroxisome proliferator–activated receptor alpha], which activated genes involved in fuel production, leading to increased production of ketone bodies.”

The findings confirm that the “effects of fasting are not only due to reduced calorie intake. Rather, fasting imposes a comprehensively different metabolic state in the body, which mediates health benefits,” Goldstein said.

Far-Reaching Benefits

Research has identified a wide range of purported health benefits of IF. Mattson and colleagues randomized 40 cognitively intact older adults with insulin resistance to either a 5:2 eating pattern or a “healthy living diet” for 8 weeks. Both diets reduced neuronal insulin resistance and the pace of brain aging. Both improved memory and executive function, with the 5:2 dietary pattern showing superiority.

An umbrella review encompassing 23 systematic reviews and meta-analyses found that compared with a nonintervention diet in adults with overweight or obesity, IF reduced waist circumference; fat mass; and fasting insulin, low-density lipoprotein cholesterol, total cholesterol, and triglyceride levels but increased fat-free mass. Modified ADF also reduced fat mass.

In other research, IF showed positive impacts on weight loss, insulin resistance, and leptin and adiponectin levels in patients with metabolic syndrome. Various IF regimens have been found to beneficially impact the cardiovascular system, decrease inflammation, strengthen immunity, protect brain health, improve sleep quality, delay aging, potentially eliminate insulin resistance, and prevent cancer.

Can Fasting Be ‘Mimicked?’

The idea behind FMD, in which the person eats specially prepared food once a month for 5 days, is to transform fasting “into something like a medicine,” Longo said. “It has calories, but the food composition is such that people respond on a molecular or endocrinologic level similarly to how they would respond to fasting.” The food products have about 60 ingredients, including “a lot of vegetables and vegetable-based fats, a lot of oils, high-fat, low-protein, low-sugar, and low-calorie foods.”

Research has demonstrated that FMD cycles promote regeneration and reduce damage in the pancreas, blood, gut, nervous system, and kidneys of mice, Longo said. This approach has been tested in humans for its impact on diabetes, prediabetes, obesity, cancer, and longevity.

“The trials point to a reduction in A1c, blood pressure, and body fat, with no reduction in lean body mass, when taken in the absence of drugs,” Longo reported.

A study compared FMD fasting cycles in patients with type 2 diabetes (T2D) and diabetic nephropathy with similar cycles of a Mediterranean diet for 6 months, with 3 months of follow-up. More improvement was found in microalbuminuria and markers of insulin resistance, lipid oxidation, and senescence in the FMD group than in the Mediterranean diet group at the end of the study period.

In multiple trials of FMD, 50%-70% of patients with diabetes reduced their medication use, Longo said. For example, a study compared a monthly FMD program with regular primary care in people with T2D who use metformin. Those who participated in FMD had less need for glucose-lowering medication and had improved A1c.

“This is important during our current era of GLP-1 RA [glucagon-like peptide 1 receptor agonist] drugs, which have a powerful effect on weight and diabetes management but also have side effects, like bone density loss, muscle loss, and optic nerve ischemia,” Longo said. With FMD, “we don’t see these side effects, and it works similarly to GLP-1 RAs.”

Potential Downsides

Some studies indicate that IF isn’t for everyone and can have side effects.

Research has found that IF is not recommended in some patients, including premenopausal women; people with hormonal imbalances; pregnant and breastfeeding women; young children; and people with a history of eating disorders, food insecurity, type 1 diabetes, advanced age or frailty, and dementia.

Among IF’s potential adverse effects are hypoglycemia, dizziness, and weakness, which can be aggravated by simultaneous use of antidiabetic drugs. Fluctuating glucose concentrations can be associated with increased instability in older adults, potentially leading to falls and fractures. A recent study of close to 3000 adolescents and young adults found IF during the previous 13 months was significantly associated with eating disorder pathology, especially in women.

An observational analysis on TRE presented on March 18, 2024, found that individuals who limited their eating to a period of

However, in a commentary for Medscape Medical News, Christopher Labos, MD, CM, MSc, a cardiologist at the Hôpital Notre-Dame, Montreal, Quebec, Canada, highlighted methodological concerns. For example, the researchers didn’t provide information about the quality of the participants’ diet, which might have consisted of “ultraprocessed junk food.”

Some participants might have adopted an IF eating pattern because they engaged in shiftwork or had an irregular sleep schedule, both independent cardiovascular risk factors. Peer review and further research are necessary, Labos concluded.

Advising Patients

Longo recommends that clinicians “start considering the option of TRE instead of [weight loss] drugs and reducing drug use in patients by using FMD diets to achieve similar if not better goals.”

Specific IF eating patterns are “safe, effective, easy to do, and inexpensive because it doesn’t cost anything or has a low cost,” he said. On the other hand, “it takes discipline so that the person is eating roughly between 7 AM and 6 or 7 PM each day.”

However, important questions remain regarding the long-term sustainability of IF. For example, in an ADF study, self-reported hunger on fasting days didn’t wane over time, so the regimen may not be a viable long-term public health intervention.

It takes ≥ 2-4 weeks for a person who’s accustomed to consuming three meals per day plus snacks to adapt to an IF eating pattern, Mattson said. He likened the process to initiating an exercise routine. “It takes time to adjust.”

TRE and FMD aren’t “quick fixes” for obesity or other health problems, Longo said. “The idea is not to adopt any weight loss method that will set a person up to regain the weight multiple times. At our clinics, dietitians and clinicians take time helping people with prediabetes, diabetes, or obesity get where they need to be, which can take as long as 1-2 years.”

These dietary approaches aren’t “one-size-fits-all” or “all-or-nothing,” he added. “We adopt a version that a person can handle. We mainly focus on selecting a combination of diets, for example, FMD and TRE, that the person can keep long term.”

During the 5-day FMD, the person is “always eating, which may help prevent the person from going into ‘thrifty mode,’ when weight loss is reduced because the body isn’t receiving enough calories and the metabolism starts slowing down to conserve energy,” Longo said.

During the nonfasting portion of an IF plan, people should avoid eating an unhealthy diet high in sugar or ultraprocessed foods, Mattson said. He recommends “what’s generally considered a healthy balanced diet,” including vegetables, beans, fruit, nuts, whole grains such as oats and wheat, Greek yogurt, and some meat, usually fish or chicken. Mattson himself follows this eating pattern.

He offered these tips for physicians recommending IF to their patients:

• Outline the plan with the patient.
• Keep in touch with the patient via text or internet portal daily during the first week and weekly during the first 2 months.
• See the patient for follow-up after 2 months. Evaluate body weight, pulse rate, blood pressure, blood glucose and A1c levels — ideally at the end of the person’s fasting period — and measure ketone levels.
• See patient every 6 months thereafter for repeat evaluations/consultation.

“We now have enough evidence from human studies to justify prescribing IF to people with obesity and T2D, and emerging evidence is supporting this approach for a wide range of other conditions,” Mattson said. “These exciting developments can usher in a new era of improved health for our patients.”

Mattson is the author of the Intermittent Fasting Revolution. Goldstein and Labos declared no relevant financial relationships. Longo has equity interest in L-Nutra, a company that develops medical food, and is the author of several books, including The Longevity Diet.

Batya Swift Yasgur, MA, LSW, is a freelance writer with a counseling practice in Teaneck, New Jersey. She is a regular contributor to numerous medical publications, including Medscape Medical News and WebMD, and is the author of several consumer-oriented health books, as well as Behind the Burqa: Our Lives in Afghanistan and How We Escaped to Freedom (the memoir of two brave Afghan sisters who told her their story).