It sounds like a form of torture. Consuming nothing but at least a liter of water a day for 25 to 30 days. But behind the Iron Curtain in the 1950s, psychiatrist Dr Yuri Nikolayev was treating patients at a Moscow sanatorium with a radical form of fasting that was hailed by American orthomolecular psychiatrist Dr Allan Cott as an “unparalleled achievement” in restoring schizophrenics to full function.1
What first surprised Nikolayev was that his mentally ill patients suffering depression, phobias and obsessive syndromes also showed improvements in physical conditions such as hypertension, arthritis, asthma and eczema. Smokers quit their addiction, and even alcoholics became near-teetotalers.
“Fasting not only has an impact on mental illness, but also the entire personality,” said Dr Valeri Gurvich, a psychiatrist at the Moscow Psychiatric Institute who worked under Nikolayev for 18 years.2
The finding suggested that improvements in systemic health naturally flow through to the alleviation of mood disorders, whether or not mental illness is the primary target of treatment.
Seven decades later, what we now know about the neurochemistry of the brain is shedding light on why Nikolayev’s work was so successful, and how less radical forms of this therapy—such as intermittent fasting—can improve depression through metabolic detoxification.
Intermittent fasting includes hours or days of no or minimal food consumption without deprivation of essential nutrients. The most common versions are alternate-day fasting, 5:2 fasting (fasting two days each week) and daily time-restricted fasting, such as only eating during six- or eight-hour windows.
A review of research into intermittent fasting published in The New England Journal of Medicine in 2020, coauthored by professor of neuroscience at Johns Hopkins University Dr Mark Mattson, noted that weight loss was not the main driver of the health benefits shown by clinical studies. Instead, it is metabolic switching, when fasting triggers the body to move from sourcing its energy from glucose, which is stored in the liver, to ketones, which are stored in fat.
“Ketone bodies are not just fuel used during periods of fasting,” the authors write. “They are potent signaling molecules with major effects on cell and organ functions. Ketone bodies regulate the expression and activity of many proteins and molecules that are known to influence health and aging.”3
Animal studies reveal that levels of brain-derived neurotrophic factor (BDNF) begin to surge as soon as 12 hours after a fast begins.4 This molecule is vital to the survival, growth and maintenance of neurons in key brain circuits involved in emotional and cognitive function.5
Brain imaging studies have consistently shown a reduction in the size of brain regions that regulate mood and cognition in depressed patients, including the prefrontal cortex (which modulates cognitive control) and the hippocampus (responsible for learning and memory). Furthermore, postmortem studies report fewer synapses in these areas.6
Autopsies of suicide victims also found only about half the levels of BDNF in certain key brain regions compared to the control group.7
This is where fasting-induced BDNF production may play a crucial role in mediating the symptoms of depression by promoting synaptic plasticity, a process that enables learning and memory through changes in the connections between individual neurons and neuronal networks.
“We know in animals that intermittent fasting increases BDNF levels and that it has an anti-anxiety effect, and often depression and anxiety go hand in hand,” says Mattson.
“In particular, chronic anxiety is often a precursor to clinical depression. So the available data are consistent with the possibility that intermittent fasting could help people mitigate or protect them against anxiety and depression.”
The theory of mood disorders as primarily based on a chemical imbalance in the brain is being supplanted by a more holistic understanding of the many factors that influence depression and cognition.
“Chemical imbalance is sort of last-century thinking. It’s much more complicated than that,” Dr Joseph Coyle, a professor of neuroscience at Harvard Medical School, told National Public Radio as far back as 2012. “It’s really an outmoded way of thinking.”
In a landmark meta-analysis of clinical trial data submitted to the US Food and Drug Administration (FDA) for the licensing of new-generation antidepressants, no significant difference was found between the effects of the drugs and the placebo effect except among the severely depressed.
However, the study found that the severely depressed had become less responsive to the placebo, rather than more responsive to the drugs.8
British psychiatrists Mark Horowitz and Michael Wilcock write in the Drug and Therapeutics Bulletin that in the UK, one in six adults was prescribed an antidepressant between 2019 and 2020.9
“Much of the evidence of their efficacy comes from short-term placebo-controlled trials,” they write, “which tend not to include outcomes that are of greatest relevance to patients, such as social functioning or quality of life, but rather restrict outcomes narrowly to symptom measures.”
A 2022 paper on the relationship between the gut and major depressive disorder argued that depression treatment tends to fail when it is exclusively focused on a chemical cause.
“[I]t is becoming more evident that the rising prevalence of depression, especially in developed countries, is linked to changes in dietary and sleep patterns derived from high levels of stress,” the authors write.10
Various forms of fasting may be one way of resetting the physiology impacted by stress and supporting the neuroplasticity required to move out of the negative fixed states of mind that characterize depression.
In 2019, researchers from the Icahn School of Medicine at Mount Sinai reported that fasting reduces inflammation, a known biological marker and risk factor for depression, and improves chronic inflammatory diseases.11 Reduced levels of inflammation may also help enhance BDNF expression.12
“The bad kinds of stress are things that you’re constantly ruminating about, something that you don’t have direct control over, and you can’t really do anything to mitigate it,” Mattson says. “Stress where the [hormone] cortisol levels stay up chronically has negative effects on neurons in the brain and reduces BDNF levels.”
French researchers published the first quantitative analysis of how well fasting interventions alleviated stress, anxiety and depressive symptoms in late 2021. After analyzing 11 studies with a total of 1,436 participants, they found that fasting groups had lower anxiety, depression and body mass index without an increase in fatigue.13
“When they’ve done studies with a prolonged amount of fasting, you’ll get a reduction in depression and anxiety,” says Cynthia Thurlow, a nurse practitioner, functional nutritionist and author of Intermittent Fasting Transformation (Avery, 2022). Patients self-report improvements and often need less medication.
Cynthia Thurlow likes to remind her patients that digestion begins in the brain, in the way people think about their food before they have even taken a bite. Conversely, 95 percent of the mood-regulating neurotransmitter serotonin, which is targeted by conventional anti-depressant drugs, is produced in the gut.
It is a reversal in the way we have been taught to think about food and mood.
The gut microbiome—the range of microorganisms in the gut, including bacteria, fungi and viruses—plays a major role in the bidirectional communication between the gut and the brain.
Researchers in Finland recently found a link between a specific gut microbe, Morganella, and depression. This is further evidence that people with mental health conditions often have very different microbes in their gut.1
Alterations in the composition of gut microbiota are implicated in causing leaky gut (an increased permeability of the gut barrier), activating systemic inflammation, affecting the efficacy of serotonin and changing levels of brain-derived neurotrophic factor (BDNF).2
However, a Chinese study last year found that intermittent fasting enriched the gut composition of diabetic mice and pointed to several other potential benefits, including increased microbial diversity, reduced inflammation and increased production of short-chain fatty acids, which inhibit the growth of bad bacteria.3
When it is time to break the fast, the Mediterranean diet, abundant in plant-based ingredients, fiber and omega-3 fatty acids, has been found to establish a diverse microbiome associated with protection against depression. Aromatic spices and herbs such as oregano, rosemary and thyme common to that diet are also good for gut microbiota.4
A Harvard study of over 80,000 nurses found that a diet high in flavonoids is associated with lower risk for depression, especially among older women.5 Two clinical
trials also found that high-flavonoid fruit and vegetable intake led to significant improvements in cognitive performance and increases in serum BDNF levels.6
Alternations of food availability and scarcity have been normal for most humans throughout history, who coped with periods of restricted food intake by storing food as fat. It is a feast-or-famine model of evolution in stark contrast to the modern-day diet of continuous consumption of energy-rich food.
“This is the ancient secret. This is the cycle of life,” writes Dr Jason Fung in The Obesity Code: Unlocking the Secrets of Weight Loss (Greystone Books, 2016). “Fasting follows feasting. Feasting follows fasting. Diets must be intermittent, not steady.”
The three-meals-a-day lifestyle, with its abundance of macronutrients, pushes the cellular activity of the human body toward the ‘feast’ phase of growth, in which muscle is built and fat is laid down as a future resource. However, without periods of fasting, there is no counterbalancing repair-and-restore phase triggered by the metabolic switch.
According to Thurlow, the past two years of the pandemic have given many of her patients the time and space to question the modern diet.
“We need to get beyond that antiquated dogma that we have to eat every two to three hours to stoke our metabolism,” she says. “We wouldn’t be here as a species if we couldn’t go through periods of food scarcity, and that was way before refrigeration and pasteurization.”
Mattson says the need to find sources of food for survival led to the selection of genes that strengthened our capacity for learning and memory. The same brain areas involved in learning and memory are associated with defective neural plasticity in major depressive disorder and treatment-resistant depression.
Intermittent fasting and exercise are two of the chief ways to induce greater plasticity as a protective mechanism against depression.
“People in general, when they think of fasting, they’re thinking of a week or more. But very short fasts are very normal from an evolutionary perspective,” says Mattson. “The modern environments are silos, and organ systems become complacent.
“They’re not exposed to the kinds of mild, beneficial stressful conditions that we evolved in. Therefore, the ability to cope with stress, whether it’s psychological stress or even physical trauma or a disease, is compromised.”
Mattson uses the analogy of what happens after a workout to illustrate how the cascade of metabolic, cellular, circadian and neural benefits from fasting actually take place after a fast is broken. Just as muscle is built when the body is at rest after exercise, in the case of fasting, new synapses are formed between nerve cells when nutrients become available again.
“The risk factors for depression include chronic anxiety, chronic stress and, in terms of metabolic state, obesity and insulin resistance,” says Mattson.
“It’s very likely that not exercising as much as you should, overeating—particularly high-carb, simple-sugar foods—and then being under a lot of psychological stress are all contributing to the increased incidence of chronic anxiety disorders and depression. If you look at it from an epidemiological and demographic perspective, where you do statistics on big populations, the increase in depression tracks with the increase in poor metabolic health.”
The late professor John T. Cacioppo, a pioneer in the field of social neuroscience, found that loneliness wasn’t a result of depression, but actually led to depression. In Lost Connections: Why You’re Depressed and How to Find Hope (Bloomsbury Publishing, 2018), Johann Hari writes that Cacioppo went back to pre-agricultural society to find out why loneliness caused cortisol levels to spike1 and was a predictor of earlier death.2
“Against harsh odds they barely survive, but the fact that they survive at all they owe to the dense web of social contacts and the vast number of reciprocal commitments they maintain,” Cacioppo wrote to one of his colleagues of life among small tribes.
“Evolution fashioned us not only to feel good when connected, but to feel secure. The vitally important corollary is that evolution shaped us not only to feel bad in isolation, but to feel insecure.”
The idea of fasting may be a hard sell for people already struggling to balance their eating schedule and who may fear hunger pains, but Thurlow says it may be the standard Western diet itself that is creating food cravings well beyond when the belly is full.
“The highly processed, hyper-palatable foods really play a role in this because they dysregulate appetite and satiety hormones,” she says. “Most of us are overly nourished, meaning we are eating constantly. So a lot of people have lost the sensation of what it feels like to be truly hungry because we never give our bodies a break. It’s like we keep topping off the gas tank.
“If we don’t work through the fuel in our bodies, we’re never going to be metabolically efficient.”
Another review of medical fasting and depressive symptoms found that sometime between day two and day seven of a fast, patients reported improvements in mood, alertness and tranquility. This form of fasting involves consuming only mineral water and fruit juice in limited amounts, accompanied by moderate physical exercise, for one to three weeks.14
Exercise is another ‘good’ stressor that triggers the release of BDNF as well as endorphins—the body’s natural feel-good painkillers. Patients across the studies also reported a feeling of well-being and sometimes euphoria. The latter may be explained as an evolutionary adaptive response: the endorphin spike motivated the individual to search for food.
Thurlow says BDNF helps create and grow healthy mitochondria—the specialized structures found in cells that extract energy from nutrients—which in turn helps reduce oxidative stress.
Oxidative stress—the overabundance of “free radical” reactive oxygen molecules in the body—is considered a systemic marker of damage observed in patients with major depressive disorder.15
“By providing this degree of digestive rest from fasting, we will get better production of healthy dopamine and serotonin [mood-regulating neurotransmitters], as well as upregulating autophagy,” says Thurlow.
Autophagy removes diseased and disordered cells, which sets the stage for increased manufacture of new mitochondria, cell growth and plasticity during the recovery period. Mattson likens it to garbage disposal.
“Fasting and also exercise enhance that cellular garbage disposal and recycling system,” he says. “Conversely, being sedentary and overfed will impair that system. Cells go from that stress-resistance mode into the growth-and-repair mode when you start eating again.”
In a study of over 1,400 people who completed fasts from four to 21 days long, 93 percent of participants reported improvement in
“physical and emotional well-being,” and fasting for any length of time was linked to significant improvement in blood levels of fats, glucose,
and other health parameters. And among the 404 participants who had a major health complaint at the start of the study, 84 percent saw their condition improve.
Intermittent fasting reverses some of the most widely held beliefs about diet and nutrition. Breakfast may not be the most important meal of the day after all. The 16:8 variation of intermittent fasting divides the day into 16 hours of fasting and an eight-hour window for eating that pushes back the first meal of the day closer to noon.
This variation is considered the easiest to adopt. “Most of the time that you’re in a fasted state, you’re sleeping. So it’s not as if your brain is thinking, ‘I’m not eating,’” Thurlow says.
A 2018 paper coauthored by Mattson found that lifestyles that fail to flick the intermittent metabolic switch “result in suboptimal brain functionality and increase the risk of major neurodegenerative and psychiatric disorders.”16
Conversely, the same study found that all the different intermittent fasting approaches are likely to improve brain health, allowing people to choose an approach that suits their daily and weekly schedules.
Mattson, whose papers on intermittent fasting have been cited over 180,000 times, puts that knowledge to work in his own life. He hasn’t had breakfast in 40 years and does aerobic exercise before breaking his 18-hour fast to optimize the health benefits.
While human and animal studies have found that regular aerobic exercise can improve cognitive performance and protect against anxiety and depression,17 combining exercise and intermittent fasting results in better improvements in neuroplasticity than fasting alone, at least in animals.18
Thurlow says fasting is a form of hormetic stress—a biological phenomenon whereby a low dose of an otherwise detrimental or toxic agent has a beneficial effect.
“As a society, we are way too comfortable. Hormetic stress, high-intensity interval training, cold exposure, fasting and heat exposure are all beneficial stress in the right amount at the right time,” she says.
“We can improve brain health, cognitive function and mood just by changing meal frequency, anti-inflammatory nutrition and looking at things in a more proactive way.”
Dr Allan Cott was so inspired by Dr Yuri Nikolayev that he visited the Russian psychiatrist and later adopted fasting for his patients at his New York practice. He reported that Nikolayev had treated 8,000 patients with fasting with a marked improvement in 70 percent of cases. Six years later, 47 percent had maintained that improvement.
Validating these results in schizophrenic patients proved difficult because of the different diagnostic criteria and research methodology between the West and the Soviet Union.19 However, one subgroup of 100 patients did meet the definition used in American psychiatric practice, and improvements were recorded in 40 to 60 percent of such cases.20
Cott wrote that after treatment, patients were put on a meat- and dairy-free diet, and those who broke the diet relapsed.
Once again, BDNF may help explain those results. Animal studies have shown that a diet rich in saturated fat and refined sugar can influence brain structure and reduce the level of BDNF in the hippocampus.21 A Polish clinical trial of 18 healthy males reported that even a single high-fat meal reduced BDNF levels in blood-plasma almost 28 percent.22
“For a long fast, there’s the big issue of how often you do them, and will some beneficial effect disappear when you go back to eating as you previously would,” says Mattson.
“Whereas these daily short fasts and daily or three-days-a-week exercise can be maintained, and it’s engaging a lot of these beneficial mechanisms.”
Germany’s Buchinger Wilhelmi therapeutic fasting clinic collected data from 1,422 subjects who completed four- to 21-day fasts in 2016. Participants consumed only organic fruit juice and soup averaging 200–250 calories per day, accompanied by physical activity.
In 84 percent of cases, serious health conditions such as arthritis and type 2 diabetes as well as fatty liver, high cholesterol, high blood pressure and fatigue improved through fasting. The program also improved known pathways linked to depression such as obesity, and levels of the hormones insulin and leptin associated with diabetes.23
“The continuous increase in emotional as well as physical well-being was evident across all groups of different fasting period lengths,” the study authors write.
Buchinger attributes this result to its approach of integrating the physical, community and spiritual dimensions of the fast into their program.
Such holistic treatment addresses the missing link between modern stress and our evolutionary past. Those hunter-gatherers who bequeathed us a genetic predisposition to fasting did so in the context of social cohesion (see box, page 33)
According to Thurlow, fasting is not just a physiological process, but for many people, also a spiritual and emotional one. If detoxification and digestion are first addressed at the physical level, people may be better equipped to break down the modern challenges of social isolation and overwhelm associated with depression and anxiety.
“The root cause is actually more cultural than anything else, and systemic as well,” she says. “All those medications act on brain neurochemistry, but actually if we would change our diets and eat less frequently, I think there would be a significant reduction in mood disorders in general.”
There are three main forms of intermittent fasting, each with its own schedule and challenges.
Time-restricted eating
Also known as the 16:8 or 14:10 method, this fast is the easiest to manage around a regular schedule by compressing eating into an eight- or 10-hour window. It is recommended that people unaccustomed to fasting try abstaining from food for 12 hours and build their way to 14 or 16 hours.
Alternate-day fasting
This is a real feast-and-famine approach that involves limiting food intake on fasting days to 500 calories, or on stricter regimes, none at all. However, one study showed that a group of metabolically healthy obese adults who followed this pattern for six months had significantly elevated LDL cholesterol levels after another six months off the diet.1
Conversely, a randomized controlled trial found alternate-day fasting was a safe alternative to calorie restriction with a number of health benefits.2
The 5:2 fast
This variation involves picking two non-consecutive days per week in which only one moderate-sized meal under 500 calories is consumed. A normal diet is maintained for the rest of the week.
Dr Mark Mattson pioneered the 5:2 fast when he published two papers investigating the impacts of fasting in overweight women using this method.3 In the second study, the women in the 5:2 group were more likely to adhere to the protocol compared to the control group, who were put on a 25 percent calorie restriction every day.4 This suggested the 5:2 fast was more sustainable than a regular weight-loss diet.
Exercise caution
Intermittent fasting is not safe for pregnant women, children, people with advanced diabetes or on diabetes medication, and people with a history of eating disorders such as anorexia or bulimia. It is recommended that all people only consider fasting after consulting their healthcare provider.
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The power of connection
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