48- to 72-hour fast

What it is

A fast of two to three days with only water or zero-calorie drinks, done occasionally rather than every week. In the human studies found, it was tested as 24, 48 or 72 hours of fasting around chemotherapy, and as a single 72-hour fast in laboratory studies of muscle metabolism.

What the research says

Evidence is very limited: small, short studies of cancer patients fasting around chemotherapy, and laboratory studies of 8 healthy men. Fasting up to 72 hours around chemotherapy was feasible with symptoms up to grade 2 (fatigue, headache, dizziness, some low blood sugar and low sodium). Reductions in chemotherapy toxicity were either not statistically significant or limited to blood-count measures in a 13-person pilot. A 72-hour fast increased muscle protein release and made part of muscle insulin signalling resistant. Claims that a 3-day fast 'resets' the immune system or reliably triggers autophagy in humans are not supported by the human data found.

Evidence grade: Limited evidence.

The schedule

• Pattern: periodic
• Fasting hours: 72
• Calorie limit on fast days: zero, or no more than 200 kcal per 24 hours in the chemotherapy fasting trial

Why people choose it

Research on 48- to 72-hour fasts in people has focused on whether fasting around chemotherapy reduces side effects, where small studies found it feasible with mostly mild symptoms. Evidence that it improves chemotherapy toxicity overall is mixed and not statistically clear. A 72-hour fast in healthy young men increased muscle protein breakdown. No trial was found comparing 48- to 72-hour fasts with ordinary daily calorie restriction for weight loss.

Cautions

• People taking insulin or sulfonylureas: Long-acting sulfonylureas are often associated with low blood sugar when calories drop; the expert review says their doses should always be reduced on fasting days. (Source 1)
• People with gout or high uric acid: In a small 1967 study of gout patients, serum urate rose after one- and two-day fasts and acute attacks followed rapid urate swings; the authors advised that people with gout be cautioned to avoid prolonged fasting. (Source 2)
• Pregnant or breastfeeding women, older adults of advanced age, and frail older adults: An expert review says these groups have unique risks and should be dissuaded from fasting. (Source 1)
• People with an eating disorder or dementia: The same review says fasting is likely to make these conditions worse. (Source 1)
• Older adults concerned about muscle: A 72-hour fast increased muscle protein release even in healthy young men; the study notes fasting is characterised by progressive loss of body proteins. (Source 3)

What goes wrong

Fasting-related symptoms in that study included fatigue in half the patients, headache, dizziness, low blood sugar in 3, low sodium in 2 and low blood pressure in 1. (Source 4)

• Case series, Certainty not rated.
• Size: 20.
• Who: Adults with cancer receiving chemotherapy.
• How long: 24-72 hour fasts.
• Result: Fatigue 10 subjects (6 grade 1, 4 grade 2); headache 6; dizziness 6; hypoglycaemia 3; hyponatraemia 2; hypotension 1; no grade 3 or 4 fasting-related toxicity.
• Funding: V Foundation and NCI; one author holds L-Nutra equity.

Limit of this finding: Non-randomised dose-escalation feasibility trial (three sequential cohorts fasting 24, 48 or 72 hours), no control group; very small, cancer patients under close supervision.

Fasting-related symptoms included fatigue (10 subjects, 6 grade 1 and 4 grade 2), grade 1 headache (6 subjects), dizziness (6 subjects), hypoglycemia (3 subjects), grade 1 weight loss (2 subjects), hyponatremia (2 subjects) and hypotension (1 subject)

In 8 healthy young men, a 72-hour fast significantly increased the release of amino acids from forearm muscle, a sign of muscle protein breakdown. (Source 3)

• Randomized trial, Certainty not rated.
• Size: 8 healthy men, randomised crossover.
• Who: Healthy men, mean age 26, BMI about 24.
• How long: 72 hours of fasting compared with a 10-hour overnight fast.
• Result: Significantly increased net phenylalanine release; mTOR phosphorylation down about 50%.
• Funding: Independent: Danish Ministry of Food, Agriculture and Fisheries and Ministry of Family and Consumer Affairs; no competing interests declared.

Limit of this finding: Very small study in young men; older adults, who already lose muscle more easily, were not studied.

Fasting significantly increased forearm net phenylalanine release and tended to decrease phenylalanine rate of disappearance.

After the 72-hour fast, insulin's usual effect on muscle growth signalling was significantly blunted, which the authors described as insulin resistance in that pathway. (Source 3)

• Randomized trial, Certainty not rated.
• Size: 8 healthy men.
• Who: Healthy young men.
• How long: 72 hours.
• Result: Insulin-stimulated increase in mTOR and rpS6 phosphorylation significantly reduced.
• Funding: Independent Danish government funding.

the insulin stimulated increase in mTOR and rpS6 phosphorylation was significantly reduced after fasting indicating insulin resistance in this part of the signaling pathway

In an older study of 9 people with gout, serum urate rose after one- and two-day fasts; 8 of 9 had acute gout attacks during the studies, and in the majority of cases the onset appeared related to rapid urate swings from fasting or fasting plus alcohol. (Source 2)

• Case series, Certainty not rated.
• Size: 9 gout patients and 2 people with normal uric acid.
• Who: Adults with gout.
• How long: Fasts of one to two days.
• Result: Appreciable rises in serum urate after one- and two-day fasts, alongside rises in ketone bodies; 8 of 9 gout patients had one or more acute attacks.
• Funding: not stated in the text retrieved.

Limit of this finding: Published in 1967; very small experimental study with no control group; the fasts studied lasted one to two days.

In the majority of cases the onset of the attack appeared to be related to rapid fluctuations in serum urate levels induced by fasting or by fasting together with alcohol ingestion.

What the evidence supports

In a dose-escalation study of 20 cancer patients (median age 61), fasting for 24, 48 or 72 hours around platinum chemotherapy met feasibility criteria and the authors judged 72 hours safe and feasible. (Source 4)

• Case series, Certainty not rated.
• Size: 20.
• Who: Adults with cancer receiving platinum-based chemotherapy; median age 61, 85% women.
• How long: Fasts of 24, 48 or 72 hours around chemotherapy cycles.
• Result: Feasibility met (at least 3 of 6 per cohort ate 200 kcal or less per 24 hours); toxicities limited to grade 2 or lower.
• Funding: V Foundation grant and National Cancer Institute award P30CA014089; one author (V.D.L.) has equity in L-Nutra.

Limit of this finding: Non-randomised dose-escalation feasibility trial (three sequential cohorts fasting 24, 48 or 72 hours), no control group; very small, cancer patients under close supervision.

Fasting for 72 h around chemotherapy administration is safe and feasible for cancer patients.

In a randomised pilot of women with early breast cancer, a 48-hour fast (24 hours before and 24 hours after chemotherapy) was well tolerated and red cell and platelet counts a week later were higher than in women who ate normally. (Source 5)

• Randomized trial, Certainty not rated.
• Size: 13 (7 fasting)
• Who: Women with HER2-negative stage II/III breast cancer receiving TAC chemotherapy.
• How long: 48 hours around each chemotherapy cycle.
• Result: Erythrocyte counts P = 0.007; thrombocyte counts P = 0.00007, both higher in the fasting group at day 7.
• Funding: not stated in the text retrieved.

Limit of this finding: Pilot with 13 patients; blood counts are laboratory measures, not symptoms.

STF during chemotherapy was well tolerated and reduced hematological toxicity of TAC in HER2-negative BC patients

What the evidence does not support

Severe neutropenia was not significantly lower in the 48- and 72-hour fasting groups than in the 24-hour group, and the reduction in DNA damage in white cells did not reach statistical significance. (Source 4)

• Case series, Certainty not rated.
• Size: 20.
• Who: Adults with cancer receiving chemotherapy.
• How long: 24-72 hour fasts.
• Result: Grade 3/4 neutropenia trend p = 0.17; DNA damage p = 0.08.
• Funding: V Foundation and NCI; one author holds L-Nutra equity.

Limit of this finding: Non-randomised dose-escalation feasibility trial (three sequential cohorts fasting 24, 48 or 72 hours), no control group; very small, cancer patients under close supervision.

There was a non-significant trend toward less grade 3 or 4 neutropenia in the 48 and 72 h cohorts compared to 24 h cohort (p = 0.17)

In the same pilot, side effects other than blood counts did not differ between the fasting and eating groups. (Source 5)

• Randomized trial, Certainty not rated.
• Size: 13.
• Who: Women with early breast cancer receiving chemotherapy.
• How long: 48 hours around each cycle.
• Result: No difference in non-haematological toxicity.
• Funding: not stated in the text retrieved.

Non-hematological toxicity did not differ between the groups.

Where the evidence is mixed

The growth factor IGF-1 fell by about a third after 24- and 48-hour fasts but by only 8% after 72 hours, so longer fasting did not give a larger drop in this marker. (Source 4)

• Case series, Certainty not rated.
• Size: 20.
• Who: Adults with cancer receiving chemotherapy.
• How long: first fasting period.
• Result: IGF-1 -30% (24 h), -33% (48 h), -8% (72 h)
• Funding: V Foundation and NCI; one author holds L-Nutra equity.

Limit of this finding: Non-randomised dose-escalation feasibility trial (three sequential cohorts fasting 24, 48 or 72 hours), no control group; very small, cancer patients under close supervision.

IGF-1 levels decreased by 30, 33 and 8 % in the 24, 48 and 72 h fasting cohorts respectively after the first fasting period

A marker of autophagy rose about 30% during the 72-hour fast, but another marker moved in the opposite direction, so the authors called autophagy interpretation problematic. (Source 3)

• Randomized trial, Certainty not rated.
• Size: 8 healthy men.
• Who: Healthy young men.
• How long: 72 hours.
• Result: LC3B-II up about 30%; p62 up about 10%.
• Funding: Independent Danish government funding.

p62 is degraded during autophagy but was increased by ∼10% during fasting making interpretation of autophagic flux problematic

Where the research disagrees

Whether fasting 48-72 hours around chemotherapy reduces side effects

• de Groot and colleagues (Leiden), rct: A 48-hour fast reduced blood-count toxicity in a 13-patient pilot (Source 5)
• Dorff and colleagues (USC), case-series: Longer fasts showed only a non-significant trend toward less severe neutropenia (Source 4)

A common belief, and what the research shows

The belief: A 3-day fast is proven to switch on autophagy and clear out damaged cells in people.

What the research shows: In the human 72-hour fasting study found, one autophagy marker rose but another moved the wrong way, and the authors said autophagic flux was problematic to interpret; the same fast increased muscle protein release.

References

1. Nutrients. Clinical Management of Intermittent Fasting in Patients with Diabetes Mellitus. 2019. PMID 31003482, DOI 10.3390/nu11040873. Read the source
2. The American Journal of Medicine. Effects of food, fast and alcohol on serum uric acid and acute attacks of gout. 1967. DOI 10.1016/0002-9343(67)90005-8. Read the source
3. PLoS One. Fasting Increases Human Skeletal Muscle Net Phenylalanine Release and This Is Associated with Decreased mTOR Signaling. 2014. PMID 25020061, DOI 10.1371/journal.pone.0102031. Read the source
4. BMC Cancer. Safety and feasibility of fasting in combination with platinum-based chemotherapy. 2016. PMID 27282289, DOI 10.1186/s12885-016-2370-6. Read the source
5. BMC Cancer. The effects of short-term fasting on tolerance to (neo) adjuvant chemotherapy in HER2-negative breast cancer patients: a randomized pilot study. 2015. PMID 26438237, DOI 10.1186/s12885-015-1663-5. Read the source