Studies that use the grapefruit itself (whole fruit) tend to use one half of a grapefruit at 2-3 meals throughout the day.
Grapefruit is a food product known for having a high level of bioactives, similar to the pomegranate. It does appear to be effective at reducing fat mass when a mixture of polyphenols are used, and may work nicely with caffeine.
Our evidence-based analysis features 37 unique references to scientific papers.
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Q: Can food have negative calories?
A: ‘Negative calorie’ foods (foods that have fewer calories than your body expends to digest them) likely don't exist. However, food typically thought of as ‘negative calorie’ are often low in total calories and high in fiber and water content — so their regular consumption may aid in weight loss.
Read full answer to "Can food have negative calories?"
The Human Effect Matrix looks at human studies (it excludes animal and in vitro studies) to tell you what effects grapefruit has on your body, and how strong these effects are.
|Grade||Level of Evidence|
|Robust research conducted with repeated double-blind clinical trials|
|Multiple studies where at least two are double-blind and placebo controlled|
|Single double-blind study or multiple cohort studies|
|Uncontrolled or observational studies only|
Level of Evidence
? The amount of high quality evidence. The more evidence, the more we can trust the results.
Magnitude of effect
? The direction and size of the supplement's impact on each outcome. Some supplements can have an increasing effect, others have a decreasing effect, and others have no effect.
Consistency of research results
? Scientific research does not always agree. HIGH or VERY HIGH means that most of the scientific research agrees.
|Fat Mass||Minor||- See study|
|Insulin Sensitivity||Minor||- See study|
|LDL-C||Minor||- See study|
|Total Cholesterol||Minor||- See study|
|Weight||Minor||Very High See all 3 studies|
|Blood Flow||-||- See study|
|Heart Rate||-||- See study|
Table of Contents:
- 1 Source and Composition
- 2 Pharmacokinetics
- 3 Interactions with Obesity
- 4 Interactions with Neurology
- 5 Longevity
- 6 Exercise and Performance
- 7 Cardiovascular Health
Interactions with Glucose Metabolism
- 8.1 Interventions
Inflammation and Immunology
- 9.1 Mechanisms
Interactions with Hormones
- 10.1 Estrogen
- 11 Nutrient-Nutrient Interactions
- 12 Safety and Toxicity
Grapfruit contains the following bioactives:
The polyphenol Naringenin at approximately 32.64mg/100g fresh weight (pink grapefruit); also its glycoside (bound to carbohydrate storage form) Naringin
Hesperiden at approximately 0.35mg/100g, and its aglycone (without sugar) form Hesperitin; Hesperidin is technically called Hesperitin-7-rhamnoglucoside (attached to a rutinose sugar) and a molecule called neohesperidin is short for Hesperitin-7-b-neohesperidoside
Poncirin and Didymin
Isosakuranetín and its glycoside, isosakuranetín-7-O-rutinoside (possible other glycosides)
Spermidine, a polyamine also found in some other vegetables and semen
Kaempferol and glycosides
Two scopoletin glycosides
Sinapic Acid, Ferulic Acid, and aromatic compounds
In general, when the bioactives of a 'Grapefruit' are referred to it tends to refer to the Naringenin class of flavonoids and the Hesperidin class of flavonoids. The furanocoumarin class (things related to Bergamottin in structure) may also be mentioned due to drug-drug interactions, and Nootkatone is both similar in actions to the former two classes and aromatic (tasty) and also deserves mention. These four classes are mostly unique to Grapefruit and more likely to be related to 'Grapefruit related effects', unlike stuff like Quercetin or Apigenin which are present in most plants
When looking at the average phenolic content of grapefruit juice, one study noted that it ranged from 1173–2216mg/L and appeared to be greater than tangerine, sweet orange, and lemon juice on average. Most of these polyphenols, particularily the ones unique to Grapefruit and listed first in the list, are localized more in the peel than in the juice. Despite the higher content of bioflavonoids, grapefruit tends to be more bitter than the other fruits mentioned; partially due to having more neohesperidin than other fruits which confers a bitter taste (hesperidin is fairly tasteless) and the peel is even more bitter due to a high limolin content.
One study using a lone grapefruit (to reduce variability of components) and subjecting segments to different processing techniques (juicing, hand squeezing, and blending the entire grapefruit with peel as the third group) noted that the blended juice (with peel) had 7-fold higher levels of naringin (160.79mg/100mL) relative to juiced (26.25) and hand-squeezed (22.51) and this trend of the peel-containing juice having more bioactives extends to poncirin and didymin; however, it also possessed a higher limonin content which confers a bitter taste, having 2.45mg/100mL relative to 0.14 and 0.09 with juiced and hand-squeezed grapefruit juice.
Oddly, handsqueezed juice had higher levels of 6'7'-dihydroxybergamottin (0.38mg/100mL) relative to juiced (0.10mg) and blended (0.20mg) although Bergamottin itself was highest in blended as was a third tested furanocoumarin, 5-methoxy-7 gernoxycoumarin. Vitamin C was lower in the blended juice due to higher concentrations of other bioactives, and relatively higher in hand-squeezed and juiced.
Many of the unique bioactives of grapefruit are highest in the peel, and thus a pulpy juice is likely to hold more of these bioactives than is a juice made without the peel blended into it
Hesperidin (glycone) is tan or yellowish in color, and forms long needles when pure. Its melting point ranges from 258-262°C and is easily soluble in dilute alkali, slightly soluble in methanol and almost insoluble in acetone. Its solubility in water is 1 in 50, and it has a habit of forming crystals similar to other glycosides of flavonoids; hesperidin is tasteless and odourless.
Naringin seems to be able to inhibit Organic Anion-Transporting Polypeptide (OATP1A2) and Grapefruit Juice in general also appears to inhibit the 2B1 isoform, OATP2B1. Both of these transports absorb drugs from the intestines, and their inhibition may reduce systemic availability of the drugs.
The Grapefruit effect refers to the ability of Grapefruit juice and supplements to interact with a wide variety of pharmaceuticals, either enhancing or limiting their systemic availability. Due to altering the active dosage of the pharmaceutical, Grapefruit Juice is commonly contradindicted (to not be used alongside) many drugs.
This is due to different bioactives, such as Naringin which can inhibit absorption of some drugs (via OATP inhibition) but more commonly 6'7'-dihydroxybergamottin, which inhibits CYP3A4; this latter enzyme metabolizes pharmaceuticals, and its inhibition results in less metabolism and thus higher circulating levels. Despite also being a CYP3A inhibit in vitro, the Quercetin content of Grapefruit appears to not be a significant concern.
A few compounds in Grapefruit act on AMPK (adenosine monophosphate kinase) to activate it and draw nutrients into tissue, including Nootkatone and Naringenin.
Nootkanone appears to active AMPK and LKB1 in the liver (hepatocytes) and muscle (myocytes), which has been confirmed with oral feeding of 200mg/kg Nootkatone to rats within 30-60 minutes. Nootkatone acts on the isoforms of AMPKα1 and AMPKα2 mostly, and is partly mediated in muscles by activation of CaMKK and intracellular calcium, and the calcium appears to act via AMPK isoforms as incubation Nootkatone in HeLa cells (lacking the other AMPK-like protein, LKB1) is fully calcium dependent. Interestingly, these mechanisms are not dependent on reactive oxygen/nitrogen species.
Naringenin appears to stimulate glucose uptake at 50uM concentration (without significant influence at 10uM and 20uM) to 141+/-5.5% of control, with most significant effects at 75uM (165+/-4.9%) and no further effects at 100uM and 150uM. Naringenin appears to act via the insulin receptor, as aside from phosphorylating Akt Naringenin loses efficacy when the in vitro assay is saturated with insulin and the receptors occupied. Naringenin did activate AMPK as well, unlike insulin, in a dose and time-dependent manner which is not mediated by the SIRT1 protein and its maximum efficacy (205+/-24%) was more potent than resveratrol (168+/-12%) which acts by similar mechanisms.
Nootkatone does not appear to interact with PPARα nor PPARδ.
The mechanisms of Grapefruit polyphenols appear to be related to activating AMPK, which is a mechanism of producing ATP (cellular energy) and increasing the metabolic rate
A blend of polyphenols known as SINETROL (anthocyanins, flavonoids and caffeine) appear to influence Phosphodiesterase (PDE) enzymes via inhibition, which in a whole-cell culture can influence AMPK activation in a similar manner as resveratrol. When tested in vitro, this SINETROL mixture at 0.01% was able to inhibit an average of 97+/-1% of active PDE, while the same dose of caffeine inhibited 56+/-5% and two of the bioactives in SINETROL (Naringin and Cyanidin-3-Glucoside) inhibited 87+/-6% and 99+/-8% at the same concentration. SINETROL by itself is able to increase free fatty acid release from fat cells in vitro, to about twice the level of Guarana (12% caffeine) but to lesser extents than theopylline and Isoproterenol; concentrations varied with these two making direct comparisons difficult.
It is possible that grapefruit polyphenols act on phosphodiesterase enzymes (PDEs) and inhibit them, which would increase activity of AMPK and increase glucose uptake into cells. A mechanistic chain somewhat similar to the wine polyphenol resveratrol
One study in rats using isolated Nootkatone noted an increase in measured VO2 and metabolic rate, without significantly influencing respiratory quotient (percentage of energy coming from lipids or glucose). Elsewhere in this study, rats were fed Nootkatone at 0.1-0.3% of the diet by weight and the expected increase in diet-induced obesity was significantly attenuated (with high fat control being increase to 187% of baseline bodyweight and Nootkatone at 0.1, 0.2, and 0.3% of the diet reducing this increase to 162%, 160%, and 147%).
A human study using overweight/obese subjects that were otherwise healthy compared a control diet to a diet with a moderate amount of grapefruit (one half of a fresh Rio-Red grapefruit with each of three meals) for 6 weeks, and noted that grapefruit consumption was associated with modest weight loss (-0.61+/-2.23 kg) that came with a modest decrease in blood pressure (−3.21+/-10.13 mmHg) while no changes occurred in control. Self-reported intake as assessed by 24-hour dietary recall did not differ between groups, and estimated intake of Naringenin and Hesperiden was 146.2mg and 1.57mg daily. A later study in obese persons compared solid grapefruit with grapefruit juice and a third group with grapefruit capsules of 500mg extract (blinded) noted that over the course of 2 weeks that all groups were able to lose weight with 1.1kg (capsules) 1.5kg (juice) and 1.6kg (fruit). The fruit was significantly more effective than placebo at weight loss while the other two groups trended towards being more effective, and this trend toward increased efficacy also appeared to hold for blood pressure (although did not reach statistical significance).
One study using a SINETROL mixture (grapefruit polyphenols, anthocyanins, caffeine) noted that this mixture, when taken by healthy overweight/obese persons at 1.4g daily (four capsules of 350mg) over 12 weeks had their BMI reduced by 2.2+/-0.9 points from a baseline status of 28.1+/-2.45, which was accompanied by a reduction of their body fat percentage from 30.7+/-1.9% to 29.0+/-0.8% at 4 weeks (5.4% reduction) and 25.9+/-1.0% (15.6% reduction) at 12 weeks; this study did not disclose any affiliations with the patent owners or producers of SINETROL.
Grapefruit polyphenols do appear to be effective at reducing bodyweight, reliably but not outright potently. The efficacy of grapefruit polyphenols in reducing body weight may be better if consumed via the grapefruit itself (possibly through fibers also acting) and appear to be synergistic with anthocyanins (blue-red pigments in fruits like berries)
Hesperidin, a flavonoid glycoside found in grapefruit, appears to have anti-depressant effects in mice when injected at doses of 0.3mg/kg and appears to be mediated by serotonergic mechanisms as it is inhibited by serotonin receptor antagonists and when serotonin synthesis is inhibited, and 0.1mg/kg is augmented with selective serotonin reuptake inhibitors (SSRIs).
In a study screening Traditional Chinese Medicine for bioactives, Naringenin was found to induce GRP78 (an endoplasmic reticulum protein) in a dose-dependent manner up to 3-fold luciferase activity at 0.2mM and showing statistically significant effects at 0.05mM; naringin and glycyrrhizic/glycerrhezic acids were all found to be inactive. Subsequently, Naringenin was found to suppress protein aggregation in HeLa-tetQ97 cells and in cells expressing EGFP-polyQ97 (as GRP78 reduces aggregation), suggesting Naringenin may be useful for neural diseases associated with polyglutamine aggregation.
Hesperidin, a flavonoid glycoside from Grapefruit, appears to be associated with increased longevity in yeast related to its anti-oxidant abilities. This was observed to occur with 5uM and 10uM concentrations, and was not associated with Hesperitin (the aglycone of Hesperidin) implicating the sugar moiety on C-7 of hesperitin as critical to the observed effects; and the gene UTH1 (not present in humans) appears to be implicated in the yeast, although in vitro assays suggested induction of both SIRT1 and Superoxide Dismutase which may have relevance to humans.
Too preliminary to draw any conclusions
One study in mice assessing swimming performance noted a 21% increase after Nootkatone administration at 0.2% of the diet, relative to control mice.
Consumption of a half a small grapefruit thrice a day for 6 weeks is associated with a moderate drop in systolic blood pressure (-3.21+/-10.13 mmHg) with no influence on diastolic or heart rate.
Mechanistically, the Nootkatone component of grapefruit has been shown to inhibit platelet aggregation when it is isolated from the plant Cyperus Rotundus, and was able to significantly suppress thrombin and arachidonic-acid induced clotting at 30uM while needing 100uM to suppress collagen-induced clotting. However, nootkatone in isolation was able to suppress platelet aggregation induced by collagen at 30mg/kg bodyweight oral ingestion in rats to a greater extent than aspirin at 30mg/kg, and of equal potency when nootkatone was dosed at 10mg/kg; Nootkatone appears to mediate most anti-platelet effects of Cyperus Rotundus ethanolic extract. 30mg/kg Nootkatone also prolonged tail bleeding time in rats to the same degree as 50mg/kg Aspirin.
In one study comparing grape juice, orange juice, and grapefruit juice on platelet aggregation it was found that only grape juice was active. 5-7.5mL/kg juice for 7-10 days in otherwise healthy persons, prior to a collagen-induced clotting test, noted that grape juice was associated with a significant 77% reduction in clotting while grapefruit was not significantly different than control. These observed effects may be due to Nootkatone being localized to the peel of the grapefruit and being in ethanolic rather than water extracts, both of which may preclude its exclusion in juice.
Has the ability to reduce platelet aggregation with large potency via the Nootkatone component, but this has not yet been demonstrated in humans and the one study in humans (that may have not been designed to properly assess this question) had null results
One study using half a small grapfruit thrice a day with meals noted that the grapefruit group had reductions in lipoproteins and triglycerides, but control also had a reduction and this it was deemed insignificant.
A study conducted on the Grapefruit pectin (fiber component) noted that consumption of grapefruit pectin in a blinded manner for 16 weeks in person at risk for cardiovascular disease risk was associated with improvements in the lipid profile (7.6% reduction in total cholesterol and 10.8% LDL-C reductions).
One intervention assessing 500mg Grapefruit capsules, grapefruit juice, and grapefruits themselves noted that after 12 weeks of supplementation that both the juice and fruit groups appears to improve insulin sensitivity in obese persons in response to an oral glucose tolerance test.
Nootkatone, also a component of Cyperus rotundus, appears to be able to induce Heme-Oxygenase 1 induction (HO-1) and is one of the two most active components of Cuperus Rotundus in doing so (the other being valencene ). This induction of HO-1 mediates suppression of iNOS induction by LPS in macrophages, and anti-inflammatory effects in the presence of pro-inflammatory stimuli, and this induction has been associated with less death from sepsis in mice (via HO-1 suppressing HMGB1 release).
In ovariectomized women given 2mg of estrogen, grapefruit juice appeared to increase the kinetics of exogenous estrogen by interfering with estrogen metabolism.
Nicotine appears to be metabolized into Cotinine via the enzyme CYP2A6, which grapefruit inhibits, and relative to consuming water alongside 2mg nicotine the consumption of grapefruit juice (large dose, 1L) can delay the Tmax (time to peak concentration) by an extra 8-47% while attenuating the Cmax (peak concentration), although renal clearance of nicotine is also enhanced and overall exposure (AUC) is unaffected.
Xanthine compounds, most notably caffeine and its metabolite theophylline (found in teas), are metabolized by the same general class of enzymes that Grapefruit components inhibit. In studies investigated the interactions between the two, theophylline may have its absorption reduced by grapefruit if coingested although another study suggests that there is no significant difference between theophylline kinetics and theophylline kinetics under the influence of grapefruit juice.
Two studies conducted on the interaction of caffeine and grapefruit juice note no significant effects of grapefruit components on caffeine kinetics, with a study measuring the increase in metabolic rate from caffeine finding that naringenin did not enhance it (from theoretically increasing exposure to caffeine, which naringenin also failed to accomplish at 100 and 200mg).
SINETROL is a mixture of grapefruit polyphenols (Narirutin, Naringin, Hesperidin, Neohesperidin) anthocyanins (Delphinidin-3-glucoside, Pelargonidin-3-Glucoside, Cyanidin-3-Glucoside, peonidin-3-glucoside, Malvidin-3-Glucoside) and caffeine, and appears to possess some synergistic components.
In an assay for PDE inhibition, 0.01% of SINETROL is able to inhibit an equal amount of PDE as 0.01% Cyanidin-3-Glucoside despite having a much smaller concentration of Cyanidin-3-glucoside; the Naringen appears to be bioactive but to a lesser degree than Cyanidin-3-glucoside, but not enough to account for the discrepancy.
Grapefruit polyphenols and Anthocyanins appear to possess synergism in regards to PDE inhibition, but the exact molecules that are causative of this are not known
A combination of Hesperidin (Hesperitin glycoside) and Diosmin (Diosmetin glycoside) in a 1:9 ratio (50mg and 450mg; respectively) is called Daflon500, and two capsules daily of Daflon has been associated with benefits in humans with chronic venous insufficiency and reducing related symptoms such as cramps and edema.
When looking at components in isolation, Hesperidin appears to be safe when fed to both animals and humans and in various forms (methyl hesperidin, phosphorylated hesperidin) with the only known toxicity those being mediated by drug-drug interactions.
- Zygmunt K, et al. Naringenin, a citrus flavonoid, increases muscle cell glucose uptake via AMPK . Biochem Biophys Res Commun. (2010)
- Garg A, et al. Chemistry and pharmacology of the Citrus bioflavonoid hesperidin . Phytother Res. (2001)
- Murase T, et al. Nootkatone, a characteristic constituent of grapefruit, stimulates energy metabolism and prevents diet-induced obesity by activating AMPK . Am J Physiol Endocrinol Metab. (2010)
- Kakar SM, et al. 6'7'-Dihydroxybergamottin contributes to the grapefruit juice effect . Clin Pharmacol Ther. (2004)
- Uckoo RM, et al. Grapefruit (Citrus paradisi Macfad) Phytochemicals Composition Is Modulated by Household Processing Techniques . J Food Sci. (2012)
- Abad-García B, et al. On line characterization of 58 phenolic compounds in Citrus fruit juices from Spanish cultivars by high-performance liquid chromatography with photodiode-array detection coupled to electrospray ionization triple quadrupole mass spectrometry . Talanta. (2012)
- Zoumas-Morse C, et al. Development of a polyamine database for assessing dietary intake . J Am Diet Assoc. (2007)
- Quantitative survey of narirutin, naringin, hesperidin, and neohesperidin in citrus .
- Bailey DG, et al. Naringin is a major and selective clinical inhibitor of organic anion-transporting polypeptide 1A2 (OATP1A2) in grapefruit juice . Clin Pharmacol Ther. (2007)
- Tapaninen T, Neuvonen PJ, Niemi M. Grapefruit juice greatly reduces the plasma concentrations of the OATP2B1 and CYP3A4 substrate aliskiren . Clin Pharmacol Ther. (2010)
- Rashid J, et al. Quercetin, an in vitro inhibitor of CYP3A, does not contribute to the interaction between nifedipine and grapefruit juice . Br J Clin Pharmacol. (1993)
- Park SJ, et al. Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases . Cell. (2012)
- Dallas C, et al. Lipolytic effect of a polyphenolic citrus dry extract of red orange, grapefruit, orange (SINETROL) in human body fat adipocytes. Mechanism of action by inhibition of cAMP-phosphodiesterase (PDE) . Phytomedicine. (2008)
- Dow CA, et al. The effects of daily consumption of grapefruit on body weight, lipids, and blood pressure in healthy, overweight adults . Metabolism. (2012)
- Fujioka K, et al. The effects of grapefruit on weight and insulin resistance: relationship to the metabolic syndrome . J Med Food. (2006)
- Souza LC, et al. Evidence for the involvement of the serotonergic 5-HT(1A) receptors in the antidepressant-like effect caused by hesperidin in mice . Prog Neuropsychopharmacol Biol Psychiatry. (2012)
- Yamagishi N, et al. Naringenin Inhibits the Aggregation of Expanded Polyglutamine Tract-Containing Protein through the Induction of Endoplasmic Reticulum Chaperone GRP78 . Biol Pharm Bull. (2012)
- Yamagishi N, et al. Endoplasmic reticulum chaperone GRP78 suppresses the aggregation of proteins containing expanded polyglutamine tract . Biochem Biophys Res Commun. (2012)
- Sun K, et al. Anti-aging effects of hesperidin on Saccharomyces cerevisiae via inhibition of reactive oxygen species and UTH1 gene expression . Biosci Biotechnol Biochem. (2012)
- Seo EJ, et al. Antiplatelet effects of Cyperus rotundus and its component (+)-nootkatone . J Ethnopharmacol. (2011)
- Keevil JG, et al. Grape juice, but not orange juice or grapefruit juice, inhibits human platelet aggregation . J Nutr. (2000)
- Njoroge SM, et al. Volatile constituents of redblush grapefruit (Citrus paradisi) and pummelo (Citrus grandis) peel essential oils from Kenya . J Agric Food Chem. (2005)
- Cerda JJ, et al. The effects of grapefruit pectin on patients at risk for coronary heart disease without altering diet or lifestyle . Clin Cardiol. (1988)
- Tsoyi K, et al. (+)-Nootkatone and (+)-valencene from rhizomes of Cyperus rotundus increase survival rates in septic mice due to heme oxygenase-1 induction . J Ethnopharmacol. (2011)
- Schubert W, et al. Inhibition of 17 beta-estradiol metabolism by grapefruit juice in ovariectomized women . Maturitas. (1994)
- Hukkanen J, Jacob P 3rd, Benowitz NL. Effect of grapefruit juice on cytochrome P450 2A6 and nicotine renal clearance . Clin Pharmacol Ther. (2006)
- Gupta MC, et al. Effect of grapefruit juice on the pharmacokinetics of theophylline in healthy male volunteers . Methods Find Exp Clin Pharmacol. (1999)
- Fuhr U, et al. Lacking effect of grapefruit juice on theophylline pharmacokinetics . Int J Clin Pharmacol Ther. (1995)
- Maish WA, et al. Influence of grapefruit juice on caffeine pharmacokinetics and pharmacodynamics . Pharmacotherapy. (1996)
- Ballard TL, et al. Naringin does not alter caffeine pharmacokinetics, energy expenditure, or cardiovascular haemodynamics in humans following caffeine consumption . Clin Exp Pharmacol Physiol. (2006)
- Guillot B, et al. A long term treatment with a venotropic drug. Results on efficacy and safety of Daflon 500 mg in chronic venous insufficiency . Int Angiol. (1989)
Via HEM and FAQ:
- Dhingra D, et al. Dietary fibre in foods: a review . J Food Sci Technol. (2012)
- Mattes RD, Kris-Etherton PM, Foster GD. Impact of peanuts and tree nuts on body weight and healthy weight loss in adults . J Nutr. (2008)
- de Jonge L, Bray GA. The thermic effect of food and obesity: a critical review . Obes Res. (1997)
- Clegg ME and Cooper C. Exploring the myth: Does eating celery result in a negative energy balance? . Proc Nutr Soc. (2012)
- Rezaeipour M, Apanasenko GL, Nychyporuk VI. Investigating the effects of negative-calorie diet compared with low-calorie diet under exercise conditions on weight loss and lipid profile in overweight/obese middle-aged and older men . Turk J Med Sci. (2014)
- Holt SH, et al. A satiety index of common foods . Eur J Clin Nutr. (1995)
Cite this page
"Grapefruit," Examine.com, published on 12 July 2013, last updated on 4 July 2018, https://examine.com/supplements/grapefruit/