Description
Fermented wheat germ extract (FWGE) is industrially produced by fermenting wheat germs of the genus Triticum vulgaris with the addition of baker’s yeast (Saccharomyces cerevisiae). The medicinally active substances of FWGE are not yet known.
FWGE has been marketed as a dietary supplement for cancer patients. In the context of cancer, FWGE is believed to increase efficacy of chemo- and radiotherapy, to reduce their adverse effects and to improve quality of life.
Efficacy
Although six controlled trials consistently reported positive results, the evidence for the claimed benefits is very weak, due to high risk of bias in trials published. No placebo-controlled trials have been carried out.
The main results of the published studies report that patients using FWGE showed:
- Overall and progression-free survival times: Evidence from one RCTs (n=58) and an uncontrolled trial (n=176) suggest intake of FWGE leads to longer overall and progression-free survival times.
- Relapse rates: Two non-randomized CTs (n=45, n=176) found FWGE reduces relapse rates.
- Quality of life: Evidence from two small non-randomized CTs (n=16, n=60) suggest FWGE improves quality of life.
- Febrile neutropenia: One small non-randomized CT (n=22) suggests intake of FWGE reduces incidence of febrile neutropenia.
Safety
FWGE is generally considered safe; reported adverse events have been rare and mild. There is no known toxicity from ingestion of FWGE.
Description
FWGE involves fermenting wheat germs of the genus Triticum vulgaris by adding baker's yeast (Saccharomyces cerevisiae). Wheat germ is the embryo portion of the wheat kernel. It is a concentrated source of vitamins, minerals, and protein, and is sustained by the larger, starch storage region of the kernel. During the production of wheat flour, the wheat germ is usually removed. In whole wheat products, however, the wheat germ is either not removed or added again after processing. Fermented wheat germ extract (FWGE) is industrially produced and in clinical use.
The idea of using FWGE for medical purposes was introduced by Hungarian Nobel laureate for medicine Dr Albert Szent-Györgyi. He proposed the conjecture, that the benzoquinone found in wheat germ might act antiproliferative because of its high redox potential (Johanning 2007). Subsequently, a way of industrially producing FWGE was invented and patented by Hungarian biochemist Mate Hidvegi.
FWGE is produced as an over-the-counter product in more than ten countries and marketed under the names Avemar, Avemar pulvis, Ave Ultra, MSC and Avé.
Ingredients and quality issues
The production of FWGE involves fermenting (i.e. transforming sugar into ethanol by microorganisms) wheat germs of the genus Triticum vulgaris by adding baker`s yeast (Saccharomyces cerevisiae), adding filtered air and controlling the pH-level and temperature. The process takes about 18 hours. The dried product which is available on the market contains 63.2% FWGE and as technological additives 35% maltodextrin and 1.8% kolloidal silicondioxid (Hidvegi 2002, Pfeifer 2006, Sukkar 2008). Dimethoxy-p-benzoquinone is used to standardize the production process and amounts up to 0.4 mg/g are found in the final product. 2-Methoxy benzoquinone can also be detected in the final product (Hidvegi 2002).
Alleged indications
According to the manufacturer, “AVEMAR helps to support the immune system, quality of life, mental clarity, and cellular health”. (Avemar 2024)
In the context of cancer, FWGE has been marketed as a supplement to chemo- and radiotherapy in the treatment of solid malignant tumors, as it is believed to improve both the success of treatment, as well as patients` quality of life (Barabas 2006, Demidov 2008, Hidvegi 2003, Jakab 2003, Sukkar 2008, Patel 2014). Furthermore, there are claims that FWGE can be used in chemotherapy to reduce the risk of neutropenic fever (Garami 2004).
Application and dosage
FWGE is dissolved in water and applied orally. The authors of clinical trials used dosages of FWGE ranging from 8.5 g once to 9 g twice daily (Barabas 2006, Demidov 2008, Jakab 2003, Sukkar 2008). In a study of children, the authors administered 12 g/m2/day (Garami 2004). A dose of 8.5 g/day contains 1.7 mg of 2,6-dimethoxy-p-benzoquinone which is equivalent to the consumption of 700 g of whole wheat bread (Posner 1985).
Mechanisms of action
To date, the bioactive principles involved in the anti-cancer mechanisms mentioned below have not been fully elucidated. A methoxy-substituted benzoquinone, DMBQ or 2,6-DMBQ, was identified to inhibit mTOR signalling, causing cell cycle arrest in gastric cancer cells (Zu 2020). However, previous in vitro studies suggested that the fermented wheat germ whole extract exhibits more potent anti-cancer activity compared to DMBQ (Johanning 2007).
Animal and in vitro studies of FWGE including various different cancer types, reported enhanced effects of common drugs (cisplatin, 5-fluorouracil, tamoxifen, oxaliplatin, and irinotecan), dose-dependent apoptosis induction, and anti-angiogenic effects. The primary mechanisms involved include (Zhurakivska 2018; Johanning 2007):
- Caspase-3 activation, DNA fragmentation, cell cycle arrest, and immune modulation (see below);
- Decreased expression of major histocompatibility complex class I (MHC class I) antigens in cancer cells, enhancing recognition by immune cells;
- Regulation of altered glucose metabolism in cancer cells, hindering nucleic acid synthesis and arresting proliferation;
- Cyclooxygenase-2 (COX-2) inhibition, which favoured metastasis reduction in animal models;
- VEGF inhibition, exerting anti-angiogenic effects;
- Increased ICAM-1 expression in microvascular endothelial cells, possibly promoting leukocyte infiltration into tumours;
- Mitochondrial-mediated apoptosis in cancer cells (prostate, colon, breast cancer, ovarian teratocarcinoma, and mouse melanoma). The treatment itself showed no toxic effect on liver tissue in a murine melanoma model (Bencze 2020);
Legal issues
FWGE products are available as nutritional supplements in many countries.
Five controlled clinical trials have been carried out. Four in adult patients diagnosed with head and neck cancer, malignant melanoma, prostate cancer, and colorectal carcinoma (Barabas 2006, Demidov 2008, Jakab 2003, Sukkar 2008) and one in children with diverse malignancies (Garami 2004). These trials are described in Table 1.
Description of included studies
Despite encouraging results from the studies reported here, the evidence that treatment with FWGE confers benefits to cancer patients is very limited, as all study data were at high risk of bias: only one study was a randomized clinical trial (RCT), and all studies were open label, most had small sample sizes, and poor reporting quality. All trials used the same patented FWGE from one manufacturer.
Overall and progression-free survival times
Three studies reported benefits of FWGE treatment on survival and tumour progression. (Demidov 2008, Jakab 2003, Barabas 2006). In an RCT, overall and progression-free survival was evaluated in 58 patients with malignant melanoma. The results showed that after seven years of follow-up, overall and progression-free survival improved in the group that received FWGE (Demidov 2008).
In a non-randomized controlled trial of 176 patients undergoing oncological therapy, patients receiving FWGE had higher overall and progression-free survival rates, with metastases occurring less frequently in the group receiving FWGE (Jakab 2003).
A non-randomized study of 45 patients diagnosed with head and neck cancer found significantly fewer local recurrences and progression events in the group receiving FWGE (Barabas 2006).
Quality of life
One non-randomized controlled study (n=60) reported significantly better quality of life in head and neck cancer patients taking FWGE (Sukkar 2008).
Febrile neutropenia
A non-randomized controlled trial found a reduced incidence of febrile neutropenia among 22 children with various tumours being treated with chemotherapy and FWGE (Garami 2004).
Adverse events
The clinical trials included in this summary reported mild and transient adverse events affecting the gastrointestinal tract including diarrhoea, nausea and vomiting, flatulence, a feeling of fullness, soft stool, constipation, and fever/infection (Jakab 2003: Demidov 2008). No serious adverse events, NCI-CTC Grade 3-4, were reported in the included trials (Jakab 2003; Garami 2004; Weitzen 2022).
In animals: the study mentioned in this review (Heimbach 2007) reported no adverse effects, toxicity or mutagenic potential.
Contraindications
Due to a lack of data, use during pregnancy and breastfeeding should be avoided (MSKCC 2023). The available evidence regarding the safety of FWGE in children is currently limited to a single clinical study (Garami 2004).
Hypothesized contraindications based on mechanistic studies (in vivo and in vitro) include hormone-sensitive cancers (MSKCC 2023) and transplant patients (Hidvegi 1999). However, data from oestrogen receptor-positive breast cancer cells showed increased tamoxifen activity when co-administered with FWGE (Marcsek 2004).
The manufacturer of the commercial formula advises against its use in cases of bleeding erosions or ulcers of the gastrointestinal tract, malabsorption syndrome, and gluten sensitivity (coeliac disease) (Avemar 2014). The basis for these contraindications is unclear. In fact, anti-bleeding effects were observed in mice treated with FWGE, and sublethal irradiation, or cyclophosphamide (Gidali 2000), while in porcine intestinal epithelial cells, FWGE reduced inflammation and intracellular reactive oxygen species levels (Karancsi 2020).
Interactions
Hypothesized interactions based on the known mechanisms of action of FWGE include the following:
- FWGE contains DMBQ, which, similarly to other benzoquinones, may be metabolized by cytochrome P450 and interact with P-glycoprotein (P-gp) affecting the metabolism of concomitant therapies. However, no experimental data are available.
- FWGE was reported to increase lymphocyte blast transformation (Hidvegi 1999), which could potentially influence the efficacy or toxicity of checkpoint inhibitor drugs. It may also counteract drugs that suppress T-cell function, or antagonize anti-inflammatory treatments. However, these hypotheses are not yet supported by clinical data in humans.
- Avemar was shown to increase TNF-α production in various cell lines (Johanning 2007). Since TNF-α modulates inflammation, interleukin synthesis, and reactive oxygen species production, this might sensitize cancer cells to chemotherapeutic agents. However, confirmatory experimental data are lacking.
Manufacturers recommend the treatment be temporarily discontinued for two days before any procedure that involves the administration of contrast to the intestinal tract (Avemar 2014). This hypothesized interaction could be linked to FWGE's stimulation of T-cells, which may worsen contrast-induced hypersensitivity, or because 2,6-DMBQ, a redox-active quinone, could synergize with contrast-induced oxidative stress, potentially causing tissue damage. However, no studies have investigated the interactions between FWGE and contrast media.
References
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Bencze G, Bencze S, Rivera KD, et al. Mito-oncology agent: fermented extract suppresses the Warburg effect, restores oxidative mitochondrial activity, and inhibits in vivo tumor growth. Sci Rep. 2020 Aug 25;10(1):14174. Erratum in: Sci Rep. 2021 Jan 29;11(1):3036.
Boros LG, Nichelatti M, Shoenfeld Y. Fermented wheat germ extract (Avemar) in the treatment of cancer and autoimmune diseases. Ann N Y Acad Sci. 2005;1051:529-42.
Demidov LV, Manziuk LV, Kharkevitch GY, Pirogova NA, Artamonova EV. Adjuvant fermented wheat germ extract (Avemar) nutraceutical improves survival of high-risk skin melanoma patients: a randomized, pilot, phase II clinical study with a 7-year follow-up. Cancer Biother Radiopharm. 2008;23:477-82.
Garami M, Schuler D, Babosa M, Borgulya G, Hauser P, Muller J et al. Fermented wheat germ extract reduces chemotherapy-induced febrile neutropenia in pediatric cancer patients. J Pediatr Hematol Oncol. 2004;26:631-35.
Gidali J, Hidvégi M, Fehér I, et al. The effect of Avemar treatment on the regeneration of leukocytes, thrombocytes and reticulocytes in sublethally irradiated or cyclophosphamide treated mice. First Congress of the Hungarian Society of Clinical Oncology, Budapest, Hungary, November 10-11, 2000.
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Citation
CAM Cancer Consortium. Fermented wheat germ extract [online document], April 2025.
Document history
Update of “Mechanisms of action” and “Is it safe” sections in January 2025 by Lisa Dal Pozzo; “What is it” and “Does it work” sections by the CAM Cancer Collaboration. Updated literature search in March 2025.
Assessed as up to date in January 2019, February 2017, April 2016, January 2015 and August 2013 by Barbara Wider. Revised and updated in June 2012 by Alexander Kalisch and Markus Horneber. Summary first published in February 2011, authored by Alexander Kalisch and Markus Horneber.
