Graviola

Graviola (Annona muricata L.)

1. Identity: Botanical Names, Natural Source, and Common Forms

Botanical classification: Graviola (Annona muricata) is a small deciduous tropical evergreen fruit tree belonging to the Annonaceae family, widely grown and distributed in tropical and subtropical regions around the world. Accepted botanical synonyms include Annona macrocarpa, A. bonplandiana, A. cearensis, and Guanabanus muricatus.

Common names: A. muricata is commonly known as soursop, graviola, guanabana, or Brazilian paw-paw. Other regional names include guanábano, guanavana, corossol épineux, huanaba, toge-banreisi, durian benggala, nangka blanda, and cachiman épineux.

Morphology and habitat: Annona muricata is a lowland tropical, fruit-bearing tree found in the rainforests of Africa, South America, and Southeast Asia. It has large, glossy, dark green leaves and edible, green heart-shaped fruits; the leathery skin of the fruits is covered with soft, curved spines, and each fruit may contain 55–170 black seeds distributed in a creamy white flesh with a characteristic aroma and flavor. The tree bears large, heart-shaped, edible green fruits, ranging from 15 to 20 cm in diameter and weighing between 0.4 and 4 kg depending on the country.

Plant parts used: All portions of A. muricata — including leaves, pericarp, fruits, seeds, and roots — have been used in traditional medicine, but the most widely used in the preparation of traditional medical decoctions are stem barks, roots, seeds, and leaves.

Commercial forms and preparations: Graviola is very popular in supplement markets, for example in the form of capsules (stem and leaf powder) and tea under various trade names (such as Soursop leaf tea). The fruits are widely used in the preparation of various foods, such as ice creams, syrups, nectars, jams, jellies, candies, and beverages. Standardized extract capsules and powders, liquid tinctures and extracts, dried leaf teas (infusions and decoctions), and juices made from the fruit pulp are the primary supplement forms encountered commercially.

2. Traditional and Historical Use

*Annona muricata* is a fruit tree with a long history of traditional use; also known as soursop, graviola, and guanabana, it is an evergreen plant mostly distributed in tropical and subtropical regions. A wide array of ethnomedicinal activities is attributed to different parts of A. muricata, and indigenous communities in Africa and South America extensively use this plant in their folk medicine.

Geographic and cultural breadth: The traditional use of graviola has been recorded in herbal medicine systems in the following countries: Amazonia, Barbados, Borneo, Brazil, Cook Islands, Curacao, Dominica, Guatemala, Guam, Guyana, Haiti, Jamaica, Madagascar, Malaysia, Peru, Suriname, Togo, and West Africa, among others. Graviola has been treasured across Afro-Caribbean, Amazonian, and Indigenous South American traditions for centuries, used extensively in medicine for fever, digestive disturbances, and nervous conditions.

Traditional preparations: The fruits of graviola have been widely used as food confectionaries, while several preparations — especially decoctions of the bark, fruits, leaves, pericarp, seeds, and roots — have been extensively used in traditional medicine to treat multiple ailments, including cancers, by local communities in tropical Africa and South America. The leaves and fruit were traditionally prepared as decoctions, poultices, and tonics.

Traditional therapeutic indications by plant part:

• All parts of the graviola tree have been used medicinally. Traditional herbal medicine practitioners have attributed graviola with the following properties and actions: anthelmintic, antiparasitic, antipyretic, sedative, antispasmodic, nervine, hypotensive, anticonvulsant, and digestive.
• The leaves are used to treat insomnia, diabetes, cystitis, and headaches; the crushed seeds have anthelmintic properties.
• The leaves are used to treat cystitis, diabetes, headaches, hypertension, insomnia, and liver problems, and as an antidysenteric, anti-inflammatory, and antispasmodic agent.
• In the Peruvian Andes, graviola leaves are used to combat parasites and treat diabetes; a leaf tea is used for catarrh, and the crushed seed is used to kill parasites.
• In folk medicine across the Amazon and Caribbean regions, graviola leaves have been applied topically or consumed as infusions to help reduce fever, ease pain, and manage infections.

3. Key Constituents and Active Compounds

Over 212 phytochemical ingredients have been reported in graviola extracts prepared from different plant parts. The specific bioactive constituents responsible for the major anticancer, antioxidant, anti-inflammatory, antimicrobial, and other health benefits of graviola include different classes of annonaceous acetogenins (metabolites and products of the polyketide pathway), alkaloids, flavonoids, sterols, and others.

Annonaceous Acetogenins (ACGs)

Phytochemical studies reveal that annonaceous acetogenins are the major constituents of A. muricata. More than 100 annonaceous acetogenins have been isolated from leaves, barks, seeds, roots, and fruits of A. muricata. The stem, leaves, and seeds of graviola contain more than 70 acetogenins, which are derivatives of long chain C35–C37 fatty acids synthesized through the polyketide pathway. These compounds are characterized by a C2 combination with 2-propanol to form a lactone ring, and generally by cyclization with oxygen to form one to three tetrahydrofuran or tetrahydropyran moieties, and complex diastereomeric mixtures are the result.

Annonaceous acetogenins (AAs) characterized by a terminal gamma-lactone ring and a single tetrahydrofuran (THF) ring in the middle of aliphatic chains are the active ingredients responsible for the cytotoxic effects of graviola. Specific, well-studied individual acetogenins from A. muricata include annonacin (one of the most abundant), annomuricins, muricatocins, bullatacin, and solamin.

Alkaloids

The fruit, bark, leaves, and roots of A. muricata are rich in flavonoids, isoquinoline alkaloids, and annonaceous acetogenins. A. muricata contains alkaloids such as coreximine and reticuline, along with acetogenins (annomuricins and annonacin) and flavonoids (quercetin), which are predicted to be responsible for the plant's biological activity. An isoquinoline backbone is a major structural alkaloid moiety of the Annona genus, and more than 83 alkaloids have been isolated from this genus alone.

Phenolic Compounds and Flavonoids

The plant is also a source of a range of phenolic compounds, essential oils, alkaloids, flavonol triglycosides, and megastigmanes, together with various minerals, including Mg, Fe, Cu, K, and Ca. Its key phenolic compounds are rutin, kaempferol, and quercetin.

Other Constituents

Graviola is also rich in alkaloids, saponins, terpenoids, flavonoids, coumarins, lactones, anthraquinones, tannins, cardiac glycosides, phenols, and phytosterols.

4. Established Mechanisms of Action

Inhibition of Mitochondrial Complex I (Primary ACG Mechanism)

The Annonaceous acetogenins have recently been determined to inhibit ATP production at a similar site of action and higher levels of potency as rotenone — i.e., at NADH-ubiquinone oxido-reductase, complex I of the mitochondrial electron-transport chain. Natural products from the plants of the family Annonaceae, collectively called Annonaceous acetogenins, are very potent inhibitors of the NADH-ubiquinone reductase (Complex I) activity of mammalian mitochondria.

The acetogenins show selective toxicity to various types of cancer cells, including multi-drug resistant cancer cell lines, at very low dosages. Studies on the pharmacological mechanisms indicated that Annonaceous acetogenins induced cytotoxicity by inhibiting the mitochondrial complex I of the electron transport chain, which is involved in ATP synthesis. Mitochondrial complex I could be a potential target in cancer therapeutics due to the higher demand for ATP in tumor cells than in normal cells.

The annonaceous acetogenins are the most potent of the known inhibitors of bovine heart mitochondrial complex I. These inhibitors act, at the terminal electron transfer step of the enzyme, in a similar way to the usual complex I inhibitors, such as piericidin A and rotenone; however, structural similarities are not apparent between the acetogenins and these known complex I inhibitors.

Apoptosis Induction and Cell-Cycle Arrest

In in vitro studies, graviola leaf and stem extract (GLSE) was found to: (i) dose-dependently suppress cell growth, motility, wound closure, and clonogenicity; (ii) induce G0/G1 cell cycle arrest by downregulating cyclin/cdk factors while upregulating cdk inhibitors; and (iii) induce apoptosis as evidenced by cleavage of caspases-3, -8, and PARP. Further, GLSE suppressed levels of activated Hedgehog (Hh) pathway components Smo, Gli 1/2, and Shh while inducing SuFu, and decreased the expression of the anti-apoptotic protein Bcl-2.

Serotonin Receptor Activity

Graviola has also been shown to stimulate serotonin receptors. This pharmacological action is considered a potential mechanism underlying the sedative and anxiolytic effects attributed to graviola in traditional medicine.

Energy Depletion in Cancer Cells

Graviola-induced cell death has been shown to be inhibited by glucose supplementation, suggesting energy depletion as a mechanism of action.

5. Scientific Evidence by Area of Use

5.1 Cancer

Overview: Numerous in vitro and preclinical in vivo studies have supported most of the traditionally acclaimed benefits, but these must be validated in human clinical trials. As of the current literature, no preparations produced from A. muricata have been tested and approved by the FDA or EMA.

In vitro studies: Lab studies have evaluated extracts from the graviola leaf, fruit, and seed for their anticancer effects. Ethnomedicinal anticancer properties have been reported on breast, prostate, pancreatic, and colorectal cancer cell lines, causing loss of clonogenicity and cell death. One study investigated the effects of crude graviola extract in vitro on breast cancer cells, specifically targeting triple negative breast cancer (TNBC) using the MDA-MB-231 cell line and the ER(+) non-TNBC MCF-7 cell line as a control.

Non-melanoma skin cancer (in vitro): Graviola has been used in traditional medicine against multiple human diseases including cancer. One study investigated the effects of a graviola leaf and stem extract (GLSE) and its solvent-extracted fractions on two human non-melanoma skin cancer (NMSC) cell lines, UW-BCC1 and A431. The anti-proliferative and pro-apoptotic activities were concentrated in an acetogenin/alkaloid-rich dichloromethane subfraction of the extract, and the data identify graviola extracts as promising sources for new chemopreventive and therapeutic agents for the control of NMSCs.

Pancreatic cancer (preclinical in vivo): In a rodent in vivo study, graviola leaf extract inhibited 59.8% of pancreatic cancer growth of cells and their metastasis induced by CD18/HPAF cells in a mouse model.

Osteosarcoma (in vitro): Two human osteosarcoma cell lines (HOS and MG63) were cultured with a graviola preparation (300 mg/mL) for 24 hours at 37°C to assess apoptotic and anti-tumor effects. This study was in vitro only.

Animal tumor models: One study investigated the anticancer effect of graviola extract on Ehrlich solid tumor (EST) mice, with or without a low dose of gamma radiation; mice were treated with graviola 50 mg/kg body weight orally for 30 days after EST induction. Results demonstrated a decrease in the growth rate of tumors as well as inhibition of metastasis, attributed to the enhancement of anticancer immunity, downregulation of CD44, TGF-β, and Bcl-2.

Human/Clinical Evidence: Human clinical evidence for graviola's anti-cancer effects is extremely limited. One patient diagnosed with breast cancer was reported to have maintained stable disease activity with no reported side effects after using an aqueous extract of A. muricata leaves for more than five years. Another patient with metastatic ovarian cancer experienced disease stability after starting a complementary medication containing A. muricata as a tablet. One randomized controlled trial found higher cytotoxicity in the supplemented group with colorectal cancer compared with the placebo group. These reports are isolated case studies and a single small trial; they do not constitute sufficient evidence for clinical recommendations.

Ongoing clinical research: One registered open-label pilot study aims to investigate the safety and tolerability of Annona muricata leaf in people living with advanced malignancy (Stage III and IV cancers of any type), allocating 24 participants to either 530 mg or 1060 mg of Annona muricata daily for 12 weeks.

Evidence strength: The anticancer evidence base for graviola in humans is very weak — it consists primarily of in vitro cell-line studies, limited animal models, and isolated case reports. No properly powered, randomized controlled trials with oncological outcomes have been published.

5.2 Antidiabetic Activity

Leaves of A. muricata are now utilized in some practices to control and treat diabetes. Preclinical studies, both in vitro and in animal models, have investigated mechanisms including inhibition of α-amylase and α-glucosidase (enzymes involved in carbohydrate digestion). A. muricata leaves have been found to exhibit antidiabetic and hypolipidemic activities among their diverse pharmacological properties. A review of 49 research articles from 1981 to 2021 found that antidiabetic activity accounted for 14% of reported activities for A. muricata.

Evidence strength: Antidiabetic evidence is preliminary — predominantly in vitro and animal studies. No clinical trials in humans with diabetes have established efficacy or safe dosing.

5.3 Antihypertensive Activity

This species possesses vasodilator, cardio-depressive, antispasmodic, antimutagen, anticonvulsant, antiviral, antidiabetic, and antihypertensive effects. Antihypertensive activity accounted for 6% of activities reported across reviewed pharmacological studies of A. muricata.

Evidence strength: Preliminary. Evidence derives from in vitro and animal studies. Human clinical data are absent.

5.4 Anti-inflammatory and Analgesic Activity

The use of anti-inflammatory natural products to treat inflammatory disorders for cancer prevention and therapy is an appealing area. Annona muricata L. is one of the many plant extracts explored for anti-inflammatory and anticancer effects. Different parts of A. muricata, especially the leaves, have been used for various ethnomedicinal purposes to treat several diseases including cancer, inflammation, diabetes, liver diseases, and abscesses.

Evidence strength: Preliminary. Studies have been conducted primarily in animal models and cell cultures; systematic clinical investigation in humans is lacking.

5.5 Antimicrobial Activity

The methanol extract of Annona muricata showed apparent antimicrobial activities. Isolated alkaloids from this genus, including liriodenine, anonaine, and asimilobine, showed sensitivity against Staphylococcus epidermidis. Antibacterial activity and antiviral activity each accounted for 8% of reported pharmacological activities in the reviewed literature on A. muricata.

Evidence strength: Preliminary; in vitro only. There are no clinical trials assessing antimicrobial efficacy in humans.

5.6 Antiparasitic and Antiprotozoal Activity

The acetogenins have been determined to be pesticidal, antimalarial, antimicrobial, anti-parasitic, cytotoxic, and in vivo active as potentially new antitumor agents. A. muricata leaves have been found to exhibit anti-plasmodial, anti-arthritic, anti-protozoal, antiparasitic, and insecticidal activities.

Evidence strength: Preliminary. Antiparasitic activity is supported by in vitro and limited in vivo animal data; no human trial evidence.

5.7 Antioxidant Activity

A. muricata leaves possess enzymatic antioxidants, including superoxide dismutase and catalase, together with non-enzymatic antioxidants such as vitamin C and vitamin E. The DPPH test revealed the significant antioxidant activity of the aqueous and ethanol extracts of A. muricata leaves.

Evidence strength: In vitro only. Antioxidant capacity measurements in test systems do not directly predict clinical benefit.

5.8 Sedative / Anxiolytic Effects

Graviola has been shown to stimulate serotonin receptors. This finding provides a potential pharmacological basis for the traditional use of graviola leaf infusions as a sedative and sleep aid. A. muricata leaves have also been found to exhibit anticonvulsant activity.

Evidence strength: Preliminary. Serotonin receptor stimulation has been observed in pharmacological studies, but there are no controlled human trials evaluating sedative or anxiolytic effects.

5.9 Gastroprotective and Antiulcer Activity

Antiulcer activity was the second most commonly reported pharmacological activity in a review of A. muricata studies, accounting for 17% of reported activities across 49 research articles from 1981–2021. Gastroprotective effects have been identified in animal models, though no human clinical data are available.

Evidence strength: Preclinical only.

6. Body Systems and Health Areas Associated with Graviola

• Oncology / Cellular biology: Cancer cell cytotoxicity, apoptosis induction, cell cycle arrest — extensively studied in vitro and in animal models; no validated human evidence.
• Metabolic / Endocrine system: Antidiabetic potential (glycemic enzyme inhibition, blood glucose regulation in animals).
• Cardiovascular system: Antihypertensive and vasodilatory effects noted in preclinical models.
• Immune and inflammatory systems: Anti-inflammatory activity; wound healing.
• Nervous system: Serotonin receptor stimulation; traditionally used as a sedative and anticonvulsant; the same system is a target of neurotoxic acetogenins (see Safety section).
• Gastrointestinal system: Antiulcer, antidiarrheal, digestive, and gastroprotective uses documented.
• Infectious disease: Antimicrobial, antiviral, antiparasitic, antimalarial activities described at preclinical level.
• Hepatic system: Hepatoprotective activities investigated in animal models.

7. Dosage Forms and Dosages Reported in Studies

Because no preparation of A. muricata has been approved by a regulatory authority such as the FDA or EMA, no officially sanctioned dosage exists. The following represent dosages used or proposed in published research:

• A registered open-label pilot clinical study in people living with advanced cancer allocated 24 participants to either 530 mg or 1060 mg of Annona muricata (leaf product) daily for 12 weeks.
• In an animal study investigating anticancer effects on Ehrlich solid tumors, mice were treated with graviola at 50 mg/kg body weight orally for 30 days.
• A systematic review on the safety and tolerability of Annona muricata leaf extract found that chemopreventive effects were observed in four in vivo studies using ethanolic and methanolic leaf extracts administered at doses ranging from 30–400 mg/kg.
• In vivo studies showed that the LD50 of ethanolic extract of Annona muricata ranged from 1000 mg/kg to 1670 mg/kg in animal models.
• A single 2000 mg/kg dose of A. muricata leaf ethanol extract administered to Sprague-Dawley rats over an observational period of 14 days showed no abnormal toxicity on physical and behavioral observation, body weight, renal function, or liver function tests.

It should be noted that one randomized clinical trial reported that the serum concentration might have been too low to significantly increase caspase-8 activity, accounting for only 10% in the cell culture media, which may have contributed to the reported results, indicating that the dose provided might be insufficient.

8. Safety Considerations

8.1 Neurotoxicity and Atypical Parkinsonism

The most significant documented safety concern for graviola relates to its acetogenin content and associated neurotoxic potential. The association of the consumption of fruit and homemade preparations of A. muricata with the appearance of atypical Parkinsonism in the Caribbean Island of Guadeloupe is based on a case study published in 1999. This association has also been reported in New Caledonia and among Caribbean patients living in London. From these studies, assessment of the neurotoxic effect of the main bioactive compounds of A. muricata alkaloids and acetogenins was initiated.

There is an unexpectedly high proportion of atypical forms of degenerative parkinsonism in the French Caribbean islands. Residents of these islands are thought to be susceptible to Caribbean atypical parkinsonism (CAP) owing to their consumption of Annonaceae plant products containing the mitochondrial toxin annonacin.

In vitro and in vivo studies have reported that Annonaceous acetogenins, especially annonacin (one of the most abundant acetogenins), can damage different populations of neurons in the brain, including dopaminergic neurons and cortical and subcortical neurons, by promoting mitochondrial dysfunction. Annonacin can also induce the redistribution of abnormally phosphorylated tau from neurites to cell bodies in striatal neuronal cultures.

Reticuline and coreximine alkaloids, and solamin, annonacinone, isoannonacinone, and annonacin acetogenins were shown to be toxic to dopaminergic cells by impairing energy production.

Quantification of acetogenins in A. muricata extracts showed an average A. muricata fruit contained about 15 mg of annonacin, a can of commercial nectar contained 36 mg, and a cup of infusion or decoction contained 140 μg.

High consumption of Annona muricata fruit has been previously identified as a risk factor for atypical parkinsonism in the French Caribbean islands. One study analyzed neurological data from 180 Caribbean parkinsonian patients and specifically looked for dose effects of lifelong, cumulative Annonaceae consumption on cognitive performance. Using unsupervised clustering, researchers identified one cluster with mild/moderate symptoms (N = 102) and one with severe symptoms including cognitive impairment (N = 78).

The evidence of neurotoxicity and cytotoxicity converges in a selectivity relationship associated with cells that require high energy demand, and this seems to be a key feature that can help to understand the synergistic effects. Chronic exposure to acetogenins can potentiate neural damage, and thus moderate consumption of infusions, extracts, and pulp of Annonaceae fruits is recommended.

8.2 EFSA Risk Assessment

A formal 2020 risk assessment conducted in the context of the EU-FORA (European Food Risk Assessment Fellowship Programme) supported by EFSA found that substantial uncertainties exist regarding the safe use of A. muricata-based supplements. The available data provide indications of neurotoxic potential of certain A. muricata preparations. The paucity of adequate studies, particularly related to long-term use of A. muricata supplements, currently does not allow the establishment of a safe intake level.

Various preparations from fruits and other plant parts of A. muricata are marketed worldwide as over-the-counter food supplements purported to support general health or to treat a wide range of health conditions, particularly cancer and parasitic infections. The EFSA assessment represents the most authoritative regulatory-level safety evaluation currently available and concluded that no safe intake level can yet be established.

8.3 AVIS Statement (French Food Safety Agency)

A study by l'Agence Française de Sécurité des Aliments (The French Food Safety Agency) reported that based on the amount of various constituents in graviola, pharmacokinetics studies (which revealed that acetogenins did not cross the blood-brain barrier easily) and daily human consumption have indicated that there is no clinical link between graviola and atypical Parkinson's and/or neurotoxicity. However, this statement predates much of the more recent mechanistic and epidemiological work, and must be interpreted alongside the more cautious subsequent EFSA (2020) assessment.

8.4 Product Quality and Variability

There is high variation in annonacin concentration (1.05–3.09 mg/g) among commercial graviola leaf products, and one product was found to have a total aerobic microbial count above the United States Pharmacopoeia limit. The variation in indicators of quality and safety of commercially available A. muricata leaf products has implications for clinicians and people who use these herbal products.

8.5 Overall Safety Profile Summary

The overall outcome of a systematic review in the Journal of Pharmacy and Pharmacology (2020) suggests that A. muricata has a favourable short-term safety and tolerability profile, and that future studies investigating its use in people diagnosed with a range of cancers are warranted. However, this must be balanced against the EFSA finding that no safe long-term intake level can be established, the epidemiological signal from Guadeloupe for high or chronic consumption, and the documented in vitro and in vivo neurotoxic potential of the acetogenin annonacin. Some phytochemical compounds isolated from A. muricata have shown a neurotoxic effect in vitro and in vivo, and therefore these crude extracts and isolated compounds need to be further investigated to define the magnitude of the effects, optimal dosage, and mechanisms of action, long-term safety, and potential side effects. More clinical studies are necessary to support the therapeutic potential of this plant.

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