Levant berry

Other Names

Anamirta baueriana Endl.Anamirta cocculus (L.) Wight & Arn.Anamirta jucunda MiersAnamirta paniculata Colebr.Anamirta populifolia (DC.) MiersAnamirta racemosa Colebr. ex Steud.Anamirta toxifera MiersAriaBayatiCoca de LevanteCocculus fructusCocculus indicusCocculus indicus RoyleCocculus lacunosus DC.Cocculus populifolius DC.Cocculus suberosus DC.Fish berryFish killerFish poisonFishberryGaralaphalaHockle elderberryIndian berryKaka-MariKakadaniKakamariKakamari-bijaKakaphalaKaki-ChampaKakkamariKakkay-Kolli-ViraiKakmariKaranta-Kattin-KayaKockel-lianKollakkayaLagtangLevant nutLigtangLouseberryMenispermum cocculiferum StokesMenispermum cocculus L.Menispermum heteroclitum Roxb.Menispermum lacunosum Lam.Menispermum monadelphum Roxb.PettumarunnaPettumarunnuPoisonberryPollaPollakaiPolluk-KayaTitta-welTuba bijiVatoliVittnYin du mu fang ji

Synopsis

Levant Berry (Anamirta cocculus): A Comprehensive Reference

1. Identity: Botanical Classification, Nomenclature, and Forms

Botanical and Scientific Names

The accepted scientific name is Anamirta cocculus Wight & Arn., though it has been recorded under several synonyms across the botanical literature. These synonyms include Anamirta paniculata, Menispermum cocculus, Menispermum lacunosum, Cocculus suberosus, and Cocculus lacunosus. The plant belongs to the family Menispermaceae. It is the only species of the genus Anamirta.

Common Names

It is known by numerous common names, including Cocculus fructus, Cocculus indicus, Fish killer, Fishberry, Hockle elderberry, Indian berry, Kockel-lian, Levant berry, Levant nut, Louseberry, Poisonberry, and Tuba biji. It is also known as coca de Levante in Spanish, and as ligtang, aria (Mindanao), and bayati (Tagalog) throughout the Philippines. In Indian vernacular traditions, it appears as Kakamari and Kakaphala in Hindi and Bengali, and under a range of regional names in Tamil, Telugu, Kannada, and Malayalam.

Botanical Description and Distribution

The plant is a Southeast Asian and Indian climbing plant, the source of picrotoxin, a poisonous compound with stimulant properties. It is large-stemmed (up to 10 cm in diameter); the bark is "corky gray" with white wood. The "small, yellowish-white, sweet-scented" flowers vary between 6 and 10 millimeters across; the fruit produced is a drupe, "about 1 cm in diameter when dry."

The plant is widely distributed in Southeast Asia and in India, mainly in the deep forests of Kadappa, Mysore, and Malabar. Its habitat in India extends through Eastern Bengal, the Khasia hills, Assam, and from Konkan and Orissa to Ceylon, up to 2,000 feet altitude.

Part Used and Pharmacopoeial Status

The dried fruits constitute the drug known as "cocculus" or "cocculus indicus." Fruits of Anamirta cocculus are officially listed in the pharmacopoeias of various countries. Vertigoheel, one of the most studied preparations containing Anamirta cocculus, is a natural over-the-counter medicinal product; its production and use are approved by the German regulatory authority and comply with the standards outlined in the German Homeopathic Pharmacopeia.

Pharmaceutical and Preparations Forms

Levant berry is the fruit from the vine (Anamirta cocculus) that grows in Southeast Asia; the dried fruit and seeds are used to make medicine in some parts of the world. Preparations documented in the literature include the following:

In homeopathy, the remedy Cocculus indicus (tincture) is prepared by macerating the powdered seeds in alcohol.
Applied externally, the fruits and seeds are made into an ointment to treat skin diseases.
Picrotoxin has been used intravenously as an antidote against poisoning by barbiturates and morphine.
Picrotoxin suppositories (1 mg inserted 3 times per week) have been evaluated in clinical research contexts.
Today, the dried and powdered seeds are mainly used in homeopathy as a motion sickness medicine; in homeopathic form, it is prepared and highly diluted in a way that is stated to remove the seed's toxic properties.

2. Traditional and Historical Use

Fishing, Pest Control, and Non-Medicinal Uses

The name "fishberry" comes from the use of the dried fruit as a method of fishing, in which the fish is "stupified and captured." Its crushed seeds are an effective pediculicide (anti-lice) and are also traditionally used to stun fish or as a pesticide. In Southeast Asia, the fruit of Anamirta cocculus is used mainly as a fish poison and as an insecticide.

Although poisonous, "hard multum" is a preparation made from Cocculus indicus that was once used by 19th-century brewers to impart a more intoxicating quality ("giddiness") to beer than was provided by the alcoholic content alone.

Traditional Medical Systems: India and Southeast Asia

In older Ayurvedic compendiums, Anamirta cocculus appears in scattered references under local names like Kakamari or Fishberry. It earned its place in early Southeast Asian and Indian traditional healing practices not for everyday use, but for very targeted problems: lethargy, certain tremors, and intestinal parasitism.

An infusion of the roots is used to treat fevers, dyspepsia, and menstrual problems. An extract of the stem is added to native wine and drunk to "make the blood strong." Leaves may be used as a poultice for headache, stomach-ache, or delayed menstruation. In India, fruits are used for bronchitis, chronic skin disease, foul ulcers, dermatophytosis, and vertigo.

According to the Unani system of medicine, the fruit is described as slightly bitter, a good expectorant, useful for removing gas from the intestine, beneficial for rheumatism, and as an application for inflammations. In Unani medicine, it was sometimes applied externally for joint pain or neuralgia, though internal use always demanded supervision.

In Unani, Anamirta cocculus (known as Mahi Zahrah) exhibits a Hot and Dry temperament (3rd degree) and is described as highly effective in expelling viscous phlegmatic humours. It is used traditionally for arthritis, gout, sciatica, ascites, and parasitic infections.

Traditional healers of Chhattisgarh have been recorded as using its seeds internally as well as externally for treatment of various types of cancer. Jungle tribes have applied picrotoxin taken from the seeds to arrow tips for hunting.

Homeopathic Tradition

Cocculus indicus was introduced into homeopathy by Dr. Samuel Hahnemann, who recognized its unique effects on the nervous and digestive systems. In homeopathic medicine, the drug is used for nervous exhaustion, attacks of dizziness, cramps, paralysis, dysmenorrhoea, and occipital headaches.

Pharmacological History in Conventional Medicine

Picrotoxin, a major toxic constituent of levant berry seeds, has historically been used to manage epilepsy and has been evaluated in studies for various nervous system disorders, including limited clinical studies of vertigo. Picrotoxin has been used intravenously as an antidote against poisoning by barbiturates and morphine; however, the safe therapeutic dose range is very narrow. Very minute doses of picrotoxin were used as a nerve tonic in schizophrenia, epilepsy, and similar afflictions. It was used in medicine as a central nervous system stimulant and antidote for barbiturate poisoning, but is not currently regarded as a useful therapeutic agent.

Medicinal use of levant berry has been abandoned in the US and Europe due to safety concerns.

3. Key Constituents and Active Compounds

Picrotoxin (the Primary Active Compound)

The seeds deliver picrotoxin, a sesquiterpene, while the seed shells contain the tertiary alkaloids menispermine and paramenispermine. The seed contains about 1.5% of a bitter, crystalline, highly toxic substance, picrotoxin. This consists of equimolecular proportions of picrotoxinin (C₁₅H₁₆O₇). Picrotoxinin is a highly oxygenated sesquiterpene derivative.

Picrotoxin (cocculin) is the major reported toxic component of the seed and is composed of poisonous picrotoxinin and the bitter but non-poisonous picrotin. Representative markers of Anamirta cocculus confirmed by analytical chemistry include picrotoxinin and picrotin.

Alkaloids

The stem and roots contain quaternary alkaloids, such as berberine, palmatine, magnoflorine, and columbamine. The pericarp of Cocculus indicus contains two isomeric, tasteless, crystallisable alkaloids termed menispermine (C₁₈H₂₄O₂N) and paramenispermine (C₁₈H₂₄C₂N), combined with an acid called hypopicrotoxic acid.

The stem and roots of Anamirta cocculus contain quaternary alkaloids, such as berberine, palmatine, magnoflorine, and columbamine, and the major tertiary alkaloid is 1-8-oxotetrahydropalmatine.

Other Phytochemicals

Roy et al. isolated stearic acid from the seeds and fumaric acid from the flowers. Lalith et al. isolated one new triterpenoid and two new triterpenoid glycosides from the stem; the major compounds isolated were arjunolic acid and its 28-O-β-D-glucopyranoside. Agarwal et al. isolated picrotoxin, picrotoxinin, methyl picrotoxate, and two new sesquiterpene lactones, dihydroxypicrotoxnin and picrotoxic acid.

4. Mechanisms of Action

GABA-A Receptor Antagonism

Picrotoxin acts as a non-competitive antagonist of GABA-A receptors by binding within or near the chloride ion channel pore, rather than at the GABA-binding site. Type A GABA receptors (GABARs) are ligand-gated ion channels (LGICs) found in the brain and are the major inhibitory neurotransmitter receptors. Upon binding of an agonist, the GABAR opens and increases the intraneuronal concentration of chloride ions, thus hyperpolarizing the cell and inhibiting the transmission of the nerve action potential. Picrotoxin is a noncompetitive antagonist for LGICs, and by inhibiting GABAR, picrotoxin can cause overstimulation and induce convulsions.

Due to its interactions with the inhibitory neurotransmitter GABA, picrotoxin acts as a stimulant and convulsant. It mainly impacts the central nervous system, causing seizures and respiratory paralysis in high enough doses.

For a number of years, it has been known that the CNS convulsant picrotoxin inhibits the GABA-A receptor, an anion-selective member of the ligand-gated ion channel (LGIC) superfamily. Due to these properties, picrotoxin serves as a valuable research tool to study inhibitory neurotransmission and the pharmacology of ligand-gated ion channels.

Adenylate Cyclase and Cyclic Nucleotide Pathways

In the context of its inclusion in the preparation Vertigoheel, Anamirta cocculus was found to stimulate adenylate cyclase activity. Investigators tested the hypothesis that Vertigoheel's anti-vertiginous properties may in part be due to a vasodilatory effect exerted via stimulation of the adenylate and/or guanylate cyclase pathways. Vertigoheel and one of its constituents, Anamirta cocculus, stimulated adenylate cyclase activity, while another constituent, Conium maculatum, inhibited phosphodiesterase 5, suggesting that the individual constituents of Vertigoheel contribute differentially to a synergistic stimulation of cyclic nucleotide signalling pathways.

CNS Stimulation and Respiratory Effects

The fruits, and especially the seeds, contain picrotoxin, a very strong poison that is toxic to all vertebrates, affecting the CNS, stimulating the respiratory and vagus centres in the medulla, and acting on the heart and lungs with diminished pulse. Levant berry contains a chemical that stimulates the central nervous system, irritates the stomach and intestines, and stimulates the brain causing changes in breathing. It also slows heart rate and increases blood pressure.

5. Scientific Evidence by Area of Use

5.1 Vertigo and Vestibular Disorders

This is the area with the most clinical research, primarily in the context of the multi-ingredient preparation Vertigoheel (which contains Anamirta cocculus as one of four components).

Vertigoheel is a multicomponent medicinal product for the treatment of vertigo and dizziness, containing Anamirta cocculus, Conium maculatum, Ambra grisea, and Petroleum rectificatum. Although clinical efficacy has been reported, the chemical composition and underlying mechanisms remain incompletely characterized.

A meta-analysis of four recent clinical trials evaluated the homeopathic preparation Vertigoheel compared with usual therapies (betahistine, Ginkgo biloba extract, dimenhydrinate) for vertigo in a total of 1,388 patients. Two trials were observational studies and the other two were randomized double-blind controlled trials. The duration of treatment (6–8 weeks) and dosage were comparable in all studies. Treatments were evaluated for the variables "number of vertigo episodes," "intensity of episodes," and "duration of episodes."

A randomized double-blind controlled clinical study on homeopathic treatment (Vertigoheel) versus conventional treatment (betahistine) for the treatment of vertigo showed the therapeutic equivalence of the two drugs established statistically. Both reduced the frequency, duration, and intensity of vertiginous attacks during the 6-week treatment period. The study was not specific for Ménière's patients.

A randomized (1:1) double-blind controlled clinical trial was conducted across 15 study centres (general practice) in Germany between November 1995 and November 1996, enrolling a total of 119 patients with vertigo of various origins.

Clinical studies of picrotoxin use in Ménière's disease, alone and in combination with other natural remedies for vertigo, have been limited because of toxicity concerns. In a small clinical study (N=41), picrotoxin suppositories (1 mg inserted 3 times per week) (n=23) were more effective than betahistine (n=18) in reducing the frequency and intensity of vertigo attacks.

According to several clinical studies, Vertigoheel significantly reduces the frequency, duration, and intensity of vertigo. Beneficial effects of Vertigoheel may be mediated by the vasodilatory or neurotropic actions of the drug.

Evidence strength assessment: Picrotoxin has been evaluated in studies for various nervous system disorders, including limited clinical studies of vertigo. Clinical use of levant berry has largely been abandoned in the United States and Europe due to toxicity and a lack of studies supporting use. The vertigo evidence base relates principally to a multi-component formulation (Vertigoheel) rather than to levant berry or picrotoxin in isolation; the contribution of the Anamirta cocculus fraction cannot be separated from the other three ingredients.

5.2 Nystagmus

In more recent times, picrotoxin has been used in the treatment of peripheral and vestibular nystagmus, and in both long- and short-term therapy for peripherally based dizziness and travel sickness. Some people take levant berry to treat abnormal movement of the eyeball and dizziness. Clinical evidence in this area consists of isolated historical studies; no robust modern randomized controlled trials specifically examining Anamirta cocculus or pure picrotoxin for nystagmus could be identified.

5.3 Epilepsy and Neurological Conditions

Picrotoxin taken from levant berry seeds has historically been used for epilepsy, night sweats, and as a stimulant. Very minute doses of picrotoxin were used as a nerve tonic in schizophrenia, epilepsy, and similar afflictions. These uses are historical; picrotoxin itself is a convulsant at higher doses, and there are no current peer-reviewed clinical trials in humans supporting its therapeutic use for epilepsy as an isolated compound from levant berry.

5.4 Cognitive Performance (Preclinical)

Investigators examined the effects of Vertigoheel (VH-04) on cognitive performance in standard behavioral tests assessing different types of memory and explored the cellular and molecular underpinnings of VH-04's biological activity. Vertigoheel is a multicomponent, multitarget drug containing Anamirta cocculus as one ingredient. According to several clinical studies, VH-04 significantly reduces the frequency, duration, and intensity of vertigo. Beneficial effects of VH-04 may be mediated by vasodilatory or neurotropic actions of the drug. This cognitive enhancement research is preclinical (animal) only, and no human clinical data exists on this endpoint.

5.5 Antimicrobial Activity (In Vitro)

Modern studies confirm antibacterial, antioxidant, and larvicidal properties of Anamirta cocculus. Studies have assessed the antibacterial efficacy of seed extracts of Anamirta cocculus against pathogenic bacterial strains including Staphylococcus aureus, Proteus vulgaris, Escherichia coli, and Salmonella typhi. The seed extracts of A. cocculus have shown larvicidal and adulticidal activities against the dengue vector mosquito, Aedes aegypti, in a study assessing its bioefficacy. In general, the alkaloids isolated from the plant have antibacterial, antimicrobial, and antifertility activities. All antimicrobial findings are in vitro or laboratory-based; no clinical trials in humans have been conducted.

5.6 Ectoparasiticide (Pediculicidal Use)

Levant berry has traditionally been used topically as a parasiticide to treat lice. The seeds are applied to the scalp to kill head lice. Cocculus indicus has been traditionally used as an insecticide and pesticide, particularly for controlling certain fish and aquatic invertebrate pests. The compound picrotoxin in the plant is believed to be responsible for these insecticidal and pesticidal effects. No controlled clinical trials exist to establish efficacy or safety of topical levant berry preparations for pediculosis.

5.7 Barbiturate and Morphine Poisoning Antidote (Historical Medical Use)

Picrotoxin can be used as a specific barbiturate poisoning antagonist, although its safety limits are very narrow. This application is historical and has been superseded by safer antidotal agents.

6. Body Systems and Health Areas of Association

Central Nervous System: Due to its interactions with the inhibitory neurotransmitter GABA, picrotoxin acts as a stimulant and convulsant.
Vestibular System: Picrotoxin has been used in the treatment of peripheral and vestibular nystagmus, and in both long- and short-term therapy for peripherally based dizziness and travel sickness.
Respiratory Centre: Picrotoxin stimulates the respiratory and vagus centres in the medulla.
Cardiovascular System: Levant berry contains a chemical that acts on the brain causing changes in breathing, and also slows heart rate and increases blood pressure.
Gastrointestinal System: Levant berry irritates the stomach and intestines.
Skin (Topical): The fruits and seeds are made into an ointment traditionally used to treat skin diseases.
Reproductive System (Traditional): The leaves may be used as a poultice for delayed menstruation.

7. Dosage Forms and Dosages Reported in Sources

The appropriate dose of levant berry depends on several factors such as the user's age, health, and several other conditions. At this time there is not enough scientific information to determine an appropriate range of doses for levant berry.

Where dosages have been specifically reported in source documents:

Picrotoxin suppositories at a dose of 1 mg inserted 3 times per week were used in a small clinical study (N=41) for vertigo.
One manufacturer of the homeopathic preparation instructs users to dissolve five pellets of Cocculus indicus 6C under the tongue every hour as needed.
The Homeopathic Pharmacopoeia of the United States (HPUS) has determined that homeopathic dilutions of Cocculus indicus 6X and above are safe to be sold as over-the-counter medicines.
In preclinical (rat) research, the Vertigoheel solution contained 70 µg/mL extract of dried, ripe fruit of Anamirta cocculus L., together with extracts of the other three components, manufactured according to international Good Manufacturing Practice standards.

8. Safety Considerations and Interactions

Systemic Toxicity

The fruits, and especially the seeds, contain picrotoxin, a very strong poison that is toxic to all vertebrates, affecting the CNS, stimulating the respiratory and vagus centres in the medulla, and acting on the heart and lungs with diminished pulse. The toxicity results in vomiting, purging, profuse sweating, dimness of vision, unconsciousness, and clonic convulsions. Death occurs rapidly due to respiratory failure, or slowly from gastrointestinal symptoms.

The picrotoxin it contains can cause death, even in small amounts. Accidentally taking levant berry requires immediate medical attention. Levant berry can cause side effects such as headache, dizziness, nausea, coordination problems, depression, spasms, twitching, increased saliva, vomiting, increased emptying of the bowels, rapid breathing, drowsiness, irregular heartbeat, decreased heart rate, unconsciousness, and death.

Topical Safety

Levant berry may also be unsafe when put on the skin.

Narrow Therapeutic Index

The safe therapeutic dose range of picrotoxin is very narrow. Its use is limited by severe toxicity risks associated with picrotoxin, making proper dosage, correctives (Musalihat), and therapeutic supervision essential in traditional contexts where it has historically been used.

Pregnancy and Lactation

During pregnancy and breastfeeding, it is unsafe to take levant berry, as it is poisonous and can cause death.

Regulatory Status

Medicinal use has been abandoned in the US and Europe due to safety concerns. Clinical use of levant berry has largely been abandoned in the United States and Europe due to toxicity and a lack of studies supporting use. Due to toxicity concerns and a lack of clinical trial data, use cannot be recommended for any indication. Clinical studies are lacking to support any clinical applications of levant berry; toxicity of the constituent picrotoxin has been established.

Homeopathic products containing this ingredient have not been evaluated by the Food and Drug Administration for safety or efficacy; the FDA is not aware of scientific evidence to support homeopathy as effective.

Pre-Surgical Concerns

This product may adversely interact with certain health and medical conditions, other prescription and over-the-counter drugs, foods, or other dietary supplements. It may be unsafe when used before surgery or other medical procedures.

Research Tool Status

Picrotoxin, the active chemical in levant berry, is still used in research. Due to its properties as a GABA-A receptor antagonist, picrotoxin serves as a valuable research tool to study inhibitory neurotransmission and the pharmacology of ligand-gated ion channels.

References

Health Conditions

Health conditions that Levant berry may help support.

No conditions available.

Body Systems

Body systems that Levant berry may help support.

No body systems available.