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Levant Berry

Scientific Name(s): Anamirta cocculus Wight & Arn.
Common Name(s): Cocculus fructus, Cocculus indicus, Fish killer, Fishberry, Hockle elderberry, Indian berry, Kockel-lian, Levant berry, Levantnut, Louseberry, Poisonberry, Tuba biji

Clinical Overview

Use

Levant berry has traditionally been used to relieve malaria, treat lice, stun or kill fish and game, and manage epilepsy. Clinical use of levant berry has largely been abandoned in the United States and Europe because there are no studies supporting its use. The constituent picrotoxin has been evaluated in limited clinical studies for vertigo.

Dosing

No clinical evidence supports any clinical applications of levant berry. In a small clinical study, picrotoxin suppositories (1 mg 3 times per week) were more effective than betahistine in reducing the frequency and intensity of vertigo attacks.

Contraindications

Toxicity of the constituent picrotoxin has been established.

Pregnancy/Lactation

Avoid use. Adverse effects have been documented.

Interactions

None well documented.

Adverse Reactions

Picrotoxin stimulates the CNS and is a GI irritant.

Toxicology

High doses can cause salivation, vomiting, purging, rapid shallow respiration, palpitations or heart slowing, stupor, loss of consciousness, and death. Death from doses of 2 to 3 g of the fruit has been reported.

Botany

A. cocculus, known as levant berry, is a climbing woody shrub native to India, Burma, and other parts of Malaysia. It has wide thick leaves and rootlets that ooze a white milky latex. The fragrant flowers produce U-shaped seeds. The fruit dries to a bitter, nearly black wrinkled shape.1, 2, 3

History

The fruit of levant berry is gathered from the wild and sun dried for export. In India, the leaves have been inhaled as a snuff to relieve malaria, and the leaf juice used in combination with other natural products as a vermifuge.1 Extracts of the plant have been applied topically for lice, but the toxic nature of the components (in particular picrotoxin) makes this application dangerous, especially in cases of abraded or irritated skin. For centuries, fishermen in Asia used the seeds to produce a poison to stun fish,4 and in some societies, ground whole dried fruit has been used to kill birds or dogs, and to stupefy game as well as fish.5 Picrotoxin has been used as a stimulant for the management of morphine and barbiturate poisoning and was considered an official remedy for epilepsy at the turn of the 19th century into the 20th in the United States; however, it is no longer used for this condition because of severe toxicity.1, 3 Use as a biological weapon has been suggested for picrotoxin because of the ease of chemical isolation and purification.5

Chemistry

The fruit flesh and seed shells contain the nontoxic alkaloids menispermine and paramenispermine.1, 6 The seed, however, contains the bitter, toxic principle picrotoxin (1.5% to 5%); this compound can be separated into picrotoxinin and picrotin, which are oxygenated sesquiterpene derivatives.7 The tasteless compounds anamirtin and cocculin are also present, along with a fixed oil (11% to 24% of the seed).1 The seed is also rich in fatty acids. The stem and roots of the plant contain quaternary alkaloids (eg, berberine, palmatine).6

Uses and Pharmacology

CNS effects

Animal data

Picrotoxin acts as gamma-aminobutyric acid (GABA) receptors, blocking conductance enhancement of agonists such as propofol and barbiturates, hence its historical application as an antidote to barbiturate poisoning.4, 8 Studies conducted in rodents have shown improved sexual behavior in adult rats and their offspring due to possible action of picrotoxin on GABA receptors.9, 10, 11

Clinical data

Clinical studies of picrotoxin use in Meniere disease, as well as in combination with other natural remedies for vertigo, have been limited because of toxicity concerns.12, 13 In a small clinical study, picrotoxin suppositories (1 mg 3 times per week) were more effective than betahistine in reducing the frequency and intensity of vertigo attacks.12

Other uses

Picrotoxin, not levant berry itself, has been studied for effect on acute hypoxic states, potentially via activity on GABA receptors, in rats14 and on cognitive decline in mice.15

Dosing

No clinical evidence supports any clinical applications of levant berry. In a small clinical study, picrotoxin suppositories (1 mg 3 times per week) were more effective than betahistine in reducing the frequency and intensity of vertigo attacks.12

Pregnancy / Lactation

Avoid use. Adverse effects have been documented. Exposure to picrotoxin has been shown to induce demasculinization of male offspring.11

Interactions

None well documented.

Adverse Reactions

Picrotoxin stimulates the CNS and is a GI irritant.1

Toxicology

High doses can cause salivation, vomiting, purging, rapid shallow respiration, palpitations or heart slowing, stupor, loss of consciousness, and death.3, 8 Death from doses of 2 to 3 g of the fruit have been reported.3

References

1. Morton JF. Major Medicinal Plants: Botany, Culture, and Uses. Springfield, IL: Thomas; 1977.
2. USDA. NRCS. 2015. The PLANTS Database (http://plants.usda.gov, 2015). National Plant Data Center, Baton Rouge, LA 70874-4490 USA.
3. Duke JA, Bogenschutz-Godwin M, duCellier J, Duke PK. Handbook of Medicinal Herbs. 2nd ed. Boca Raton, FL: CRC Press; 2002.
4. Bause GS. From fish poison to Merck picrotoxin. Anesthesiology. 2013;118(6):1263.23695089
5. Jablonski JE, Jackson LS. Stability of picrotoxin during yogurt manufacture and storage. J Food Sci. 2008;73(8):T121-T128.19019133
6. Verpoorte R, Siwon J, Tieken MEM, Svendsen AB. Studies on Indonesian medicinal plants. V. The alkaloids of Anamirta cocculus. J Nat Prod. 1981;44(2):221-224.
7. Duke JA. Handbook of Biologically Active Phytochemicals and Their Activities. Boca Raton, FL: CRC Press Inc; 1992.
8. Belcher SF, Morton TR. Tutu toxicity: three case reports of Coriaria arborea ingestion, review of literature and recommendations for management. N Z Med J. 2013;126(1370):103-109.23474518
9. Teodorov E, Moraes AP, Felicio LF, Varolli FM, Bernardi MM. Perinatal maternal exposure to picrotoxin: effects on sexual behavior in female rat offspring. Pharmacol Biochem Behav. 2005;81(4):935-942.16098570
10. Bernardi MM, Scanzerla KK, Chamlian M, Teodorov E, Felicio LF. Maternal treatment with picrotoxin in late pregnancy improved female sexual behavior but did not alter male sexual behavior of offspring. Behav Pharmacol. 2013;24(4):282-290.23838964
11. Baso AC, Goulart FC, Teodorov E, Felicio LF, Bernardi MM. Effects of maternal exposure to picrotoxin during lactation on physical and reflex development, square crossing and sexual behavior of rat offspring. Pharmacol Biochem Behav. 2003;75(4):733-740.12957213
12. Weikert S, Rotter A, Scherer H, Hölzl M. Picrotoxin in the treatment of Menière's disease. Laryngorhinootologie. 2008;87(12):862-866.18720328
13. Heinle H, Tober C, Zhang D, Jäggi R, Kuebler WM. The low-dose combination preparation Vertigoheel activates cyclic nucleotide pathways and stimulates vasorelaxation. Clin Hemorheol Microcirc. 2010;46(1):23-35.20852360
14. Sanotskaya NV, Matsievskii DD, Lebedeva MA. Effect of picrotoxin on organism's resistance to acute severe hypoxia. Bull Exp Biol Med. 2008;145(2):177-180.19023962
15. Yoshiike Y, Kimura T, Yamashita S, et al. GABA(A) receptor-mediated acceleration of aging-associated memory decline in APP/PS1 mice and its pharmacological treatment by picrotoxin [published online August 21, 2008]. PLoS One. 2008;3(8):e3029.1871665610.1371/journal.pone.0003029

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This information relates to an herbal, vitamin, mineral or other dietary supplement. This product has not been reviewed by the FDA to determine whether it is safe or effective and is not subject to the quality standards and safety information collection standards that are applicable to most prescription drugs. This information should not be used to decide whether or not to take this product. This information does not endorse this product as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this product. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this product. This information is not specific medical advice and does not replace information you receive from your health care provider. You should talk with your health care provider for complete information about the risks and benefits of using this product.

This product may adversely interact with certain health and medical conditions, other prescription and over-the-counter drugs, foods, or other dietary supplements. This product may be unsafe when used before surgery or other medical procedures. It is important to fully inform your doctor about the herbal, vitamins, mineral or any other supplements you are taking before any kind of surgery or medical procedure. With the exception of certain products that are generally recognized as safe in normal quantities, including use of folic acid and prenatal vitamins during pregnancy, this product has not been sufficiently studied to determine whether it is safe to use during pregnancy or nursing or by persons younger than 2 years of age.

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