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The Mechanism of Gingko Induced Seizures

Summary:

  • Ginkgo (Ginkgo biloba) mainly comes from the leaves and seeds of its tree, which is indigenous to China, Japan, and Korea, but also found in Europe and the US and is most known for its use to improve memory and to prevent and/or treat of Alzheimer's related dementia.
  • The active compounds found in Ginkgo include flavonoids, bioflavonoids, proanthocyanidins, and trilactonic diterpenes (ginkgolide A, B, C). Unfortunately, depending on the part of the plants used, when they are used, and how they undergo the extraction procedures can result in the presence of a substance called ginkgotoxin, which can increase the risk for seizures.
  • The increase risk for developing seizures comes from an imbalance in the amount of glutamate compared to GABA seen in the presence of ginkgotoxin.

Editor-in-Chief: Anthony J. Busti, MD, PharmD, FNLA, FAHA
Last Reviewed: October 2015

Explanation

  • Ginkgo (Ginkgo biloba) is herbal product that is extracted from the leaves and seeds of its tree, which is indigenous to China, Japan, and Korea, but also found in Europe and the US.1  It is most known for its use to improve memory and for the treatment of Alzheimer's related dementia.1  However, it has many other claimed benefits for other medical conditions as well.  Once the harvested leaves have been dried, they are then pressed into balls where they are put through extraction methods with acetone/water and then undergo a number of purification procedures.   

    The most common active compounds found in ginkgo extract include flavonoids, bioflavonoids, proanthocyanidins, and trilactonic diterpenes (ginkgolide A, B, C).  Unfortunately, depending on the part of the plants used and the method used for extraction, there is chance that the extract can contain a substance known as ginkgotoxin, which also has the names 4'-O-methylpyridoxine or "B6 antivitamin".2-5  Unfortunately, overconsumption of sources or supplements containing this compound has resulted in seizures and possible death.2 

    The increase risk for developing seizures comes from an imbalance in the amount of glutamate compared to GABA (see the figure provided).5  This adverse effect appears to occur from a competition with vitamin B6 (pyridoxine) for binding to pyridoxal kinase, an enzyme needed in the formation of pyridoxal pyrophosphate.  Interestingly, vitamin B6 and ginkgotoxin are structurally very similar, but it appears that ginkgotoxin has a stronger binding affinity for pyridoxal kinase than vitamin B6, as suggested by its lower Km.  As a result of the reduction in pyridoxal pyrophosphate, there is less formation of the major inhibitory neurotransmitter, g-aminobutyric acid (GABA).5   This causes the neuron to be in a state that is more likely to achieve its threshold for another nerve impulse (or action potential).  Furthermore, the increased concentration of glutamate worsens the risk because of its ability to lower the seizure threshold.  Together this environment is ideal for increased and possible, erratic nerve impulses that can result in a seizure.

     

    It is unknown how much ginkgotoxin containing substances needs to be consumed and over what period of time before a seizure will occur for any patient.  It is likely that not only the dose of ginkgotoxin and time of consumption play an important role in this risk, but the patient's baseline risk for seizures, use of concomitant medications also known to lower the seizure threshold, and the nutritional status of the patient, especially as it relates to vitamin B6.  While many name brand supplements probably do not contain ginkgotoxin, their lack of accountability for the manufacturing process by the Food and Drug Administration offers no guarantees.

    References:

    1. National Institutes of Health. National Center for Complementary and Alternative Medicine. Ginkgo.  NCCAM Publicaton No. D290. July 2010. 
    2. Wada K, Ishigaki S, Ueda K et al.  An antivitamin B6, 4'-methoxypyridoxine, from the seed of Ginkgo biloba L.  Chem Pharm Bull  1985;33:3555-7. 
    3. Arenz A, Klein M, Fiehe K et al. Occurrence of neurotoxic 4'-O-methylpyridoxine in Ginkgo biloba leaves, Ginkgo medications and Japanese Ginkgo food.  Planta Med  1996;62:548-51.  
    4. Van Beek TA, Montoro P.  Chemical analysis and quality control of Ginkgo biloba leaves, extracts, and phytopharmaceuticals.  J Chromatogr A  2009;1216:2002-32.
    5. Kastner U, Hallmen C, Wiese M et al.  The human pyridoxal kinase, a plausible target for ginkgotoxin from Ginkgo biloba.  FEBS J  2007;274:1036-45.

MESH Terms & Keywords

  • Ginkgo, Ginkgo Biloba, Ginkgo Mechanism Seizures