Benzodiazepines

Summary

drug class: Benzodiazepines

related drugs and trade names:
• Alprazolam: Xanax®
• Chlordiazepoxide: Librium®
• Clonazepam: Klonopin®
• Diazepam: Valium®
• Flurazepam: Dalmane®
• Lorazepam: Ativan®
• Temazepam: Restoril®
• Triazolam: Halcion®

type of drug: Sedatives, induce dose-related depression of the central nervous system

used to treat: Anxiety, insomnia, seizures, and muscle spasms; agitation, tremors, delirium, seizures, and hallucinations as a result of alcohol withdrawal; to abort active seizures

overview of interactions:
• herb affecting drug toxicity: Valeriana officinalis (Valerian)

• herb with related action: Piper methysticum (Kava)

• possible herb effect on drug performance: Hypericum perforatum (St. John's Wort)

• herb potentially affecting drug toxicity: Silybum marianum (Milk Thistle)




Interactions

herb affecting drug toxicity: Valeriana officinalis (Valerian)

• interaction: Valerian has the potential to interact with sedative drugs.

• mechanism: There may be an accumulative sedative effect between the two compounds

herb with related action: Piper methysticum (Kava)

• mechanism: Kava is sometimes used by practitioners of natural medicine in cases where benzodiazepines might be prescribed or where a patient is attempting to wean themselves off of benzodiazepines. Even though research has moved past presumptive notions that kava acted via the same manner as benzodiazepines, it mechanism of action has not yet been fully determined. According to current research, kava appears to have its primary effect on the limbic system, a part of the brain involved in regulating emotions, mood and wakefulness.
(Holm, E, Staedt, U, Heep, J, et al. Arzneim Forsch 1991;41:673-683.)

• interaction: According to a case published in Annals of Internal Medicine a man reportedly went into a state of lethargy and disorientation after taking kava in combination with Xanax® (alprazolam) and other drugs. Until more solid research appears, kava should not be combined with benzodiazepines without supervision by an appropriately trained healthcare professional, even though these symptoms are not uncommon as side effects of Xanax® (alprazolam) alone.
A review of the Almeida case by Bergner detailed that the patient was also concurrently taking Cimetidine and Terazosin. Cimetidine is known to reduce hepatic clearance of alprazolam, and Terazosin is associated with "somnolence" as a side effect.This suggests at very least the original report to be an oversimplification of a possible four-way inyteraction rather than a simple Kava-benzodiazeopine interaction.
(Almeida, JC, Grimsley, EW. Ann Intern Med 1996 Dec 1;125(11):940-941; Bergner P, Med Herbalism 1999, 11.1:16-17)

possible herb effect on drug performance: Hypericum perforatum (St. John's Wort)

• research: Amentoflavone, a constituent of various Hypericum species, efficiently inhibited binding of [3H]flumazenil to rat brain benzodiazepine binding sites of the GABAA-receptor in vitro.
(Baureithel KH, et al. Pharm Acta Helv 1997 Jun;72(3):153-157.)

• nutritional concerns: Any individual using a benzodiazepine and considering using St. John's Wort as a substitute or as a means of weaning themselves from the drug should do so only under supervision of a trained healthcare professional. Caution is especially indicated given the potential for the amentoflavone component of Hypericum to inhibit the action of the benzodiazepine.

herb potentially affecting drug toxicity: Silybum marianum (Milk Thistle)
• mechanism: Several benzodiazepenes (Halcion, Lorazepam) are known to be substrates of hepatic Cytochrome P450 3A4. Milk thistle is known to affect clearance of cyclosporine, also a substrate of 3A4, and although evidence it is not available, it is likely that Milk Thistle extracts may increase first pass metabolism of benzodiazepines.

• herbal concern: Milk thistle may reduce circulating levels of benzodiazepines during concurrent administration. This potential interaction may be helpful for those considering weaning from benzodiazepines, but may also be considered potentially to reduce effectiveness of a given dose of the drug.

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Do not rely solely on the information in this article.

The information presented in Interactions is for informational and educational purposes only. It is based on scientific studies (human, animal, or in vitro), clinical experience, case reports, and/or traditional usage with sources as cited in each topic. The results reported may not necessarily occur in all individuals and different individuals with the same medical conditions with the same symptoms will often require differing treatments. For many of the conditions discussed, treatment with conventional medical therapies, including prescription drugs or over-the-counter medications, is also available. Consult your physician, an appropriately trained healthcare practitioner, and/or pharmacist for any health concern or medical problem before using any herbal products or nutritional supplements or before making any changes in prescribed medications and/or before attempting to independently treat a medical condition using supplements, herbs, remedies, or other forms of self-care.


References

Abernethy DR, Greenblatt DJ, Divoll M, Moschitto LJ, Harmatz JS, Shader RI. Interaction of cimetidine with the triazolobenzodiazepines alprazolam and triazolam. Psychopharmacology (Berl) 1983;80(3):275-278.

Almeida, JC, Grimsley, EW. Coma from the health food store: interaction between kava and alprazolam. Ann Intern Med 1996 Dec 1;125(11):940-941.

Baureithel, KH, Buter, KB, Engesser, A, Burkard, W, Schaffner, W. Inhibition of benzodiazepine binding in vitro by amentoflavone, a constituent of various species of Hypericum. Pharm Acta Helv 1997 Jun;72(3):153-157.
Abstract: Flower extracts of Hypericum perforatum, Hypericum hirsutum, Hypericum patulum and Hypericum olympicum efficiently inhibited binding of [3H]flumazenil to rat brain benzodiazepine binding sites of the GABAA-receptor in vitro. Single constituents of the extracts like hypericin, the flavones quercetin and luteolin, the glycosylated flavonoides rutin, hyperoside and quercitrin and the biflavone 13, II8-biapigenin did not inhibit binding up to concentrations of 1 microM. In contrast, amentoflavone revealed an IC50 = 14.9 +/- 1.9 nM on benzodiazepine binding in vitro. Comparative HPLC analyses of hypericin and amentoflavone in extracts of different Hypericum species revealed a possible correlation between the amentoflavone concentration and the inhibition of flumazenil binding. For hypericin no such correlation was observed. Our experimental data demonstrate that amentoflavone, in contrast to hypericin, presents a very active compound with regard to the inhibition of [3H]-flumazenil binding in vitro and thus might be involved in the antidepressant effects of Hypericum perforatum extracts.

Bergner P. Drug Herb Interactions. Medical Herbalism 1997;9(2):1.

Bergner P. A second Opinion on reported kava-alprazolam herb -drug interaction. Medical Herbalism 1999, 11(1) :16-17.

Cupp MJ. Herbal remedies: adverse effects and drug interactions. Am Fam Physician 1999 Mar 1;59(5):1239-1245.

Davies, LP, Drew, CA, Duffield, P, Johnston, GA, Jamieson, DD. Kava pyrones and resin: studies on GABAA, GABAB and benzodiazepine binding sites in rodent brain. Pharmacol Toxicol 1992 Aug;71(2):120-126 .

Heiligenstein, E, Guenther, G. Over-the-counter psychotropics: a review of melatonin, St John's wort, valerian, and kava-kava. J Am Coll Health 1998 May;46(6):271-276.

Hoffman, David. How herbs help in benzodiazepine dependence. J Alternative Medicine 1985;27:10-11.

Holm, E, Staedt, U, Heep, J, Kortsik, C, Behne, F, Kaske, A, Mennicke, I . [The action profile of D,L-kavain. Cerebral sites and sleep-wakefulness-rhythm in animals]. Arzneimittelforschung 1991 Jul;41(7):673-683. [Article in German]

Jussofie, A, Schmiz, A, Hiemke, C. Kavapyrone enriched extract from Piper methysticum as modulator of the GABA binding site in different regions of rat brain. Psychopharmacology (Berl) 1994 Dec;116(4):469-474 .

Kinder, C, Cupp, MJ. Kava: an herbal sedative. Nurse Pract 1998 Jun;23(6):14 .

Miller LG. Herbal medicinals: selected clinical considerations focusing on known or potential drug-herb interactions. Arch Intern Med 1998 Nov 9;158(20):2200-2211.

Nowakowska, E, Ostrowicz, A, Chodera, A. [Kava-kava preparations--alternative anxiolytics]. Pol Merkuriusz Lek 1998 Mar;4(21):179-180A. [Article in Polish]

Pourbaix S, Desager JP, Hulhoven R, Smith RB, Harvengt C. Pharmacokinetic
consequences of long term coadministration of cimetidine and triazolobenzodiazepines, alprazolam and triazolam, in healthy subjects. Int J Clin Pharmacol Ther Toxicol 1985 Aug;23(8):447-451.