US Pharm. 32(11)12-15.

The potential number of interactions between nonprescription products and psychotropic medications is difficult to estimate due to the number of OTC products and the immense probability that many will interact with psychotropics. Known or suspected interactions fall into two categories. One is the group of OTC/psychotropic interactions that were considered to be of such gravity that the FDA required a warning label on the products. However, there is a second group composed of interactions that are not found on the labeling of any nonprescription product.

Monoamine Oxidase Inhibitor Warnings
In the late 1970s, a specific group of medications was indicated for depression or hypertension: monoamine oxidase inhibitors (MAOIs). At that time, several were actively marketed as single-entity or combination products, including pargyline (Eutonyl) and pargyline/methyclothiazide (Eutron) for hypertension and phenelzine (Nardil), tranylcypromine (Parnate), and isocarboxazid (Marplan) for depression. Eventually, selegiline (Eldepryl, Emsam) was marketed, with enhanced affinity for MAOI type B active sites. It was referred to as an MAOI "B" medication, and the older products became known as MAOI "A" medications. Eutonyl, Eutron, and Marplan are no longer marketed.

Regarding MAOI therapy, one set of precautions is paramount. MAOIs block the body's ability to metabolize tyramine, carrying a high potential for drug and food interactions. Patients prescribed MAOIs are cautioned strongly against ingestion of tyramine-rich foods and drinks, such as anchovies, certain alcoholic beverages (e.g., sherry, beer), pepperoni, salami, strong/aged cheeses, raisins, bananas, and soy sauce. Failure to observe this precaution can cause cerebral hemorrhages and severe headaches.

When the nonprescription cough/cold expert panel originally appointed by the FDA issued its report in 1976, it indicated evidence of the same type of interaction between MAOIs and oral nasal decongestants (e.g., pseudoephedrine, phenylephrine, phenylpropanolamine).1 In the panel's words, "Patients taking other drugs whose action can intensify the sympathomimetic drug action, e.g., monoamine oxidase inhibitors, should not take nasal decongestants orally except under the advice and supervision of a physician. The Panel does not feel these restrictions should apply to topically applied nasal decongestants when administered in recommended doses because of their localized action, i.e., minimal systemic absorption." Accordingly, the panel recommended the following labeling for oral nasal decongestants: "Drug Interaction Precaution: Do not take this product if you are presently taking a prescription antihypertensive or antidepressant drug containing a monoamine oxidase inhibitor except under the advice and supervision of a physician." In 1985, the FDA issued its Tentative Final Monograph for nasal decongestants.2 In responding to requests that the warning be clarified for consumers, FDA suggested similar labeling: "Do not take this product if you are presently taking a prescription drug for high blood pressure or depression, without first consulting your doctor." Identical labeling was also proposed for other nonprescription products containing sympathomimetic amines, such as bronchodilator products with ephedrine or epinephrine for asthma.

In 1992, the FDA became aware of an additional issue regarding MAOIs. Dextromethorphan was found to be a possible cause of a potentially deadly interaction in patients taking MAOIs.3 Among the numerous cases reported, a 26-year-old female had been taking 15 mg of phenelzine four times daily for a month but took a 30-mg dose after she missed an earlier one. She also ingested 2 oz. of a dextromethorphan-containing cough syrup, which led to nausea, dizziness, and collapse. She was severely hypotensive when taken to the hospital, with a systolic that did not rise above 70 mmHg and a temperature of 107.6 to 107.96° F. She died of a cardiac arrest four hours postadmission.

A 15-year-old female taking 15 mg of phenelzine three times daily for depression took eight capsules containing 15 mg of dextromethorphan, 6.25 mg of phenindamine, and 5 mg of phenylephrine, followed by another five capsules three hours later. She was found to have fixed, dilated pupils, lack of a gag reflex, mild spasticity, and hyperreflexia of the upper limbs. Resuscitation efforts were unsuccessful. Her autopsy revealed acute cerebral edema, marked acute pulmonary edema, and hemohydrothorax.

The FDA observed that prescribing of MAOIs had increased in the years preceding 1992. Thus, FDA proposed in the 1992 document to extend the MAOI warning to dextromethorphan, with wording as follows, "Do not use this product if you are taking a prescription drug containing a monoamine oxidase inhibitor (MAOI) (certain drugs for depression or psychiatric or emotional conditions), without first consulting your doctor. If you are uncertain whether your prescription drug contains an MAOI, consult a health professional before taking this product." In 1993, the FDA published the final monograph on this topic, including a discussion of the comments it had received.4 In response to two such comments, the agency decided to include selegiline as a possible source of drug interactions, to require a reference to selegiline's use in Parkinson's disease, and to indicate that a two-week washout period should be observed. The final label required by the FDA reads: "Do not use this product if you are now taking a prescription monoamine oxidase inhibitor (MAOI) (certain drugs for depression, psychiatric or emotional conditions, or Parkinson's disease), or for 2 weeks after stopping the MAOI drug. If you are uncertain whether your prescription drug contains an MAOI, consult a health professional before taking this product." The proposed labels for nasal decongestants and bronchodilators for asthma were identical to that proposed for dextromethorphan, as well as in the final monograph that eventually appeared for bronchodilators.

The FDA Panel assigned to review anorectal products recognized in its 1980 report that topical vasoconstrictors in hemorrhoid products (e.g., phenylephrine) could be absorbed in sufficient quantities to interact with MAOIs.5 The FDA-required label for these products is not as complete as the labels above, stating only, "Ask a doctor or pharmacist before use if you are presently taking a prescription drug for high blood pressure or depression."6 Furthermore, the label ignores the use of selegiline for Parkinson's disease.

Additive Sedation
Brompheniramine, chlorpheniramine, clemastine, cyclizine, dexbrompheniramine, dimenhydrinate, doxylamine, meclizine, phenindamine, pheniramine, pyrilamine, and triprolidine must carry warnings advising the patient about possible drowsiness if they are taken concurrently with alcohol, sedatives, or tranquilizers.6 Diphenhydramine products also carry this warning but must state that they can cause "marked drowsiness." These ingredients are found in products indicated for allergic rhinitis, the common cold, motion sickness, insomnia, and menstrual discomfort.

Nicotine and Prescription Antidepressants
Nonprescription nicotine cessation products carry a specific warning against concurrent use with prescription antidepressants unless the patient first speaks to a physician or pharmacist. This warning appears on nicotine gum, patches, and lozenges and is required because cessation of smoking can increase the plasma concentrations of some antidepressant medications.6

Omeprazole and Diazepam
Nonprescription omeprazole carries a drug interaction warning against concomitant use with diazepam.6 Omeprazole can inhibit the metabolism of diazepam, elevating its blood concentrations.

Global Warnings Against Use with Prescription Products
Several nonprescription medications contain nonspecific warnings against use with any prescription product without a pharmacist or physician's advice, which of necessity would include all psychotropic medications. They include naproxen, ibuprofen, and codeine-containing schedule V cough syrups.6 As an example of the importance of these warnings, naproxen and ibuprofen both increase serum lithium levels when given concurrently with it.7

A global precaution also applies to medications that could alter the absorption of others, such as psyllium. One manufacturer warns against taking any other prescription medication two hours before or two hours after ingesting psyllium, as the medication may be trapped in the psyllium matrix and unavailable for absorption.6

Nonlabeled Psychotropic Interactions
The medical literature mentions numerous potential interactions between nonprescription products and psychotropic medications. Despite their inclusion in the literature, many are not included on the FDA-required label. Thus, the patient contemplating purchase of products without physician advice encounters no label warning and can rely only on the help of an informed pharmacist. For instance, cimetidine can interact with benzodiazepines, a fact not required on the cimetidine label.

Dietary supplements seldom, if ever, carry drug interaction warnings. Nevertheless, they can be the source of interactions with psychotropic medications. The following have been observed: St. John's wort and other SSRI antidepressants (serotonin syndrome); St. John's wort and lowered plasma concentration when used with amitriptyline, alprazolam, or midazolam; black cohosh and sedatives/hypnotics; capsicum and barbiturates or MAOIs; cat's claw and Halcion; chamomile and benzodiazepines or sedatives; coenzyme Q10 and phenothiazines or tricyclics; ephedra and MAOIs or tricyclics; eucalyptus and amphetamines or barbiturates; fish oil and antipsychotics; gingko and MAOIs; ginseng and MAOIs or stimulants; and kava and numerous psychotropics.7-10

1. Establishment of a monograph for OTC cold, cough, allergy, bronchodilator and antiasthmatic products. Fed Reg. 1976;41:38312-38424.
2. Cold, cough, allergy, bronchodilator, and antiasthmatic drug products for over-the-counter human use. Tentative final monograph for over-the-counter nasal decongestant drug products. Fed Reg. 1985;50:2220-2241.
3. Cold, cough, allergy, bronchodilator, and antiasthmatic drug products for over-the-counter human use. Proposed amendment of final monograph for OTC antitussive drug products. Fed Reg. 1992;57:27666-27670.
4. Cold, cough, allergy, bronchodilator, and antiasthmatic drug products for over-the-counter human use. Amendment of final monograph for OTC antitussive drug products. Fed Reg. 1993;58:54232-54236.
5. Anorectal drug products for over-the-counter human use; Establishment of a monograph. Fed Reg. 1980;45:35576-35677.
6. Pray WS. Nonprescription Product Therapeutics, 2nd ed. Baltimore, MD: Lippincott Williams & Wilkins; 2005.
7. Honig PK, Gillespie BK. Drug interactions between prescribed and over-the-counter medication. Drug Saf. 1995;13:296-303.
8. Clark A. Finding health in folklore, herbs, and supplements: The good, the bad & the ugly. Part III--the ugly. Mo Med. 2003;100:91-93.
9. Pal D, Mitra AK. MDR- and CYP3A4-mediated drug-herbal interactions. Life Sci. 2006;78:2131-2145.
10. Magee K, Loiacono C. A review of common herbs and potential interactions. Int J Dent Hyg. 2004;2:111-121.
11. Nguyen MH, Ormiston T, Kurani S, et al. Amphetamine lacing of an Internet-marketed neutraceutical (sic). Mayo Clin Proc. 2006;81:1627-1629.

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