Diphenhydramine Interactions: What Not To Take With Benadryl?

Last Updated: July 16, 2020

Authored by Sharon Levy, MD, MPH

Benadryl is a branded diphenhydramine, an over-the-counter, first-generation antihistamine, that is accessible without a doctor’s prescription. The key Benadryl uses involve treating allergy symptoms, and it is commonly used as a sleeping pill. About 830 drugs and other substances are known to cause interactions with Benadryl and may lead to dangerous circumstances. Take a look at Benadryl interactions with other popular medications and substances to avoid their negative effect on patient’s health.

Antidepressants And Benadryl Interactions

Taking diphenhydramine, particularly nightly, will have long-term effects on the sleep patterns of the user. They may find it harder to enter deep sleep, and this could conversely affect their anxiety or depression the antidepressant drugs were being used for in the first place. However, there are also various types of antidepressants, so these effects may also not be exactly mirrored in every antidepressant.
The most harmful interactions of Benadryl and antidepressants occur with antidepressants from tricyclic group. TCAs are known to be histamine H1 receptors antagonists so as  diphenhydramine, which is also known as first-generation antihistamines. Tricyclic antidepressants are known to cause extreme sedation and drowsiness in patients, so their effect musn’t be combined with Benadryl.

unhealthy woman feel unwell taking benadryl pill

Zoloft And Benadryl

Using Zoloft and Benadryl can lead to the increased strength of side-effects such as confusion, drowsiness, and difficulties in concentrating. Additionally, severe side-effects of diphenhydramine such as lack of motor coordination, impairment in judgment, and thinking may occur, especially in seniors.

Xanax And Benadryl Interactions

Can one take Benadryl with Xanax? The answer to this question is negative. Xanax and Benadryl are both central nervous system depressants. It means that they both can slow down heart and respiratory rates. The effects of both working at the same time in the body can vary from moderate to fatal, as it is possible to depress the central nervous system to death – depending on the strength of the dosage and the physiological make-up of the user.
Other possible adverse reactions of using Xanax with Benadryl are quite similar to the ones seen with Zoloft. The user risks experiencing all the same adverse effects, including the severe ones. Users that are already struggling with these effects can begin their efforts at rehabilitation by registering for a detoxification program to clear the body system from these meds.

Benadryl Interactions With Other Drugs

Other most popular medications Benadryl drug interactions are known with include:

Adderall And Benadryl

As at the time of writing, there are no officially confirmed interactions between diphenhydramine and Adderall. On the other hand, there are reports from users, who have used small diphenhydramine doses to help offset the strength of Adderall. Although, reducing the effects of Adderall doses with Benadryl medication might not be the best decision. For one, it may result in Benadryl dependence, particularly when diphenhydramine was not prescribed initially by the doctor.

Percocet And Benadryl

Using Percocet and Benadryl is generally not a good idea. This interaction will be similar to as with Xanax. Both drugs can cause respiratory depression, so one needs to be careful using them together. It might mean that the user should look to reduce the doses to a lower level than the average recommended dose to make up for the combined effect of both in the body. Oxycodone and Benadryl will have the same adverse reactions, as with Percocet.
Just like opioids such as Percocet, it is possible for a user to get addicted to diphenhydramine. Dependency is more likely to happen when the user has been dosing on the drug for a long time. In such cases, the patient will need to seek professional help at a rehabilitation center.

Ambien And Benadryl Interactions

This combination is known to increase the risk of adverse reactions like drowsiness or dizziness. It is often hard to concentrate after mixing Ambien and Benadryl. These two also may result in impairment in coordination or thinking in senior patients.

guy having dizziness from ambien and benadryl

Tramadol And Benadryl

The interaction level between Tramadol and Benadryl is moderate. While the former may not directly interact with diphenhydramine, dosing on both drugs will increase the risk of drowsiness, and reduce concentration. This means that the user will be unable to carry out tasks that require concentration effectively.
The user may also find that deep sleep is more frequent, and there may be a kind of hangover effect when they wake up from this sleep.
Lastly, the medical conditions behind the reason why the user is taking Tramadol should be considered, as it might be dangerous for users with such condition to take diphenhydramine.

What Food and Substances Should Be Avoided When Using Diphenhydramine?

Benadryl And Grapefruit Juice Interactions

Grapefruit juice is commonly known to interfere with the efficiency of specific drugs, and diphenhydramine is one of them. There are substances in the composition of grapefruit that affect transporter proteins on the surface of cells in the body. As the result of this interference, diphenhydramine is unable to enter into the cells as effectively as it should, and this leads to a loss of drug efficiency.

Benadryl And Weed Interactions

Cannabis has a tranquilizing effect. Sometimes, when a person uses the substance, they begin to feel drowsy. Diphenhydramine also has a tranquilizing and sedative effect. Consequently, the result of mixing these two is that the likelihood of their adverse reactions occurring is significantly increased.
Additionally, using cannabis and Benadryl together leads to the possibility of Tachycardia – a medical condition that causes the heart to beat faster than the normal rate of a hundred times per minute.

Benadryl And Alcohol Interactions

The major food and substances that can cause a major interaction with diphenhydramine is alcohol. Using diphenhydramine with alcohol shares a similar effect with some of the medication discussed above. The occurrence of side effects will become more pronounced, and the chances for the user to experience some of the more severe side effects are also significantly increased.

bottle of alcohol and benadryl pills

In the case of interacting with alcohol, Benadryl and Zyrtec are quite similar, even though the second one is a second-generation non-sedative antihistamine.

Caffeine And Benadryl Interactions

On the surface, Benadryl and caffeine seem to perform two completely different functions. One (caffeine) is seen to be a stimulant, and the other is seen to have a sedative effect. However,  while diphenhydramine does have a sedative effect overall, it has a stimulant effect on the heart. This is one of the reasons why people with heart conditions are advised to seek professional advice before using the drug.

businesswoman holding cup of coffee and benadryl pills

If caffeine and Benadryl are used simultaneously, the stimulant’s effect on the heart is significantly increased, and there is a higher chance of an abnormal heart rate. This interaction could well lead to serious heart conditions as well, especially on the long-term. A person with heart issues must consult with a doctor before attempting to use diphenhydramine. A doctor helps to determine the appropriate amount of Benadryl to use in particular condition.
Being an over-the-counter drug, diphenhydramine is relatively easily accessible. Also there are high chances of inappropriate dosing and bad interactions, because of misinformation or negligence on the user’s side.

Page Sources

  1. https://www.ncbi.nlm.nih.gov/pubmed/39202
  2. https://www.ncbi.nlm.nih.gov/pubmed/8321577

Published on: June 5th, 2019

Updated on: July 16th, 2020

About Author

Sharon Levy, MD, MPH

After successful graduation from Boston University, MA, Sharon gained a Master’s degree in Public Health. Since then, Sharon devoted herself entirely to the medical niche. Sharon Levy is also a certified addiction recovery coach.


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  • bruce moore
    what does gabapentin and benadryl do/ is it safe?