Does CBD Interact with Benadryl?

In our latest question and answer, our medical cannabis pharmacist discusses if CBD interacts with Benadryl.
Does CBD Interact with Benadryl?

Bart Asked

Does CBD interact with Benadryl?


There is no evidence of a significant interaction between cannabidiol (CBD) and Benadryl (Diphenhydramine).
However, using CBD may increase the severity of drowsiness seen with Benadryl.
Despite this possibility of an interaction, taking this combination appears to be safe.


There is no evidence of a significant interaction between cannabidiol (CBD) and Benadryl (Diphenhydramine). However, depending on your personal response to CBD and the dose utilized, CBD may cause sedation. Benadryl is a first generation antihistamine and is well known for causing drowsiness as a side effect. Therefore, there is a potential that using both CBD and Benadryl at the same time would make this side effect more pronounced. There are no documented reports of this interaction, but it is plausible. Despite this interaction, taking this combination appears to be safe. I just wouldn’t recommend operating heavy machinery or doing any tasks that demand a high degree of alertness until you know how taking this combination affects you.

CBD (Cannabidiol)

Cannabidiol, also known as CBD, is a major component of cannabis/marijuana. While THC (delta-9-tetrahydrocannabinol) is likely more well-known due to its psychoactive effects, CBD makes up almost 40% of cannabis extracts and has a wide range of effects and potential benefits when used as a health aide.

Many people are drawn to CBD due to the fact that it does not appear to impair mental functioning or cause euphoria like THC does. In fact, when CBD is combined with THC, CBD may work to counteract some of the negative side effects of THC (such as sedation or paranoia).

Numerous studies, suggest CBD may provide numerous benefit for a wide range of conditions such as:

  • Epilepsy
  • Anxiety Disorders
  • Dystonia
  • Neuropathy
  • Parkinson’s Disease
  • Multiple Sclerosis
  • Insomnia

Benadryl (Diphenhydramine)

Benadryl (diphenhydramine) is a first generation antihistamine. This class of drugs is noted for their relatively short duration of action (~4 to 8 hours) and for their tendency to cause drowsiness and sedation.

Benadryl is commonly used for treating seasonal allergies, but can also be effective for nausea, vomiting, and vertigo or motion sickness.

CBD Drug Interactions

CBD is a popular health supplement and is now found in an endless variety of products. However, due to the fact that CBD is relatively new to the market and that Federal cannabis prohibition impeded research on CBD’s effects for many years; there is a lack of studies when it comes to potential drug interactions between CBD and prescription and over the counter medications, such as Benadryl.

CBD is metabolized by cytochrome P450 enzymes found primarily in the liver. Studies show that CBD may inhibit the following metabolic enzymes:

  • CYP 3A4
  • CYP 2C9
  • CYP 2C19

When one of the above enzymes are inhibited, it can increase the concentration of other drugs that are substrates of that same enzyme.

CBD Interaction with Benadryl

Benadryl (diphenhydramine) is known to be metabolized mainly by CYP2D6 but is also metabolized (to a lesser extent) by the following cytochrome P450 enzymes; CYP1A2, CYP2C9, and CYP2C19.

Due to how Benadryl is metabolized, the concentrations of the drug could potentially be increased when taken together with CBD.

However,  studies show that the enzyme inhibition produced by CBD may not be clinically significant. Many studies use doses of CBD in the range of 100mg to 600mg (much higher than what is typically used by the average consumer). It is possible that lower doses of CBD, that are more commonly used by consumers, don’t result in substantial enzyme inhibition.

With regard to the potential for CBD to worsen the sedation seen with Benadryl, the effects of CBD are thought to vary substantially individual to individual and depending on the specific product utilized. Different varieties of CBD products may contain different chemicals such as cannabinoids and terpenes and at different concentrations. Terpenes are aromatic compounds found in cannabis responsible for its distinct aroma.

Therefore, while one CBD product may cause sedation in some individuals, a different CBD product could potentially increase alertness and focus for others.

Until more studies examining how CBD interacts with Benadryl (diphenhydramine) we can only draw conclusions based on what we do know about both drugs. It appears that there could potentially be additive sedation seen when combining CBD and Benadryl, but the risk of any serious side effects is low.


Although there is a theoretical possibility for CBD to interact with Benadryl, the overall likelihood of this interaction seems quite low. Hopefully this helps answer your question! Feel free to reach back out anytime!


  1. Epidiolex. Greenwich Biosciences Inc.; 2018. Package Insert.
  2. Benadryl. Johnson & Johnson Consumer Inc.; 2022 Package Insert.
  3. Open label evaluation of cannabidiol in dystonic movement disorders (PubMed).
  4. Cannabidiol Claims and Misconceptions (ScienceDirect).

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