Over-The-Counter Medications and Ketamine

How antacids, anti-gas/GI meds, antihistamines, painkillers, and cold medicines interact w/ Ketamine.

Winter season brings allergies, colds, and headaches; temperature-drops (mixed with high humidity) aggravate arthritic pain; our favorite hot chocolate drinks can trigger acid reflux. 

Over-the-Counter (OTC) medications are a cost-effective, low-barrier option for relieving the worst of a wide range of symptoms. 

But some of them interact with drugs in ways that people who use either, or both, should be aware of.

This post will be about how Ketamine and OTC medications interact.

The most important part of OTC medications are their individual active ingredients; and the most important part of understanding drugs are through effects on the body.

As for Ketamine, two main things are happening:

• Your central nervous system is depressed (reduced motor control, reflexes, signaling to the rest of the body)

• Your sympathetic nervous system is stimulated (faster heart rate, increased blood flow to muscles causing stiffness, higher blood pressure). 

Certain ingredients in OTC medications also depress the central nervous system (like dextromorphan), or stimulate the sympathetic nervous system (caffeine).

Antacids

Antacids work by releasing their active ingredients, bases, to increase the pH of stomach acid. While some antacids may slow the metabolism of Ketamine, prolonging its effects, none of those antacids are over-the-counter.

Medications	Active Ingredients	Interactions w/ Ketamine
TUMS	Calcium Carbonate	No Known Interactions
Nauzene	Sodium Citrate	No Known Interactions
Pepto-Bismol	Bismuth Subsalicylate	No Known Interactions

Anti-Gas/GI

There are no known adverse or significant interactions for Ketamine use with over-the-counter anti-gas medications:

Medications	Active Ingredients	Interactions w/ Ketamine
Emetrol	Sodium Citrate, Glucose	No Known Interactions
Imodium	Loperamide HCl, Simethicone	No Known Interactions
Gas-X	Simethicone	No Known Interactions
Midol Anti-Bloat	Pamabrom	No Known Interactions

Antihistamines

Histamines are chemicals released to promote an immune response, by increasing blood flow to areas of the body (boosting inflammation), and causing sneezing. They also play a part in sleep, mood, and the GI tract. Antihistamines are used when these immune responses cause undesirable symptoms.

Older, “first-generation” antihistamines also depress the central nervous system, making them particularly risky to mix with Ketamine.

First-generation antihistamines include:

• Dimenhydrinate (Dramamine)

• Meclizine (Bonine)

• Diphenhydramine (Benadryl; also in several “PM” formulations, such as Advil PM & Aleve PM)

• Pyrilamine Maleate* (an ingredient in Midol)

Newer, “second-generation” antihistamines generally do not cross the blood-brain barrier, and don’t depress the central nervous system. 

Second-generation antihistamines include:

• Cetirizine (Zyrtec)

• Loratadine (Claritin)

• Fexofenadine (Allegra)

Active Ingredient	Meds w/ Ingredient	1st or 2nd Gen?	Interactions w/ Ketamine
Dimenhydrinate	Dramamine	1st Gen	Drowsying
Diphenhydramine	Benadryl, Advil PM, Aleve PM	1st Gen	Drowsying
Fexofenadine	Allegra	2nd Gen	Non-Drowsying
Loratadine	Claritin	2nd Gen	Non-Drowsying
Meclizine	Bonine	1st Gen	Drowsying
Pyrilamine Maleate	Midol	1st Gen	Drowsying
Cetirizine	Zyrtec	2nd Gen	Non-Drowsying

Painkillers

Acetaminophen

The active ingredient acetaminophen is in many painkillers (Tylenol, Midol, Excedren), cold medicines (DayQuil, Daytime Cold & Flu), and nasal decongestants (Muxinex). 

Tylenol - Acetaminophen - no known interactions

Midol - Acetaminophen + Caffeine + Pyrilamine Maleate

• Caffeine and Ketamine both increase heart-rate and blood-pressure

Pyrilamine maleate (first-gen antihistamine) and Ketamine both depress central nervous system; can reduce breathing and cause sedation.

NSAIDS

NSAIDs (Non-Steroidal Anti-Inflammatory drugs) are a different class of painkillers that have the added benefit in targeting inflammation, as well as reducing fever. NSAIDs include Naproxen (Aleve), Ibuprofen (Motrin, Advil), and Aspirin. 

NSAIDs can also be mixed safely with acetaminophen, and often are combined in the same medication (Excedrin, Advil Dual-Action). 

NSAIDs themselves can be safely mixed with Ketamine; however, risks come from other active ingredients and additives that are added to certain medications, especially “PM versions” which include first-generation antihistamines.

Medications	Active Ingredients	Interactions w/ Ketamine
Tylenol	Acetaminophen	No known interactions
Midol	Acetaminophen + Caffeine + Pyrilamine Maleate	Caffeine - both increase heart-rate and blood-pressure Pyrilamine maleate - both depress central nervous system; can reduce breathing and cause sedation.
Aleve	Naproxen	No known interactions
Aleve PM	Naproxen + Diphenhydramine	Diphenhydramine - both depress central nervous system; can reduce breathing and cause sedation

Medications	Active Ingredients	Interactions w/ Ketamine
Advil	Ibuprofen	No known interactions
Advil Dual-Action	Ibuprofen + Acetaminophen	No known interactions
Advil PM	Ibuprofen + Diphenhydramine	Diphenhydramine - both depress central nervous system; can reduce breathing and cause sedation.
Bayer Aspirin	Aspirin	No known interactions
Excedrin	Acetaminophen + Aspirin + Caffeine	Caffeine - both increase heart-rate and blood-pressure
AZO (for UTIs)	Phenazopyridine Hydrochloride	No known interactions

Cold Medicines

Aside from antihistamines, some cold medicines are “decongestants” (phenylepherine), which narrow the nose’s blood vessels, reducing swelling of the nasal passages. These can increase blood pressure and heart rate, as do most medicines that constrict blood vessels. The other type, “expectorants” (guaifenesin) thins mucus, making it easier to cough and sneeze out. 

Medications	Active Ingredients	Interactions w/ Ketamine
Mucinex	Guaifenesin	No known interactions
Sudafed PE*	Phenylepherine	Phenylepherine - both increase heart-rate and blood-pressure
DayQuil Cold & Flu	Acetaminophen + Dextromethorphan + Phenylepherine	Dextromethorphan - both depress central nervous system; can reduce breathing and cause sedation.   Phenylepherine - both increase heart-rate and blood-pressure

Whether Ketamine is safe to use with other over-the-counter medications depend on the medicine’s active ingredients, and an individual’s health. 

Those prone to high/low blood pressure and heart problems should use extra caution while using both Ketamine and over-the-counter medications.  

Lastly, always consult with a doctor if unsure about how you might respond to either Ketamine or an over-the-counter medication.

Works Cited

Ward JL, Adams SD, Delano BA, Clarke C, Radhakrishnan RS, Weisbrodt NW, Mercer DW. Ketamine suppresses LPS-induced bile reflux and gastric bleeding in the rat. J Trauma. 2010 Jan;68(1):69-75. doi: 10.1097/TA.0b013e3181a8b3a7. PMID: 20065760.

Hsu HR;Mei YY;Wu CY;Chiu PH;Chen HH; “Behavioural and Toxic Interaction Profile of Ketamine in Combination with Caffeine.” Basic & Clinical Pharmacology & Toxicology, U.S. National Library of Medicine, pubmed.ncbi.nlm.nih.gov/19413657/. Accessed 24 Sept. 2025. 

Surgery, Hospital for Special. “Novel Combination of Oral Ketamine and Aspirin Is Safe Form of Pain Medication after Total Knee Replacement Surgery.” PR Newswire: Press Release Distribution, Targeting, Monitoring and Marketing, Cision PR Newswire, 16 Aug. 2023, www.prnewswire.com/news-releases/novel-combination-of-oral-ketamine-and-aspirin-is-safe-form-of-pain-medication-after-total-knee-replacement-surgery-301902136.html. 

Shulpekova, Yulia O, et al. “Food Intolerance: The Role of Histamine.” Nutrients, U.S. National Library of Medicine, 15 Sept. 2021, pmc.ncbi.nlm.nih.gov/articles/PMC8469513/. 

Pappachan JM, Raj B, Thomas S, Hanna FW. Multiorgan dysfunction related to chronic ketamine abuse. Proc (Bayl Univ Med Cent). 2014 Jul;27(3):223-5. doi: 10.1080/08998280.2014.11929117. PMID: 24982568; PMCID: PMC4059572.

Davis A, Fassassi C, Dove D, Drapkin J, Likourezos A, Gohel A, Favale P, Hossain R, Butt M, Gerges L, Motov S. Analgesic Efficacy of Oral Aspirin/Ketamine Combination for Management of Acute Musculoskeletal Pain in the Emergency Department - A Proof of Concept Pilot Study. J Emerg Med. 2022 Jun;62(6):750-759. doi: 10.1016/j.jemermed.2022.01.029. Epub 2022 May 24. PMID: 35624056.