Benadryl is a brand name for a variety of over-the-counter (OTC) medications containing the chemical diphenhydramine, an antihistamine. The drug was initially synthesized in 1943, was acquired by Pfizer in 1946, and became the first antihistamine to receive FDA approval in the United States. The brand “Benadryl” was acquired by Johnson & Johnson (from Pfizer) circa 2007 for approximately $16.6 billion and it remains arguably the single most popular antihistamine on the market.
Makers of Benadryl manufacture it in a variety of formulations targeted to treat a broad spectrum of conditions such as: allergies, coughing, insomnia, itchiness, motion sickness, and nausea. The diphenhydramine within Benadryl is thought to elicit therapeutic effects via antagonism of the H1 histamine receptors and mAChRs (muscarinic acetylcholine receptors), and to a lesser extent, inhibition of intracellular sodium channels. As a result, users often experience reductions in histaminergic symptoms, but the reduction may come with side effects.
Users of Benadryl often experience brain fog, constipation, difficulty concentrating, drowsiness, and sedation. There is also mounting evidence to suggest that antihistamines may cause dementia, decreasing the mainstream appeal of using Benadryl. As a result of long-term concerns and adverse effects, many users discontinue Benadryl only to wonder how long it stays in their system.
How long does Benadryl stay in your system?
If you’ve recently stopped using over-the-counter antihistamines, you may experience some minor Benadryl withdrawal symptoms. Most people won’t notice any discontinuation effects, but may wonder how long the drug will linger in their system after they’ve ceased usage. To determine how long Benadryl stays in your system, it is necessary to consider the elimination half-life of its active ingredient “diphenhydramine.”
The elimination half-life of diphenhydramine has been reported to range from 2.4 to 9.3 hours in healthy adults. This means that after you’ve stopped taking Benadryl, approximately 50% of the drug will be cleared from your system in less than 9.3 hours. Based on this information, we can estimate that Benadryl will be 100% eliminated from systemic circulation between 13.2 hours and 2.13 days after your final dose.
Another source (NHTSA) suggests that the half-life of diphenhydramine is approximately 8.5 hours (+/- 3.2 hours), resulting in an average elimination of ~2 days and interindividual variation in elimination between 1 and 3 days. Though diphenhydramine forms various metabolites including: nordiphenhydramine, dinordiphenhydramine, and diphenylmethoxyacetic acid – these aren’t thought to linger in the body for significantly longer than the parent drug. Therefore, nearly all Benadryl users can expect to have eliminated the drug from their systems within 3 days of discontinuation.
- Source: https://pubchem.ncbi.nlm.nih.gov/compound/diphenhydramine
- Source: http://www.nhtsa.gov/people/injury/research/job185drugs/diphenhydramine.htm
Variables that influence how long Benadryl stays in your system
It is understood that there is generally significant interindividual variation in the elimination half-life of Benadryl. This interindividual variation in elimination of Benadryl is likely a result of variables such as: a person’s age, hepatic function, dosage, frequency of ingestion, and co-administration of other drugs. It is the combination of these variables that you may want to consider when contemplating how long Benadryl stays in your system after stopping.
Age (Old vs. Young)
Research suggests that elderly individuals (over the age of 65) are likely to retain Benadryl in systemic circulation for a longer duration than young adults and children. One study evaluated the elimination half-life and clearance rate of Benadryl among three groups of individuals based on age: elderly (average age of 69.4 years), young adults (average age of 31.5 years), and children (average age of 8.9 years). They discovered that the elimination half-life of diphenhydramine was 13.5 hours in elderly, 9.2 hours in young adults, and 5.4 hours in children.
Based on this information, we can conclude that it’ll take elderly individuals around 3.1 days to completely eliminate diphenhydramine from their systems. By comparison, it’ll take around 2.11 days for young adults and just 1.24 days for children to eliminate diphenhydramine. In addition to elimination slowing with age, clearance rates are also reduced among elderly at around 11.7 ml/min/kg compared to 23.3 ml/min/kg in young adults, and 49.2 ml/min/kg in children.
Therefore if you are a young adult, your body will be able to efficiently eliminate Benadryl quicker than if you’re considered elderly. Some hypothesize that the slower elimination half-life among elderly may be a result of various age-related changes such as: diminishing hepatic function, decreased renal function, and reduced physiologic efficiency.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/2391399
The diphenhydramine within Benadryl is metabolized by enzymes in your liver, and as a result, hepatic impairment may lead to a slower elimination. Research suggests that individuals experiencing a form of hepatic impairment known as alcohol-related liver disease are likely to exhibit an elimination half-life of approximately 15.2 hours. This indicates that it may take around 3.48 days for those with compromised liver function to clear it from their systems.
If you have severe hepatic impairment, it could take around 4 days for your body to eliminate the active ingredients within Benadryl from systemic circulation. Researchers noted that longer elimination half-lives among cirrhotic patients may be due to reduced distribution and increases in serum bilirubin. Among adults with normative hepatic function, systemic elimination of Benadryl should occur in just over 2 days.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/2866055
- Source: http://www.ncbi.nlm.nih.gov/pubmed/6705445
Dosage (Low vs. High)
It is understood that the dosage of Benadryl ingested can affect how long it stays in your system. A person who takes 100 mg as a single dose will likely eliminate the drug slower than if they had taken just 25 mg. Assuming the elimination half-life of Benadryl was 8.5 hours in your body, if you took the 100 mg dose, you’d still have 50 mg in your system after 8.5 hours. On the other hand, if you had taken the 25 mg dose, only 12.5 mg would remain in your system after 8.5 hours.
The recommended dosages of Benadryl are generally based on age: adults take between 25 mg and 50 mg, whereas children take considerably less (0 mg to 25 mg). The greater the dosage of Benadryl takes relative to their age and body size, the longer a person can expect the drug to remain in their system. This is due to the fact that when taken at large doses, increased levels of diphenhydramine circulate throughout your body.
Additionally, a greater burden is placed on hepatic enzymes to process larger doses, and metabolism is likely to be less efficient than it would be at a low dose. After a high dose is fully metabolized, greater levels of metabolites are formed, and there remains an increased amount of both the parent drug diphenhydramine and its metabolites to eliminate via the kidneys. Therefore if you are a low dose user, you can expect to clear the Benadryl at a faster pace than a person taking a high dose.
Frequency (Single vs. Multi Dose)
How often you take Benadryl may also affect the speed by which it is eliminated from your system. A person taking a “single dose” of Benadryl per day will eliminate the drug quicker than someone dosing several times throughout the day. This is due to the fact that a single dose user is unlikely to have accumulated a significant amount of diphenhydramine within their body.
After administering a single dose, the drug is metabolized, distributed, and eliminated with efficiency. However, those who ingest multiple doses are essentially adding more of an exogenous substance to be metabolized, distributed, and eliminated. As a result, this places a greater burden on liver enzymes to continuously metabolize each successive dose, as well as on the kidneys to constantly eliminate the drug.
Those who use the drug at a high frequency (e.g. several times throughout the day) are also more likely to be taking higher doses. This is due to the fact that frequent users may become tolerant to the effects of low doses and require upward titrations in dosing to maintain therapeutic efficacy. On the other hand, single dose users are less likely to have developed tolerance to low doses, resulting in faster systemic clearance and excretion.
Co-administration of drugs (CYP2D6)
If you’re taking other drugs along with Benadryl, it is possible that they may increase or decrease its elimination half-life based on how they affect hepatic enzymes. Diphenhydramine, the active ingredient within Benadryl, is hepatically metabolized by CYP450 (cytochrome P450) enzymes. Of all CYP450 enzymes, the CYP2D6 isoenzyme facilitates the majority of its breakdown to form metabolites.
For this reason, any drugs that directly affect the functionality of CYP2D6 are likely to influence how long Benadryl stays in your system. Drugs known as CYP2D6 inducers are thought to activate CYP2D6 enzymes, thereby expediting the metabolism of diphenhydramine. On the other hand, substances known as CYP2D6 inhibitors are thought to interfere with CYP2D6 function, thereby prolonging metabolism of diphenhydramine – leading to slower elimination.
Examples of potent CYP2D6 inducers include: Dexamethasone, Glutethimide, and Rifampicin. Should you have taken any of these “inducers” along with Benadryl, it may get metabolized and eliminated quicker than usual. On the other hand, taking CYP2D6 inducers such as: Cinacalcet, Paxil, Prozac, Quinidine, Ritonavir, and Wellbutrin – will prolong elimination.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/17020955
Miscellaneous individual factors
It may be necessary to account for other individual factors when attempting to estimate how long Benadryl stays in your system. Examples of some miscellaneous factors to consider include: your body mass, genetic expression, metabolic rate, and renal function. Understand that these factors may not be as significant as some of the aforementioned factors, but shouldn’t be overlooked.
Body mass: Usually the more massive an individual relative to the dosage of Benadryl ingested, the quicker it’ll get eliminated. For this reason, children are recommended to take a considerably lower dose than adults; they aren’t able to efficiently metabolize and eliminate high doses due to their small size. If you are a massive individual taking a small dose of Benadryl, you can expect to eliminate it faster than a less massive person.
That said, it may be necessary to account for body fat percentage in regards to Benadryl’s elimination. Those with a high percentage of body fat may accumulate a greater quantity of Benadryl (especially when administered regularly) due to the fact that the drug is lipophilic, meaning it’s fat-soluble. If you have a low percentage of body fat, you’ll likely have fewer fat stores to accumulate the drug, resulting in slightly quicker elimination.
Genetics: It is understood that the CYP2D6 gene is highly polymorphic, meaning you could carry certain CYP2D6 alleles that facilitate ultrarapid or poor metabolism of diphenhydramine. If you happen to have alleles that make you a rapid metabolizer of diphenhydramine, you can expect to eliminate the drug substantially faster than a poor metabolizer. Poor CYP2D6 metabolizers tend to exhibit elevated plasma concentrations of drugs metabolized by CYP2D6 enzymes such as diphenhydramine.
The elimination half-life of diphenhydramine may be considerably increased among a poor metabolizer (possibly by hours) compared to an ultrarapid metabolizer. To determine whether you have alleles that promote rapid, extensive, intermediate, or poor CYP2D6 metabolism, you could engage in genetic testing via services like GeneSight.
- Source: http://www.ncbi.nlm.nih.gov/gene/1565
Hydration: The extent to which you stay hydrated may affect how long diphenhydramine remains in your system prior to complete excretion. Hydration is thought to affect the efficiency of renal excretion by influencing urinary flow rate. The more hydrated a person stays, the greater their urinary flow rate to facilitate efficient clearance of diphenhydramine. The extent to which hydration is thought to affect excretion is not likely to be clinically significant, but may have a small impact.
Metabolic rate: Your BMR (basal metabolic rate) can affect the metabolism and elimination of various drugs. A person with a high BMR tends to burn more energy at rest, and is thought to eliminate various drugs at a quicker-than-average rate. On the other hand, a person with a low BMR burns less energy at rest, and is thought to eliminate various drugs at a slower-than-usual rate. Though BMR is unlikely to have as big of an impact on elimination as CYP2D6 alleles, it may be worth considering.
Renal function: It is likely that individuals with compromised renal function retain Benadryl for a longer duration than those with normative renal function. Though renal impairment isn’t thought to increase elimination half-life to the same extent as hepatic impairment, it may result in longer retention of both the parent drug diphenhydramine and its metabolites prior to excretion. Since the kidneys are responsible for a majority of the excretion, it makes sense that compromised renal function leads to slower elimination.
Research of other antihistamines such as chlorpheniramine suggests that renal dysfunction prolongs elimination half-life to a significant extent. Although there’s a lack of research regarding diphenhydramine and renal impairment, impaired renal function is likely to prolong elimination relative to the degree of impairment.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/2866055
Urinary pH: There is some evidence to suggest that urinary pH is capable of affecting elimination of diphenhydramine metabolites. One study administered ammonium chloride to individuals taking diphenhydramine to lower their urinary pH. Lowering urinary pH essentially increases its acidity, whereas increasing urinary pH is associated with increased alkalinity.
Following administration of ammonium chloride, urinary pH was acidified (lowered) and a greater amount of diphenhydramine was excreted via the kidneys. This is likely due to the fact that acidification prevents reabsorption and recirculation of the parent drug prior to renal excretion. Individuals with alkaline (high pH) urine may retain diphenhydramine for a significantly longer term than those with low pH urine.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/9248784
Benadryl: Absorption, Metabolism, Excretion (Details)
Following oral administration of Benadryl, its active antihistaminergic ingredient diphenhydramine is efficiently absorbed by the gastrointestinal (GI) tract. The drug then undergoes rapid first-pass hepatic metabolism via CYP450 enzymes, chiefly CYP2D6. CYP2D6 isoenzymes mediate the metabolism of diphenhydramine (via N-demethylation) to form its principal metabolite diphenylmethoxyacetic acid.
Various enzymes such as CYP1A2, CYP2C9, and CYP2C19 also contribute to N-demethylation to a minor extent. The diphenylmethoxyacetic acid metabolite is thought to undergo additional conjugation prior to elimination. Other metabolites formed during the breakdown of diphenhydramine include: nordiphenhydramine (pharmacologically active) and dinordiphenhydramine (pharmacologically inactive).
After first-pass metabolism, only up to 60% of diphenhydramine will remain unchanged in circulation. Unchanged diphenhydramine and its metabolites will reach peak levels in the bloodstream in around 2 hours post-ingestion, with peak concentrations being maintained for an additional 2 hours thereafter. The drug is extensively bound to plasma proteins and distributed throughout the body and central nervous system where it may accumulate due to its high lipophilicity.
Approximately 4 hours after ingestion, levels of diphenhydramine plummet exponentially, exhibiting a plasma elimination half-life within the range of 4 to 9 hours. Most individuals will have completely eliminated the drug from systemic plasma circulation within 3 days of their final dose. Among healthy adults, up to 75% of the drug will have been excreted from the body within 4 days of their final dose, with a majority getting excreted in the first 1 to 2 days.
Only around 1% of an oral dose will remain unchanged (as diphenhydramine) within urine. Most of the excreted drug will appear in the urine as diphenhydramine metabolites. If the urinary pH isn’t overly acidic, diphenhydramine-N-oxide (DHNO) is likely to be the most abundant metabolite, whereas if the urinary pH is highly acidic, nordiphenhydramine (NDH) are likely to be most prevelant.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/15188248
- Source: https://pubchem.ncbi.nlm.nih.gov/compound/diphenhydramine
- Source: http://www.ncbi.nlm.nih.gov/pubmed/15188248
Tips to clear Benadryl from your system
If your goal is to eliminate Benadryl from your system as rapidly as possible, below are some suggestions that may aid in your detoxification. Keep in mind that prior to implementing any of these suggestions, you should consult a medical professional to verify their hypothesized safety and efficacy. Also realize that even if you don’t use these tips, Benadryl isn’t likely to linger in your body for an extended duration – it should be out of your plasma within 3 days.
- Stop taking it: The easiest way to completely eliminate Benadryl from your system is to stop taking it. The sooner you stop using it, the quicker your body can detoxify itself. Everyone wants to take the latest and greatest supplements to rid themselves of drugs, when in reality, the best way to ensure detoxification is to give your body time. Once you’ve stopped using the drug, your body will shuttle it out of circulation.
- Urinary pH: Research shows that excretion speed can be manipulated with urinary acidification. Acidification of urine can be accomplished by altering your diet to incorporate more acidic foods. If you have a highly alkaline urinary pH, it could result in a prolonged elimination half-life of Benadryl compared to if it was acidified. Beware that too much acidity could lead to acidosis – so don’t go overboard. (Source: http://www.ncbi.nlm.nih.gov/pubmed/9248784).
- Activated charcoal: If you took a lot of Benadryl and are hoping to get some of it out of your system, you could take activated charcoal. Activated charcoal is considered “activated” because it has an electrical charge opposite to Benadryl, therefore allowing it to bind to the chemical prior to absorption. Even if the Benadryl was fully absorbed, activated charcoal can adsorb any remaining toxins.
- Calcium-D-Glucarate: This supplement is helpful for facilitating the elimination of toxins via your kidneys. It essentially aids your kidney function by acting as a beta-glucuronidase inhibitor, thereby clearing out any toxic molecules in detoxification pathways. This is something that you may want to consider if you’ve been using Benadryl regularly for an extended duration.
- Hydration/Exercise: It may be beneficial to stay optimally hydrated to help your kidneys flush out Benadryl. Though acidic urine can expedite excretion, so can maintaining hydration. Hydration increases your urinary flow rate, which forces a slightly greater amount of Benadryl metabolites to be eliminated in a shorter duration. Getting exercise may provide some benefit as well, especially for long-term users in that it may help burn body fat and/or force lipophilic metabolites out of fat stores.
How long has Benadryl stayed in your system after stopping?
If you were a regular Benadryl user and stopped taking it, how long do you think it stayed in your system after your final dose? Even if you rarely use Benadryl, feel free to share a comment regarding how long it takes your body to excrete the drug. Do you think you’re able to eliminate Benadryl quicker than average (e.g. within 24 hours) or do you think that it takes you a bit longer to eliminate from systemic circulation (e.g. 3+ days)?
Understand that plasma elimination is likely to occur within 1 to 3 days after your last dose. Complete excretion from the body may take an additional few days (as suggested by research). If you are a healthy adult and were taking Benadryl at a sensible, recommended dose, it should be completely excreted from your body within 7 days. However, if you have compromised hepatic function, were taking a CYP2D6 inhibitor, and/or are elderly – it may take longer.