What is a Paradoxical Reaction to Diphenhydramine?
Diphenhydramine, the active ingredient in common over-the-counter medications like Benadryl, is a first-generation antihistamine widely known for its ability to cause drowsiness and help with sleep. However, a phenomenon known as paradoxical excitation occurs when a drug produces a reaction opposite to its intended effect. In the case of diphenhydramine, this means feeling excitable, restless, or hyperactive instead of sleepy. This effect has been documented in both adults and children, although it is more frequently reported in younger individuals.
The symptoms of this paradoxical reaction can include:
- Agitation or restlessness
- Anxiety
- Insomnia
- Irritability
- Excitement or feeling 'wide awake'
- Tremors or shaking
Understanding the potential reasons behind this unusual reaction is crucial for those who experience it, as it can be distressing and disrupt sleep patterns. It's important to remember that this reaction is not a sign of an allergy but rather a specific and uncommon side effect of the medication.
The Role of Genetics in Drug Metabolism
One of the most prominent theories explaining why some individuals experience hyperactivity from diphenhydramine involves a genetic variation affecting how the drug is broken down by the body.
The CYP2D6 Enzyme
Diphenhydramine is metabolized in the liver primarily by an enzyme known as cytochrome P450 2D6, or CYP2D6. The gene for this enzyme is highly variable within the population, meaning people can metabolize drugs at different rates. Some individuals are classified as "ultrarapid metabolizers," meaning they have multiple active copies of the CYP2D6 gene and produce more of this enzyme.
The Ultrarapid Metabolizer Theory
A 2008 case report described three individuals who were CYP2D6 ultrarapid metabolizers and experienced paradoxical excitation when taking diphenhydramine. The researchers hypothesized that the unusually high enzyme activity in these individuals could cause diphenhydramine to be broken down so quickly that it creates an excitatory compound, or metabolite, in the body, rather than the sedating one. Although this theory requires more research to be definitively confirmed, it provides a plausible explanation for why this effect occurs in some and not others. Approximately 1% to 2% of the U.S. population may have this genetic variation, putting them at higher risk for such reactions.
Other Contributing Factors
Beyond genetic metabolism, other factors can influence a person's reaction to diphenhydramine.
Anticholinergic Effects
Diphenhydramine is not only an antihistamine but also a potent anticholinergic agent. This means it blocks the action of acetylcholine, a neurotransmitter in the central nervous system (CNS). While anticholinergic effects can contribute to side effects like dry mouth and blurred vision, they can also affect CNS function and, in some cases, contribute to paradoxical stimulation. In overdose situations, these effects can become more pronounced, leading to agitation and restlessness.
Interaction with Other Stimulants
Consuming other stimulants, such as caffeine or nicotine, while taking diphenhydramine can further exacerbate feelings of hyperactivity. These substances can counteract or overpower the drug's sedative properties, leading to heightened alertness and anxiety. It's best to avoid other stimulants while taking any medication that affects the central nervous system.
Misconception about ADHD
There is a misconception that a paradoxical reaction to diphenhydramine indicates the presence of attention-deficit hyperactivity disorder (ADHD). This is not true. While both ADHD and a paradoxical reaction involve hyperactivity, current medical evidence does not support using the drug response as a diagnostic indicator for ADHD. A proper ADHD diagnosis should involve a comprehensive assessment by a qualified professional, not based on a single medication reaction.
Comparison: Diphenhydramine vs. Newer Antihistamines
If you have experienced paradoxical excitation with diphenhydramine, alternative options are available. Newer, second-generation antihistamines are a popular choice because they are less likely to cause significant drowsiness or cross the blood-brain barrier.
| Feature | Diphenhydramine (Benadryl) | Second-Generation Antihistamines (e.g., Zyrtec, Claritin, Allegra) |
|---|---|---|
| Classification | First-generation H1-antihistamine | Second- or third-generation H1-antihistamine |
| Sedative Potential | High; commonly causes drowsiness. Can cause paradoxical excitation. | Low to none; typically non-drowsy. |
| Mechanism | Crosses the blood-brain barrier easily and is a potent anticholinergic. | Does not easily cross the blood-brain barrier, resulting in fewer CNS effects. |
| Duration of Action | Relatively short, often requiring multiple doses (e.g., every 4-6 hours). | Longer-acting, with most dosed once daily. |
| Common Side Effects | Drowsiness, dry mouth, blurred vision, dizziness. | Fewer side effects; can include headache, dry mouth (Claritin), or fatigue (Zyrtec). |
| Best For | Short-term allergy relief, motion sickness, or as a sleep aid if no paradoxical reaction occurs. | All-day allergy relief with minimal impact on cognitive or psychomotor function. |
What to Do If You Experience Paradoxical Hyperactivity
If you find that diphenhydramine makes you hyper, there are several steps you can take:
- Stop taking it: The most immediate solution is to stop taking the medication. The effects typically wear off within a few hours.
- Contact a healthcare provider: Discuss your reaction with a doctor or pharmacist. They can help you identify a more suitable alternative, such as a second-generation antihistamine.
- Manage symptoms: For restlessness or anxiety, try calming activities like deep breathing, meditation, or light exercise. Avoid other stimulating substances, like caffeine.
- Consider an alternative: As discussed, newer antihistamines like cetirizine, loratadine, or fexofenadine are less likely to cause CNS side effects.
Conclusion
While most people experience sedation when taking diphenhydramine, a small subset of the population, often due to genetic variations in the CYP2D6 enzyme, can experience the opposite effect: paradoxical excitation. This can manifest as restlessness, anxiety, and insomnia. It is not a sign of ADHD but rather an individual drug response. If you have this reaction, discontinuing the medication and consulting a healthcare provider about non-drowsy alternatives is the best course of action. Understanding this rare but notable side effect can help you make safer, more effective choices for managing allergies or sleep issues.
For more detailed information on drug interactions and side effects, you can visit the Drugs.com diphenhydramine side effects page, a reliable resource for medication information.
