Antihistamines

Antihistamines are a class of drugs that reduce the effects of histamine, a chemical involved in allergic responses and other functions. There are four histamine receptor types: H1, H2, H3, and H4, but antihistamines mainly act on H1 and H2, which have different roles in the body. 

• Antihistamines that target the histamine H1 receptor (H1R) are used to relieve the symptoms of allergy and inflammation such as allergic rhinitis and chronic urticaria.
• H2 receptor antagonists reduce stomach acid production and are used to treat digestive conditions such as gastroesophageal reflux disease (GERD) and functional dyspepsia. They can also be combined with proton pump inhibitors for stronger acid control.

Antihistamines work by binding to histamine receptors (mainly H1 and H2) and keeping them inactive. They do not block or decrease the release of histamine, but rather ameliorate its actions. In other words, histamine is still present, but its ability to signal - and therefore trigger a reaction - is reduced.

H1 and H2 antihistamines work in slightly different ways. 

• H1 antihistamines (allergy symptoms)
  H1 receptors are located in blood vessels, sensory nerves, and smooth muscle. H1 antihistamines such as cetirizine and loratadine act as inverse agonists at H1 receptors, stabilizing them in an inactive state to reverse histamine-induced effects such as vasodilation, itching, and bronchoconstriction.¹ At higher doses, some also inhibit specific signalling pathways (NF-κB and calcium) for greater anti-inflammatory benefits.

• H2 antihistamines (gastric acid)
  H2 receptors are mostly located on gastric parietal cells, where histamine stimulates acid secretion. Common H2 agents such as cimetidine, famotidine, and ranitidine bind to H2 receptors as inverse agonists, reducing gastric acid output. 

There are two main categories of antihistamines: first-generation and second-generation. 

• First-generation antihistamines are able to cross the blood-brain barrier (BBB) and enter the central nervous system where they block central H1 receptors, causing sedation.
  These antihistamines also block the neurotransmitter acetylcholine in the brain and body, inhibiting the parasympathetic nervous system. Brands include Diphenhydramine (Benadryl), Chlorpheniramine, Hydroxyzine, Promethazine.²
• Second-generation types are more polar, which makes them less able to pass through the BBB efficiently. They target H1 receptors throughout the rest of the body, and brain concentrations remain low.³ Second-generation antihistamines are considered superior to first-generation antihistamines due to high H1 receptor selectivity, low brain permeability, and longer-lasting action with fewer adverse effects.⁴ Brands include Cetirizine (Zyrtec), Loratadine (Claritin), Fexofenadine (Allegra), and Desloratadine (Clarinex).
• H2 antihistamines (H2 blockers) are used mainly to treat conditions caused by excess stomach acid, such as reflux and ulcers. They are highly selective, competitive antagonists of histamine H2 receptors found on gastric parietal cells. By blocking these receptors on the stomach lining, they reduce the amount of acid produced. Common examples include famotidine (Pepcid), cimetidine (Tagamet), and nizatidine (Axid).

The side effects of antihistamines can vary depending on the type, dosage, and individual response. 

Many first‑generation H1 antihistamines (for example, diphenhydramine/Benadryl) are also anticholinergic, which means they competitively inhibit acetylcholine at muscarinic receptors.

Common side effects include dry mouth, constipation, urinary retention, and blurred vision, drowsiness, dizziness, impaired coordination, headache, dry mouth, constipation, hypotension, palpitations, tachycardia, and more.⁵ A recent study found that first-generation antihistamines were associated with a 22% higher seizure risk in children, especially in those aged 6-24 months.⁶

Second-generation antihistamines are generally considered safe with reduced anticholinergic effects compared to first-generation. Common side effects are usually mild and include headache, dizziness, fatigue, dry mouth. New versions of antihistamines created from derivatives of these second-generation products have been introduced, but research is pending as to whether they are safer or more effective.⁷

Some natural plant extracts may also help to relieve histamine-related reactions.

A diet of low histamine foods is often recommended for people with histamine intolerance. These are not the same as ‘antihistamine foods’, which are foods containing certain compounds that may help relieve allergic reactions. However, it’s important to note that most claims about antihistamine foods are based on animal or in vitro studies of isolated compounds, not the ingestion of whole foods by humans.

Flavonoids are known to inhibit the release of histamine from mast cells. Quercetin is a flavonoid found in fruits and vegetables and has been shown to decrease mast cell degranulation and subsequent histamine release, which then reduces the allergic response. Several clinical studies have indicated that quercetin may be effective in alleviating symptoms of allergies such as itching, sneezing, and nasal congestion. Quercetin also may help to relieve inflammation associated with allergic conditions.⁸

A 2016 study found that quercetin was more effective in inhibiting some inflammatory compounds than the anti-allergic drug cromolyn.⁹

Foods rich in quercetin include red leaf lettuce, asparagus, and onions.¹⁰

Some online sources claim that bromelain may reduce edema and sinus congestion. There is some evidence of bromelain’s anti-inflammatory and antioxidant properties, including that it may modulate mast cells and allergic inflammation. However, evidence of direct “antihistamine” effects is lacking.¹¹

Vitamin C is an important antioxidant with anti‑inflammatory and immunomodulatory actions rather than direct antihistamine effects. 

Animal studies have suggested that vitamin C may relieve bronchoconstriction and airway resistance induced by histamine, but this has not been demonstrated in humans.¹²

A 2025 meta-analysis revealed that a combination of probiotics and antihistamines significantly improved urticaria compared to antihistamines alone. Dysbiosis is a common factor in allergic conditions such as urticaria, with studies showing that higher quantities of pathogenic bacteria and impaired intestinal barrier function can lead to abnormal immune responses.¹³ Specifically, the meta-analysis found that probiotics combined with antihistamines significantly reduced adverse event rates by 61% and recurrence rate by 71% compared with antihistamines alone.

First-generation antishistamines that suppress central nervous system (CNS) arousal have been used to treat anxiety, but long-term risks may outweigh benefits. Research has linked first-generation antihistamines to higher risk of developing dementia.¹⁴

First-generation antihistamines used for treating anxiety are recommended for short-term use only.

• Diphenhydramine 
  Antihistamines such as Benadryl that contain the active ingredient diphenhydramine have a sedative effect, but are not approved for treating anxiety or other mental health disorders. When used as a sleep aid, diphenhydramine can result in poor concentration, reduced attention span, reduced memory, poor sensory-motor performance, and compromised academic performance.¹⁵ One study found that diphenhydramine was more detrimental to driving than alcohol.¹⁶
• Hydroxyzine
  The prescription-only antihistamine hydroxyzine also has sedative properties and is frequently used for conditions besides allergic reactions including insomnia and anxiety. However it is not recommended for long-term use, and no studies have firmly established the safety of its use beyond a few months.¹⁷

Antihistamines are generally considered safe, but people with high or low blood pressure should consult their healthcare practitioner before taking any antihistamine product, especially if they are already on other medication. Excessive dosages and/or formulas combined with pseudoephedrin can lead to cardiovascular symptoms including tachycardia and both hypertension and hypotension.¹⁸

Diphenhydramine should be used with caution by people with cardiovascular disease or hypertension.¹⁹

Long-term use of first-generation (sedating) histamines may lead to dependence. Sudden discontinuation of diphenhydramine may result in withdrawal symptoms such as sweating, anxiety, agitation, increased urination, nausea, vomiting, headache, and dizziness. Although these are usually mild, they may last for up to 6-8 weeks.²⁰

Using these histamines as a sleep aid may also lead to restlessness and worsening of insomnia. Gradual tapering over 1-2 weeks under the guidance of a healthcare practitioner is advised.²¹

Antihistamines and decongestants treat different aspects of nasal congestion. They can be used independently or in combination, depending on the condition they are treating. 

• Antihistamines block H1 histamine receptors to prevent the release of histamine during an allergic reaction. They are helpful for reducing sneezing, itching, runny nose, and eye symptoms as a result of hayfever (allergic rhinitis) and food sensitivities. They have a more modest effect on a stuffy nose. 
• Decongestants such as pseudoephedrine, oxymetazoline/xylometazoline, are vasoconstrictors that help to narrow the blood vessels in nasal passages, providing relief of nasal obstruction, regardless of whether the cause is allergy or viral infection. They may provide faster improvement in congestion than antihistamines alone, although using both an antihistamine and decongestant together may be more helpful than using an antihistamine alone.
  A 2022 evidence review on oral antihistamine-decongestant-analgesic combinations for the common cold showed modest overall reduction in symptoms, with the most improvement in nasal congestion, but also with more side effects. The study authors concluded that benefits must be weighed against the risk of adverse effects.²²