What antihistamine (anti-histamine) can help with weight gain?

First-Generation Antihistamines Promote Weight Gain

First-generation (sedating) antihistamines that cross the blood-brain barrier are most likely to promote weight gain, with cyproheptadine being the best-studied and most effective option for this purpose. 1

Mechanism of Weight Gain with Antihistamines

• The more potent the antihistamine's central H1 receptor antagonism, the greater the potential for weight gain. 1

• Weight gain occurs primarily through antagonism of hypothalamic H1 receptors, which increases appetite and food intake. 1

• First-generation antihistamines that act centrally are significantly more likely to promote weight gain than second- and third-generation (non-sedating) antihistamines that do not cross the blood-brain barrier. 1

Specific Antihistamine Recommendations for Weight Gain

Cyproheptadine (First Choice)

Cyproheptadine is the antihistamine with the strongest evidence for promoting weight gain and appetite stimulation. 1, 2, 3, 4, 5, 6

• Cyproheptadine has dual mechanisms: H1 antihistamine activity plus serotonin receptor antagonism, both contributing to appetite stimulation. 1, 2, 4

• In the largest randomized, double-blind, placebo-controlled trial (375 patients), cyproheptadine produced statistically significant appetite improvement and weight gain in adults with poor appetite. 2

• A systematic review of 46 studies across 21 different populations found that 39 demonstrated significant weight gain with cyproheptadine. 6

• Typical dosing: 4 mg three times daily in adults, or 0.25-0.4 mg/kg/day in children. 2, 3, 4

• In controlled trials, subjects gained significantly more weight on cyproheptadine than placebo, with corresponding increases in subjective hunger ratings and food intake. 4

Other First-Generation Antihistamines

• Diphenhydramine, hydroxyzine, and chlorpheniramine are first-generation antihistamines that may promote weight gain through central H1 antagonism, though they are less well-studied than cyproheptadine for this specific indication. 1

• Ketotifen is a sedating H1 antagonist (available as compounded tablets in the US) that may promote weight gain, though evidence is limited compared to cyproheptadine. 1

Antihistamines to AVOID for Weight Gain

Second- and third-generation antihistamines (fexofenadine, cetirizine, loratadine) should be avoided if weight gain is the goal, as they are more selective for peripheral H1 receptors and do not cross the blood-brain barrier effectively. 1

Important Clinical Considerations

Common Side Effects

• Drowsiness/sedation is the most common side effect and occurs frequently with first-generation antihistamines. 1, 2, 4

• Cognitive decline and impaired driving ability can occur, particularly concerning in elderly patients. 1

• Anticholinergic effects may include dry mouth, constipation, and urinary retention. 1

Populations Where Cyproheptadine Shows Benefit

• Healthy adults with poor appetite 2
• Undernourished children (improved body mass index after 4 weeks) 5
• Children with growth hormone deficiency (enhanced linear growth when combined with GH therapy) 3
• Various underweight populations across multiple medical conditions 6

Populations with Minimal Benefit

• Patients with malignant or progressive disease states (HIV, cancer) showed minimal to no benefit from cyproheptadine for weight gain. 6

Practical Implementation Algorithm

1. Start with cyproheptadine 4 mg three times daily (or 0.25-0.4 mg/kg/day in children) as the first-line antihistamine for weight gain. 2, 3, 4

2. Warn patients about sedation, which typically improves with continued use. 2, 4

3. Monitor weight, appetite, and food intake at 4-week intervals. 2, 5

4. Consider discontinuation if no benefit after 4-8 weeks, particularly in patients with progressive disease states. 6

5. Avoid second- or third-generation antihistamines if weight gain is the therapeutic goal. 1