Diphenhydramine for Sleep in Children with Autism

Overseen By Ryan Villacrucis

Age: < 18

Sex: Any

Trial Phase: Phase 2

Sponsor: Stanford University

Must not be taking: Beta-blockers, Benzodiazepines, Antiepileptics, others

Disqualifiers: Schizophrenia, Seizure disorder, Migraine, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 8 weeks

26 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how diphenhydramine, known for treating allergies and aiding sleep, affects sleep in children and adolescents with Autism Spectrum Disorder (ASD). The researchers aim to determine if diphenhydramine can improve sleep patterns compared to a placebo. The trial includes two groups: one starts with diphenhydramine and switches to placebo, while the other does the opposite. Children aged 8 to 17 with ASD who experience significant sleep disturbances may be suitable candidates for this trial. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group.

Will I have to stop taking my current medications?

Participants must stop taking certain medications, including beta-blockers, benzodiazepines, antiepileptic medications, melatonin, antihistamines, and any medications that interact with diphenhydramine. Other medications must be stable for at least 2 weeks, except for Prozac, which must be stable for at least 4 weeks.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research shows that diphenhydramine is generally safe for children, but strong evidence about its long-term safety is lacking. It is often used to address sleep problems, though some reports mention serious side effects. These can include unresponsiveness, anxiety, and hallucinations. Although these severe reactions are rare, they highlight the importance of monitoring safety.

Diphenhydramine is commonly used over-the-counter for short-term sleep issues and allergies, indicating it is usually well-tolerated. However, careful monitoring during a clinical trial is crucial to ensure its safety, especially in children with autism. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for autism?

Researchers are excited about using diphenhydramine for sleep issues in children with autism because it offers a potentially safe and effective alternative to the typical medications used for sleep disturbances, such as melatonin or prescription sleep aids. Diphenhydramine, an antihistamine commonly found in over-the-counter allergy medications, has sedative properties that could help improve sleep quality without the need for stronger medications. Unlike many current treatments, which may take time to show results or have concerning side effects, diphenhydramine is widely available and has a well-known safety profile in children, potentially providing a quicker and more accessible solution for families.

What evidence suggests that diphenhydramine might be an effective treatment for sleep in children with autism?

Research has shown that diphenhydramine might help children and teens with Autism Spectrum Disorder (ASD) sleep better. In this trial, participants will receive diphenhydramine in one treatment arm and a placebo in another. Early results from a carefully controlled study suggested that diphenhydramine can help them sleep longer and more efficiently. Typically used for allergies, diphenhydramine can also induce sleepiness, making it a candidate for addressing sleep problems. Although more studies are needed, the initial findings offer hope for using diphenhydramine to help children with autism who have trouble sleeping. ^{1 2 3 6 7}

Who Is on the Research Team?

Antonio Hardan, MD

Principal Investigator

Stanford University

Are You a Good Fit for This Trial?

This trial is for children and adolescents aged 8-17 with Autism Spectrum Disorder who have sleep disturbances. They must be outpatients with stable medications, not planning any treatment changes during the study, and able to provide saliva samples. Those with certain medical conditions or on conflicting medications cannot participate.

Inclusion Criteria

I am either male or female.

I am between 8 and 17 years old.

Stable medications for at least 4 weeks

Exclusion Criteria

I have tried diphenhydramine without success.

Pregnant or sexually active females not using a reliable method of contraception

I have a serious health condition like severe asthma, migraines, seizures, or problems with my liver, kidneys, or heart.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Diphenhydramine or Placebo in a crossover design for 8 weeks

8 weeks

Weekly visits for dose adjustment and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Diphenhydramine
• Placebo

Trial Overview

The trial tests if Diphenhydramine improves sleep in kids with autism using a double-blind method where neither doctors nor participants know who gets the real medicine or placebo. It's an 8-week study comparing drug effects to a fake pill (placebo) using sleep tracking and safety checks.

How Is the Trial Designed?

Group I: Placebo, then Diphenhydramine Experimental Treatment 2 Interventions

Participants will first receive Placebo (fake tablet) for a 4-week period. A 25 mg dose of matching Placebo will be given at bedtime for one week and then will increase to 50 mg if needed and if well tolerated. Participants will then receive Diphenhydramine for a 4-week period. A 25 mg dose of Diphenhydramine will be given at bedtime for one week and then will increase to 50 mg if needed and if well tolerated.

Group II: Diphenhydramine, then Placebo Experimental Treatment 2 Interventions

Participants will first receive Diphenhydramine for a 4-week period. A 25 mg dose of Diphenhydramine will be given at bedtime for one week and then will increase to 50 mg if needed and if well tolerated. Participants will then receive Placebo (fake tablet) for a 4-week period. A 25 mg dose of matching Placebo will be given at bedtime for one week and then will increase to 50 mg if needed and if well tolerated.

Diphenhydramine is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Benadryl for:

• Allergic reactions
• Insomnia
• Motion sickness
• Coughs and colds

Approved in European Union as Diphenhydramine for:

• Allergic reactions
• Insomnia
• Motion sickness
• Coughs and colds

Approved in Canada as Unisom for:

• Insomnia
• Allergic reactions

Approved in Japan as Sominex for:

• Insomnia
• Allergic reactions

Who Is Running the Clinical Trial?

Stanford University

Lead Sponsor

Trials

2,527

Recruited

17,430,000+

National Institutes of Health (NIH)

Collaborator

Trials

2,896

Recruited

8,053,000+

Published Research Related to This Trial

In a study involving 100 children with upper respiratory infections, neither dextromethorphan nor diphenhydramine showed any significant advantage over placebo in alleviating nocturnal cough or improving sleep quality for the children or their parents.

Parents reported more insomnia in children taking dextromethorphan and increased drowsiness in those taking diphenhydramine, highlighting potential adverse effects that should be considered before using these medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of dextromethorphan, diphenhydramine, and placebo on nocturnal cough and sleep quality for coughing children and their parents. Paul, IM., Yoder, KE., Crowell, KR., et al.[2019]

A study using PET imaging confirmed that diphenhydramine, a common over-the-counter sleep aid, has a significant next-day residual sedative effect, with 44.7% H₁ receptor occupancy in the brain compared to only 16.6% for the second-generation antihistamine bepotastine.

Despite the measurable sedative effects of diphenhydramine, subjective feelings of sleepiness did not differ significantly among participants, highlighting the importance of caution when using OTC antihistamines for sleep.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Next-day residual sedative effect after nighttime administration of an over-the-counter antihistamine sleep aid, diphenhydramine, measured by positron emission tomography. Zhang, D., Tashiro, M., Shibuya, K., et al.[2021]

Ketotifen, a second-generation H₁ histamine receptor antagonist, effectively increases non-REM sleep and decreases REM sleep in a dose-dependent manner, suggesting its potential as a sleep aid.

In contrast, diphenhydramine, a first-generation H₁ antagonist, shows a complex effect on sleep patterns, where higher doses can lead to increased wakefulness, indicating that its sedative effects may be influenced by receptor-independent actions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First and second generation H₁ histamine receptor antagonists produce different sleep-inducing profiles in rats. Unno, K., Ozaki, T., Mohammad, S., et al.[2013]

In a study involving 10 young, healthy adults, a single oral dose of diphenhydramine (50 mg or 75 mg) showed a mild hypnotic effect, as participants reported a slight decrease in sleep latency, although no significant differences in overall sleep quality were observed compared to placebo.

The drug did not impair psychomotor performance the following morning and did not cause rebound insomnia, suggesting it may be safe for occasional use without significant next-day effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of diphenhydramine on subjective sleep parameters and on motor activity during bedtime. Borbély, AA., Youmbi-Balderer, G.[2018]

In a study of 50 children with sleep disorders, diphenhydramine elixir (1.0 mg/kg) significantly reduced the time it took for children to fall asleep and the number of times they woke up during the night compared to a placebo.

Parents reported that diphenhydramine was more effective than placebo in improving overall sleep quality, indicating it is a safe and effective sleep aid for children.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effectiveness of diphenhydramine HCI in pediatric sleep disorders. Russo, RM., Gururaj, VJ., Allen, JE.[2019]

In a clinical trial involving 139 children aged 24-60 months with cough due to upper respiratory infections, honey was found to significantly reduce cough frequency and improve sleep quality more effectively than dextromethorphan (DM) and diphenhydramine (DPH).

The study showed that after a 24-hour intervention, children receiving honey had a cough frequency score drop from 4.09 to 1.93, while the control group only improved from 4.11 to 3.11, highlighting honey's superior efficacy in alleviating cough symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A comparison of the effect of honey, dextromethorphan, and diphenhydramine on nightly cough and sleep quality in children and their parents. Shadkam, MN., Mozaffari-Khosravi, H., Mozayan, MR.[2022]

In a study of 111 mildly to moderately insomniac patients, diphenhydramine (50 mg) significantly improved sleep parameters, such as reducing the time it took to fall asleep, compared to a placebo.

Despite experiencing more side effects, patients preferred diphenhydramine over placebo and reported feeling more rested the next morning, supporting its use as an effective over-the-counter sleep aid for temporary insomnia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Diphenhydramine in insomniac family practice patients: a double-blind study. Rickels, K., Morris, RJ., Newman, H., et al.[2019]

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