Diphenhydramine for Sleep in Children with Autism

Overseen by Antonio Hardan, MD

Age: < 18

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Stanford University

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

Disqualifiers: Schizophrenia, Seizure disorder, Migraine, others

No Placebo Group

Prior Safety Data

Trial Summary

What is the purpose of this trial?

This trial is testing if diphenhydramine can help children and teens with Autism Spectrum Disorder sleep better. Diphenhydramine is usually used for allergies but also makes people sleepy by blocking certain chemicals in the body. Diphenhydramine has been shown to be effective in reducing the time it takes to fall asleep and the number of times children wake up during the night.

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 the drug diphenhydramine effective for improving sleep in children with autism?

Research shows that diphenhydramine can help improve sleep by reducing the time it takes to fall asleep and the number of times children wake up during the night. It has been found to be more effective than a placebo in children with various sleep disorders, suggesting it may also help children with autism sleep better. ^{1 2 3 4 5}

Is diphenhydramine safe for use as a sleep aid in children with autism?

Research indicates that diphenhydramine is generally safe for use as a sleep aid in children, as studies have shown it to be effective in reducing sleep latency and awakenings without significant adverse effects compared to a placebo. ^{1 2 3 6 7}

How does the drug diphenhydramine differ from other treatments for sleep issues in children with autism?

Diphenhydramine is unique because it is an over-the-counter medication commonly used as a sleep aid, and studies have shown it can effectively reduce the time it takes to fall asleep and the number of awakenings during the night in children. Unlike some other treatments, it is widely available and has been shown to be safe and effective for temporary sleep issues in both children and adults. ^{1 2 3 4 5}

Research Team

Antonio Hardan, MD

Principal Investigator

Stanford University

Eligibility Criteria

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.

Trial Timeline

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

Treatment Details

Interventions

• Diphenhydramine (Antihistamine)
• Placebo (Behavioural Intervention)

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.

Participant Groups

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 Canada, Japan for the following indications:

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+

Dr. Richard A. Miller

Stanford University

Chief Executive Officer since 2023

Stanford University, MD

Dr. Robert Schott

Stanford University

Chief Medical Officer since 2021

University of Michigan, MD

National Institutes of Health (NIH)

Collaborator

Trials

2,896

Recruited

8,053,000+

Dr. Jeanne Marrazzo

National Institutes of Health (NIH)

Chief Medical Officer

MD from University of California, Los Angeles

Dr. Jay Bhattacharya

National Institutes of Health (NIH)

Chief Executive Officer

MD, PhD from Stanford University

Findings from Research

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]

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 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]

References

1. England pubmed.ncbi.nlm.nih.gov

Diphenhydramine in insomniac family practice patients: a double-blind study. [2019]

2. Germany pubmed.ncbi.nlm.nih.gov

Effect of diphenhydramine on subjective sleep parameters and on motor activity during bedtime. [2018]

3. England pubmed.ncbi.nlm.nih.gov

The effectiveness of diphenhydramine HCI in pediatric sleep disorders. [2019]

4. United States pubmed.ncbi.nlm.nih.gov

Effect of dextromethorphan, diphenhydramine, and placebo on nocturnal cough and sleep quality for coughing children and their parents. [2019]

5. United States 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. [2022]

6. United States 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. [2021]

7. Netherlands pubmed.ncbi.nlm.nih.gov

First and second generation H₁ histamine receptor antagonists produce different sleep-inducing profiles in rats. [2013]