Central Nervous System Effects Following Infusion of Diphenhydramine Using Pharmacokinetic and Pharmacodynamic Modeling

The Magnitude and Duration of the Central Nervous System Effects Following Intravenous Infusion of Diphenhydramine Using Pharmacokinetic and Pharmacodynamic Modeling

This study seeks to explore the magnitude and duration of central nervous system effects and pharmacokinetics after intravenous infusion of diphenhydramine.

Study Overview

• Status: Terminated
• Conditions: Central Nervous System Effects of Diphenhydramine; Pharmacokinetics of Diphenhydramine
• Intervention / Treatment: Drug: DiphenhydrAMINE Injectable Solution

• Study Type: Interventional
• Enrollment (Actual): 3
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • New York
    • Amherst, New York, United States, 14226
      • Dent Neurologic Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 35 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

1. Medically-stable volunteers of either gender between 35 and 50 years old or over the age of 65
2. No medication changes anticipated for the duration of the study except as defined in protocol

Exclusion Criteria:

1. Insulin-dependent diabetes
2. Psychiatric or neurologic disease affecting cognition in a way that may interfere with study outcomes in the opinion of the investigator
3. Unstable Coronary Artery Disease (active angina, MI within 6 months, stent placement within 6 months, cardiac surgery within 6 months)
4. Estimated CrCl < 30 mL/min using the Cockroft-Gault equation based on ideal body weight or total body weight
5. Any malignancy actively being treated or not in remission
6. Currently taking any CNS stimulant or depressant medications that may interfere with study outcomes in the opinion of the investigator unless using as defined in the protocol
7. Positive toxicology test for marijuana at screening visit or visit 2 or using marijuana not as defined in the protocol
8. Active or recent history of a substance use disorder within one year
9. Any medical condition that in the opinion of the investigator would disqualify the subject from participation in the study
10. Female subjects who are pregnant, planning to become pregnant, or breastfeeding on any study day
11. Female subjects of childbearing potential unwilling to use acceptable method of contraception during the study as defined in the protocol
12. Contraindication, known allergy, or suspected intolerability to study medication
13. Receipt of an antihistamine within 5 half-lives prior to the start of study visit 1 or study visit 2, as determined by the investigator
14. Positive toxicology test for a drug that is inconsistent with permitted medication use (defined in the protocol) as interpreted by the investigator
15. Participation in any other investigational drug study during the study or within 4 weeks prior to screening

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Score of Battery of Cognitive Function Tests (Reaction Time)	Change in the results of the CANTAB battery of cognitive function tests (reaction time, rapid visual information processing, paired associates learning, spatial working memory, digit span) and visual analog scale for sedation after diphenhydramine administration compared to baseline. Reaction Time Median Five-Choice Reaction Time is the median duration it took for a subject to release the response button after the presentation of the target stimulus, calculated across correct, assessed trials in which the stimulus could appear in any one of five locations. Lower is better. Minimum score is 100 and maximum score is 5100.	Change from before to after diphenhydramine administration (30, 60, 210, 240, 450, and 480 minutes after diphenhydramine)
Change in Score of Battery of Cognitive Function Tests (Digit Span)	Change in the results of the CANTAB battery of cognitive function tests (reaction time, rapid visual information processing, paired associates learning, spatial working memory, digit span) and visual analog scale for sedation after diphenhydramine administration compared to baseline. Digit Span Maximum Span Passed Forwards is the longest sequence problem successfully reached and passed by the subject. Higher is better. Minimum score is 0 and maximum score is 9.	Change from before to after diphenhydramine administration (30, 60, 210, 240, 450, and 480 minutes after diphenhydramine)
Change in Score of Battery of Cognitive Function Tests (Visual Analog Scale for Sedation)	Change in the results of the CANTAB battery of cognitive function tests (reaction time, rapid visual information processing, paired associates learning, spatial working memory, digit span) and visual analog scale for sedation after diphenhydramine administration compared to baseline. The Visual Analog Scale for Sedation is a scale where participants indicate their current state on a scale from "Sedated" to "Alert". Higher score is more alert. Minimum score is 0 and maximum score is 12.8.	Change from before to after diphenhydramine administration (30, 60, 210, 240, 450, and 480 minutes after diphenhydramine)
Change in Score of Battery of Cognitive Function Tests (Spatial Working Memory)	Change in the results of the CANTAB battery of cognitive function tests (reaction time, rapid visual information processing, paired associates learning, spatial working memory, digit span) and visual analog scale for sedation after diphenhydramine administration compared to baseline. Spatial Working Memory Between Errors is the number of times the subject incorrectly revisits a box in which a token has been previously found. Lower is better. Minimum score is 0 and maximum score is 63.	Change from before to after diphenhydramine administration (30, 60, 210, 240, 450, and 480 minutes after diphenhydramine)
Change in Score of Battery of Cognitive Function Tests (Paired Associates Learning)	Change in the results of the CANTAB battery of cognitive function tests (reaction time, rapid visual information processing, paired associates learning, spatial working memory, digit span) and visual analog scale for sedation after diphenhydramine administration compared to baseline. Paired Associates Learning First Attempt Memory Score is the number of times a subject chose the correct box on their first attempt when recalling the pattern locations. Higher is better. Minimum score is 0 and maximum score is 20.	Change from before to after diphenhydramine administration (30, 60, 210, 240, 450, and 480 minutes after diphenhydramine)
Change in Score of Battery of Cognitive Function Tests (Rapid Visual Information Processing)	Change in the results of the CANTAB battery of cognitive function tests (reaction time, rapid visual information processing, paired associates learning, spatial working memory, digit span) and visual analog scale for sedation after diphenhydramine administration compared to baseline. Rapid Visual Processing Median Response Latency is the median response latency on trials where the subject responded correctly, calculated across all assessed trials. Lower is better. Minimum score is 0 and maximum score is 908.	Change from before to after diphenhydramine administration (30, 60, 210, 240, 450, and 480 minutes after diphenhydramine)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Elderly vs. Adult Score of Battery of Cognitive Function Tests at Specified Time Points (Reaction Time)	Score of the CANTAB battery of cognitive function tests (reaction time, rapid visual information processing, paired associates learning, spatial working memory, digit span) and visual analog scale for sedation in elderly subjects aged 65+ compared to adult subjects aged 35 to 50 at specified time points (0, 30, 60, 210, 240, 450, 480 minutes after diphenhydramine administration). Reaction Time Median Five-Choice Reaction Time is the median duration it took for a subject to release the response button after the presentation of the target stimulus, calculated across correct, assessed trials in which the stimulus could appear in any one of five locations. Lower is better. Minimum score is 100 and maximum score is 5100.	Before and after diphenhydramine administration (30, 60, 210, 240, 450, 480 minutes after diphenhydramine administration)
Elderly vs. Adult Score of Battery of Cognitive Function Tests at Specified Time Points (Digit Span)	Score of the CANTAB battery of cognitive function tests (reaction time, rapid visual information processing, paired associates learning, spatial working memory, digit span) and visual analog scale for sedation in elderly subjects aged 65+ compared to adult subjects aged 35 to 50 at specified time points (0, 30, 60, 210, 240, 450, 480 minutes after diphenhydramine administration). Digit Span Maximum Span Passed Forwards is the longest sequence problem successfully reached and passed by the subject. Higher is better. Minimum score is 0 and maximum score is 9.	Before and after diphenhydramine administration (30, 60, 210, 240, 450, 480 minutes after diphenhydramine administration)
Elderly vs. Adult Score of Battery of Cognitive Function Tests at Specified Time Points (Visual Analog Scale for Sedation)	Score of the CANTAB battery of cognitive function tests (reaction time, rapid visual information processing, paired associates learning, spatial working memory, digit span) and visual analog scale for sedation in elderly subjects aged 65+ compared to adult subjects aged 35 to 50 at specified time points (0, 30, 60, 210, 240, 450, 480 minutes after diphenhydramine administration). The Visual Analog Scale for Sedation is a scale where participants indicate their current state on a scale from "Sedated" to "Alert". Higher score is more alert. Minimum score is 0 and maximum score is 12.8.	Before and after diphenhydramine administration (30, 60, 210, 240, 450, 480 minutes after diphenhydramine administration)
Elderly vs. Adult Score of Battery of Cognitive Function Tests at Specified Time Points (Spatial Working Memory)	Score of the CANTAB battery of cognitive function tests (reaction time, rapid visual information processing, paired associates learning, spatial working memory, digit span) and visual analog scale for sedation in elderly subjects aged 65+ compared to adult subjects aged 35 to 50 at specified time points (0, 30, 60, 210, 240, 450, 480 minutes after diphenhydramine administration). Spatial Working Memory Between Errors is the number of times the subject incorrectly revisits a box in which a token has been previously found. Lower is better. Minimum score is 0 and maximum score is 63.	Before and after diphenhydramine administration (30, 60, 210, 240, 450, 480 minutes after diphenhydramine administration)
Elderly vs. Adult Score of Battery of Cognitive Function Tests at Specified Time Points (Paired Associates Learning)	Score of the CANTAB battery of cognitive function tests (reaction time, rapid visual information processing, paired associates learning, spatial working memory, digit span) and visual analog scale for sedation in elderly subjects aged 65+ compared to adult subjects aged 35 to 50 at specified time points (0, 30, 60, 210, 240, 450, 480 minutes after diphenhydramine administration). Paired Associates Learning First Attempt Memory Score is the number of times a subject chose the correct box on their first attempt when recalling the pattern locations. Higher is better. Minimum score is 0 and maximum score is 20.	Before and after diphenhydramine administration (30, 60, 210, 240, 450, 480 minutes after diphenhydramine administration)
Elderly vs. Adult Score of Battery of Cognitive Function Tests at Specified Time Points (Rapid Visual Information Processing)	Score of the CANTAB battery of cognitive function tests (reaction time, rapid visual information processing, paired associates learning, spatial working memory, digit span) and visual analog scale for sedation in elderly subjects aged 65+ compared to adult subjects aged 35 to 50 at specified time points (0, 30, 60, 210, 240, 450, 480 minutes after diphenhydramine administration). Rapid Visual Processing Median Response Latency is the median response latency on trials where the subject responded correctly, calculated across all assessed trials. Lower is better. Minimum score is 0 and maximum score is 908.	Before and after diphenhydramine administration (30, 60, 210, 240, 450, 480 minutes after diphenhydramine administration)
Elderly vs. Adult Diphenhydramine AUC	Difference between diphenhydramine pharmacokinetic area under the curve (AUC) in elderly subjects aged 65+ vs. adult subjects aged 35 to 50	Immediately after diphenhydramine administration to 480 minutes after diphenhydramine administration
Elderly vs. Adult Change in Score of Battery of Cognitive Function Tests After Diphenhydramine (Reaction Time)	Change in the score of the CANTAB battery of cognitive function tests (reaction time, rapid visual information processing, paired associates learning, spatial working memory, digit span) and visual analog scale for sedation in elderly subjects aged 65+ compared to adult subjects aged 35 to 50 at specified time points (30, 60, 210, 240, 450, 480 minutes after diphenhydramine administration) compared to baseline. Reaction Time Median Five-Choice Reaction Time is the median duration it took for a subject to release the response button after the presentation of the target stimulus, calculated across correct, assessed trials in which the stimulus could appear in any one of five locations. Lower is better. Minimum score is 100 and maximum score is 5100.	Change from before to after diphenhydramine administration (30, 60, 210, 240, 450, and 480 minutes after diphenhydramine)
Elderly vs. Adult Change in Score of Battery of Cognitive Function Tests After Diphenhydramine (Digit Span)	Change in the score of the CANTAB battery of cognitive function tests (reaction time, rapid visual information processing, paired associates learning, spatial working memory, digit span) and visual analog scale for sedation in elderly subjects aged 65+ compared to adult subjects aged 35 to 50 at specified time points (30, 60, 210, 240, 450, 480 minutes after diphenhydramine administration) compared to baseline. Digit Span Maximum Span Passed Forwards is the longest sequence problem successfully reached and passed by the subject. Higher is better. Minimum score is 0 and maximum score is 9.	Change from before to after diphenhydramine administration (30, 60, 210, 240, 450, and 480 minutes after diphenhydramine)
Elderly vs. Adult Change in Score of Battery of Cognitive Function Tests After Diphenhydramine (Visual Analog Scale for Sedation)	Change in the score of the CANTAB battery of cognitive function tests (reaction time, rapid visual information processing, paired associates learning, spatial working memory, digit span) and visual analog scale for sedation in elderly subjects aged 65+ compared to adult subjects aged 35 to 50 at specified time points (30, 60, 210, 240, 450, 480 minutes after diphenhydramine administration) compared to baseline. The Visual Analog Scale for Sedation is a scale where participants indicate their current state on a scale from "Sedated" to "Alert". Higher score is more alert. Minimum score is 0 and maximum score is 12.8.	Change from before to after diphenhydramine administration (30, 60, 210, 240, 450, and 480 minutes after diphenhydramine)
Elderly vs. Adult Change in Score of Battery of Cognitive Function Tests After Diphenhydramine (Spatial Working Memory)	Change in the score of the CANTAB battery of cognitive function tests (reaction time, rapid visual information processing, paired associates learning, spatial working memory, digit span) and visual analog scale for sedation in elderly subjects aged 65+ compared to adult subjects aged 35 to 50 at specified time points (30, 60, 210, 240, 450, 480 minutes after diphenhydramine administration) compared to baseline. Spatial Working Memory Between Errors is the number of times the subject incorrectly revisits a box in which a token has been previously found. Lower is better. Minimum score is 0 and maximum score is 63.	Change from before to after diphenhydramine administration (30, 60, 210, 240, 450, and 480 minutes after diphenhydramine)
Elderly vs. Adult Change in Score of Battery of Cognitive Function Tests After Diphenhydramine (Paired Associates Learning)	Change in the score of the CANTAB battery of cognitive function tests (reaction time, rapid visual information processing, paired associates learning, spatial working memory, digit span) and visual analog scale for sedation in elderly subjects aged 65+ compared to adult subjects aged 35 to 50 at specified time points (30, 60, 210, 240, 450, 480 minutes after diphenhydramine administration) compared to baseline. Paired Associates Learning First Attempt Memory Score is the number of times a subject chose the correct box on their first attempt when recalling the pattern locations. Higher is better. Minimum score is 0 and maximum score is 20.	Change from before to after diphenhydramine administration (30, 60, 210, 240, 450, and 480 minutes after diphenhydramine)
Elderly vs. Adult Change in Score of Battery of Cognitive Function Tests After Diphenhydramine (Rapid Visual Information Processing)	Change in the score of the CANTAB battery of cognitive function tests (reaction time, rapid visual information processing, paired associates learning, spatial working memory, digit span) and visual analog scale for sedation in elderly subjects aged 65+ compared to adult subjects aged 35 to 50 at specified time points (30, 60, 210, 240, 450, 480 minutes after diphenhydramine administration) compared to baseline. Rapid Visual Processing Median Response Latency is the median response latency on trials where the subject responded correctly, calculated across all assessed trials. Lower is better. Minimum score is 0 and maximum score is 908.	Change from before to after diphenhydramine administration (30, 60, 210, 240, 450, and 480 minutes after diphenhydramine)

Collaborators and Investigators

• Sponsor: Dent Neuroscience Research Center
• Investigators: Principal Investigator: Michelle Rainka, PharmD, Dent Neurologic Institute

Study record dates

Study Major Dates

• Study Start (Actual): March 15, 2022
• Primary Completion (Actual): October 4, 2022
• Study Completion (Actual): October 4, 2022

Study Registration Dates

• First Submitted: January 18, 2022
• First Submitted That Met QC Criteria: January 20, 2022
• First Posted (Actual): February 2, 2022

Study Record Updates

• Last Update Posted (Actual): January 22, 2026
• Last Update Submitted That Met QC Criteria: January 2, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Autonomic Agents; Peripheral Nervous System Agents; Sensory System Agents; Anesthetics; Antiemetics; Gastrointestinal Agents; Dermatologic Agents; Hypnotics and Sedatives; Anesthetics, Local; Anti-Allergic Agents; Sleep Aids, Pharmaceutical; Histamine H1 Antagonists; Histamine Antagonists; Histamine Agents; Antipruritics; Diphenhydramine; Promethazine
• Other Study ID Numbers: DIP-PKPD

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No