Effects of Melatonin on Sleep, Ventilatory Control and Cognition at Altitude

Low oxygen at altitude causes pauses in breathing during sleep, called central sleep apnea. Central sleep apnea causes repeated awakenings and poor sleep. Low oxygen itself and the induced oxidative stress can damage mental function which is likely worsened by poor sleep. Reduced mental function due to low oxygen can pose a serious danger to mountain climbers. However there is also mounting evidence that even in populations of people that live at high altitudes and are considered adapted, low oxygen contributes to reductions in learning and memory. Therefore there is a serious need for treatments which may improve sleep, control of breathing and mental function during low oxygen.Therefore this study aims to determine how melatonin effects control of breathing, sleep and mental performance during exposure to low oxygen.

Study Overview

• Status: Completed
• Conditions: Intermittent Hypoxia
• Intervention / Treatment: Other: Placebo; Other: Melatonin

Detailed Description

Research has shown that exposure to low oxygen at altitude causes neurocognitive impairment (impaired mental processing, memory, attention, learning, etc). This impairment in cognitive performance poses a serious risk to mountain climbers and while it has traditionally been thought that people who live at high altitude have adapted to it, evidence shows there is still considerable damage to the brain and impairments in cognitive function of people who live and work at high altitude.

As every cell in the body requires oxygen to survive and function, impairment in cognitive performance at altitude is thought mainly due to reduced oxygen availability to the central nervous system. However, low oxygen at altitude also causes unstable breathing during sleep which results in short periods where the brain stops sending the signal to breath, called central sleep apnea (CSA). During apneas (pauses in breathing) blood oxygen drops even lower and people typically wake up briefly and hyperventilate after apneas. Therefore at altitude people usually get less sleep, their sleep is broken with periods of wakefulness during the night and they experience repeated bouts of severe low blood oxygen levels. Sleep plays a critical role in how the brain repairs and also converts newly acquired information into long-term memory. Therefore broken and reduced sleep can impair cognitive performance, memory and learning. Repeated bouts of severe low oxygen also produces highly reactive molecules that cause damage to cells, called oxidative stress. Oxidative stress also prevents the brain from forming long-term memories and in severe cases (such as extremely high altitude and long duration exposure) can cause neurons in the brain to die. Therefore although sustained low oxygen at altitude likely impairs cognitive function, disturbed sleep and repeated bouts of severely low oxygen likely also contribute to causing brain damage and impaired cognitive performance.

Melatonin is a hormone produced in the pineal gland of the brain during the night which signals to the brain that it is time to sleep. Melatonin is also a very powerful antioxidant which naturally helps to prevent damage in the body from oxidative stress. A study previously reported that melatonin taken 90 mins before bed at 4,300 m (14,200 ft) reduced the time taken to fall asleep, it reduced the number of times people woke up during sleep and improved cognitive performance the following day. However how melatonin caused these effects was not determined. Therefore this study aims to determine how melatonin affects ventilatory control, sleep and neurocognitive performance during sustained hypoxia.

• Study Type: Interventional
• Enrollment (Actual): 39
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • California
    • San Diego, California, United States, 92093
      • University of California, San Diego

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Healthy Males and Females
• Age:18-65 years

Exclusion Criteria:

• Sleep Disorders
• Pregnant Females
• Smokers (quit ≥ 1 year ago acceptable)
• Cardiovascular, Pulmonary, Renal, Neurologic, Neuromuscular, or Hepatic Issues
• Diabetes
• Psychiatric disorder, other than mild depression
• Recent exposure to altitude (>8000ft) in the last month or having slept at an altitude >6000ft in the last month

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: TRIPLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Normoxia; Participants will sleep in room air and receive no melatonin.
Placebo Comparator: Hypoxia and Placebo; 5mg placebo before sleep study	Other: Placebo; 5mg Placebo capsule
Experimental: Hypoxia and Melatonin; 5mg melatonin before sleep study	Other: Melatonin; 5mg Melatonin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Apnea Hypopnea Index	Measure of Sleep Apnea severity	6 weeks
Neurocognitive Scores	Reflex changes between conditions	6 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Loop Gain	Measurement of breathing characteristics during sleep using a flow meter attached to a CPAP mask that allows the measurement of expiratory flow	6 weeks
Arousal Threshold	requirements for sleep arousal to occur	6 weeks
Sleep Efficiency	Time in bed divided by total sleep time	6 weeks
Total Antioxidant Status	Measurement taken from blood draw	6 weeks
Hypoxic Ventilatory Response	Change in breathing response while breathing low oxygen	6 weeks
Hypercapnic Ventilatory Response	Change in breathing response while breathing high carbon dioxide	6 weeks

Collaborators and Investigators

• Sponsor: Robert L. Owens
• Investigators: Principal Investigator: Atul Malhotra, MD, professor; Study Director: Naomi L Deacon, Ph.D., Research Associate; Study Chair: Pamela De Young, Research Associate

Publications and helpful links

Helpful Links

• Study Website

Study record dates

Study Major Dates

• Study Start (Actual): January 10, 2018
• Primary Completion (Actual): December 10, 2018
• Study Completion (Actual): December 10, 2018

Study Registration Dates

• First Submitted: January 3, 2018
• First Submitted That Met QC Criteria: July 13, 2018
• First Posted (Actual): July 17, 2018

Study Record Updates

• Last Update Posted (Actual): August 14, 2019
• Last Update Submitted That Met QC Criteria: August 13, 2019
• Last Verified: August 1, 2019

More Information

Terms related to this study

• Keywords: Melatonin; Hypoxia; Neurocognitive; High Altitude
• Additional Relevant MeSH Terms: Signs and Symptoms, Respiratory; Hypoxia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Protective Agents; Antioxidants; Melatonin
• Other Study ID Numbers: UCSD170200

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No