Cover Page
The handle
http://hdl.handle.net/1887/68643
holds various files of this Leiden University
dissertation.
Author: Pardi, D.J.
Title: Exploring the relationships of gamma-hydroxybutyrate and sleep on metabolism,
physiology, and behavior in humans
Exploring the Relationships of
gamma-Hydroxybutyrate and
Sleep on Metabolism,
Physiology, and Behavior in
Humans
ISBN: 978-0-578-44458-1 Layout: Daniel John Pardi Cover Design: Daniel John Pardi
Printed By: Ram Print & Communications Cover Painting: “The Great Escape”, Eric Zener, 2010. Cover Icons: Vignesh Raja.
© 2019 Daniel John Pardi
Copyright of the individual chapters lies with the publisher of the journal listed at the beginning of each respective chapter. No part of this thesis may be
reproduced in any form, by print, photocopy, digital file, internet, or any other means without written permission from the author.
Exploring the Relationships of
gamma-Hydroxybutyrate and
Sleep on Metabolism,
Physiology, and Behavior in
Humans
Proefschrift
ter verkrijging van de graad van Doctor aan de Universiteit Leiden,
op gezag van Rector Magnificus prof.mr. C.J.J.M. Stolker,
volgens besluit van het College voor Promoties
te verdedigen op donderdag 24 januari 2019
klokke 16:15 uur
door
Daniel John Pardi, MS
Promotor
Prof. dr. H. Pijl
Co-promoter
Dr. G.J. Lammers
Leden Promotiecommissie
Prof. dr. N.R. Biermasz, Leiden University
Prof. dr. P.C.N. Rensen, Leiden University
Prof. dr. S. Overeem
If you don’t have time to do it right,
when will you have time to do it over?
John Wooden
1910 – 2010
I have no special talents, I am only
passionately curious.
Albert Einstein
1879 – 1955
The method of science is the method of
bold conjectures and ingenious and severe attempts to refute
them.
Karl Popper
1902 - 1994
CONTENTS
CHAPTER 1 12
-THESIS INTRODUCTION AND AIMS
12
-1.1 THESIS INTRODUCTION -13
-1.2
ABSTRACT FOR PART I-NEUROBIOLOGICAL AND CLINICAL EFFECTS OF
…SODIUM OXYBATE -13
-1.3 ABSTRACT FOR PART II-SLEEP,EATING, AND ENERGY REGULATION -15
-1.4 AIMS -17
-CHAPTER 2 23
-INTRODUCTION TO GAMMA-HYDROXYBUTYRATE (GHB) / SODIUM OXYBATE (SXB): NEUROBIOLOGY AND CLINICAL EFFECTS 23 -1. INTRODUCTION TO GHB / SXB 26
-1.1 BACKGROUND -26
-1.2 ABUSE LIABILITY -27
-2. BIOLOGY AND PHARMACOLOGY OF GHB / SXB 29
-2.1 DISTRIBUTION -29
-2.2 SYNTHESIS -30
-2.3 METABOLISM -31
-2.4 GHB AS A NEUROTRANSMITTER -32
-2.5 GHBBINDING SITE(S) IN THE BRAIN -32
-2.5.1 Stimulation of GHB Binding Site(s) 32
-2.5.2 Stimulation of GABAB Receptors by GHB 33
-2.6 INTRACELLULAR RESPONSE TO GHB -33
-2.7 EFFECTS ON NEUROTRANSMITTER SYSTEMS -34
-2.7.1 Dopaminergic System 34 -2.7.2 Serotonergic System 35 -2.7.3 Opioidergic System 35 -2.7.4 Cholinergic System 36 -2.7.5 Noradrenergic System 36 -2.7.6 Glutamatergic System 37
-3. HORMONAL AND METABOLIC EFFECTS OF GHB / SXB 37
-3.1 HORMONAL EFFECTS OF GHB/SXB -37
-3.1.1 Growth Hormone 37
-3.1.3 Prolactin 39 -3.1.4 Melatonin 40 -3.1.5 Ghrelin 40 -3.2 METABOLIC EFFECTS OF GHB/SXB -41 -3.2.1 Insulin Sensitivity 41 -3.2.2 Thermoregulation 42
-3.2.3 Weight and Energy Balance 43
-4. CLINICAL EFFECTS OF GHB / SXB 47
-4.1 HEALTHY SUBJECTS -48
-4.1.1 Sleep 48
-4.1.2 Mood, Prosocial, and Prosexual Effects 48
-4.2 CLINICAL POPULATIONS -49 -4.2.1 Insomnia 49 -4.2.2 Fibromyalgia 50 -4.2.3 Parkinson’s Disease 52 -4.2.4 Alzheimer’s Disease 52 -4.2.5 Narcolepsy 55 -5. CONCLUSIONS 61 -5.1 NEUROBIOLOGY -61 -5.2 CLINICAL EFFECTS -62 -CHAPTER 3 63
-SODIUM OXYBATE FOR EXCESSIVE DAYTIME SLEEPINESS IN PARKINSON DISEASE - AN OPEN-LABEL POLYSOMNOGRAPHIC STUDY
63 -ABSTRACT -64 -INTRODUCTION -65 -METHODS -65 -RESULTS -67 -COMMENT -69 -CHAPTER 4 73
-THE NIGHTLY ADMINISTRATION OF SODIUM OXYBATE RESULTS IN SIGNIFICANT REDUCTION IN THE NOCTURNAL SLEEP DISRUPTION OF PATIENTS WITH
NARCOLEPSY 73
-ABSTRACT -74
-METHODS -75
-RESULTS -79
-DISCUSSION -84
-CONCLUSION -85
-CHAPTER 5 91
-ILLICIT GAMMA-HYDROXYBUTYRATE (GHB) AND PHARMACEUTICAL SODIUM OXYBATE (SXB; XYREM®): DIFFERENCES IN CHARACTERISTICS AND MISUSE. - 91 -
ABSTRACT -92
-INTRODUCTION -93
-1. CHARACTERISTICS OF ILLICIT GHB COMPARED TO THOSE OF SXB -94
-2. SUBSTANCE ABUSE,SUBSTANCE DEPENDENCE, AND MISUSE WITH ILLICIT GHB
………COMPARED TO SXB -100
-3. DISCUSSION AND CONCLUSIONS -108
-CHAPTER 6 120
-THE NIGHTLY USE OF SODIUM OXYBATE IS ASSOCIATED WITH A REDUCTION IN NOCTURNAL SLEEP DISRUPTION: A DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY IN PATIENTS WITH NARCOLEPSY 120
-INTRODUCTION -122
-RESULTS -127
-DISCUSSION -130
-CONCLUSION -133
-CHAPTER 7 137
-PLASMA TOTAL GHRELIN AND LEPTIN LEVELS IN HUMAN NARCOLEPSY AND MATCHED HEALTHY CONTROLS: BASAL CONCENTRATIONS AND RESPONSE TO SODIUM OXYBATE 137
-MATERIALS AND METHODS -140
-RESULTS -142
-DISCUSSION -148
-REFERENCES -150
-CHAPTER 8 155
-INTRODUCTION TO SLEEP, EATING, AND METABOLISM - 155 - 1. SLEEP AND WEIGHT - 157 -
-1.2 OBESITY IS A MAJOR PUBLIC HEALTH CONCERN -157 -1.3 OBESITY IS MULTIFACTORIAL AND RELATED TO SLEEP -157
-1.4 SLEEP TIMES ARE REDUCED -158
-2. SLEEP TIMES IMPACT BODY WEIGHT 158
-2.1 REDUCED SLEEP,WEIGHT, AND ENERGY REGULATIONS -158
-2.1.1 Epidemiological Evidence 158
-2.1.2 Actigraphy and PSG Evidence 159
-2.2 SLEEP ELONGATION,WEIGHT, AND ENERGY REGULATION -160
-3. POTENTIAL CAUSES OF WEIGHT GAIN WITH SLEEP DISTURBANCE 161
-3.1 METABOLIC,ENDOCRINE,IMMUNE, AND AUTONOMIC RELATIONSHIPS -161
-3.1.1 Glucose Metabolism 161
-3.1.2 Fatty Acid Metabolism 163
-3.1.3 Hormones 163
-3.1.4 Endocannabinoids 165
-3.1.5 Immune system 166
-3.1.6 Energy Expenditure and Temperature 166
-3.2 CHRONOBIOLOGY -167
-3.2.1 Circadian Introduction 167
-3.2.2 Circadian Metabolism 167
-3.3 ALTERED ENERGY INTAKE AND EXPENDITURE -168
-3.3.1 Energy Intake 168
-3.3.2 Energy Expenditure 169
-3.3.3 Altered Energy Regulation Under Calorie Restriction 170
-4. SLEEP, BRAIN PROCESSING, AND ENERGY REGULATION 170
-4.1 AROUSAL,ATTENTION,COGNITION,AFFECTIVE PROCESSING, AND SLEEP
-170
-4.1.1 Vigilance Regulation 170
-4.1.2 Compensatory Sleep 171
-4.1.3 Executive Functioning 172
-4.2 SLEEP DISTURBANCE,BRAIN PROCESSING, AND ENERGY REGULATION
-175 -4.2.1 Altered Inhibitory Control and Energy Regulation 175
-4.2.2 Altered Memory and Energy Regulation 176
-4.2.3 Altered Mood and Energy Regulation 176
-CHAPTER 9 178 -EATING DECISIONS BASED ON ALERTNESS LEVELS AFTER A SINGLE NIGHT OF SLEEP MANIPULATION: A RANDOMIZED CLINICAL TRIAL - 178 -
ABSTRACT -179
-INTRODUCTION -180
-RESULTS -186
-DISCUSSION -189
-CHAPTER 10 197
-BACK TO THE FUTURE. METABOLIC EFFECTS OF A 4-DAY OUTDOOR TRIP UNDER SIMULATED PALEOLITHIC CONDITIONS – NEW INSIGHTS FROM THE EIFEL STUDY 197 -BACKGROUND -199 -METHODS -199 -RESULTS -203 -DISCUSSION -211 -CONCLUSION -215 -CHAPTER 11 222
-SUMMARY, CONCLUSIONS & FUTURE PERSPECTIVES - 222 -
SUMMARY AND CONCLUSIONS -223
-FUTURE PERSPECTIVES -233
-REFERENCES 236
-APPENDICES 274
-ACKNOWLEDGEMENTS -274
