Aus der Universitätsklinik für Psychiatrie und Psychosomatik der Albert-Ludwigs-Universität Freiburg i.Br. Illicit Recreational Drugs and Sleep A systematic review covering cocaine, ecstasy, LSD and cannabis INAUGURAL - DISSERTATION zur Erlangung des Medizinischen Doktorgrades der Medizinischen Fakultät der Albert-Ludwigs-Universität Freiburg i.Br. Vorgelegt 2007 von Thomas Schierenbeck geboren in Greven II Dekan Prof. Dr. med. Christoph Peters 1. Gutachter Prof. Dr. med. Mathias Berger 2. Gutachter Prof. Dr. med. Dr. rer. nat. Klaus Aktories Jahr der Promotion 2008 III Dedicated to Suzanne Ora Smith * 1955 † 2006 IV Table of Contents Abbreviations.......................................................................................................... VII 1. Introduction............................................................................................................1 1.1. Objectives of this dissertation.......................................................................1 1.2. Background.....................................................................................................2 1.2.1. Cocaine ......................................................................................................2 1.2.1.1. History................................................................................................. 2 1.2.1.2. Chemical structure .............................................................................. 3 1.2.1.3. Pharmacokinetics................................................................................ 3 1.2.1.4. Pharmacodynamics ............................................................................ 3 1.2.2. 3,4-Methylenedioxymethamphetamine (MDMA, “Ecstasy”) and 3,4- Methylenedioxy-N-ethylamphetamine (MDE, “Eve”) ........................................... 5 1.2.2.1. History................................................................................................. 5 1.2.2.2. Chemical structure .............................................................................. 6 1.2.2.3. Pharmacokinetics................................................................................ 6 1.2.2.4. Pharmacodynamics ............................................................................ 6 1.2.3. D-Lysergic acid diethylamide (LSD) ...........................................................7 1.2.3.1. History................................................................................................. 7 1.2.3.2. Chemical structure .............................................................................. 7 1.2.3.3. Pharmacokinetics................................................................................ 8 1.2.3.4. Pharmacodynamics ............................................................................ 8 1.2.4. Cannabis ....................................................................................................9 1.2.4.1. History................................................................................................. 9 1.2.4.2. Chemical structure .............................................................................. 9 1.2.4.3. Pharmacokinetics.............................................................................. 10 1.2.4.4. Pharmacodynamics .......................................................................... 10 2. Materials and Methods........................................................................................13 2.1. Search strategy.............................................................................................13 2.1.1. Electronic databases ................................................................................13 2.1.2. Key words.................................................................................................13 2.2. Study selection and data extraction............................................................13 V 2.3. Statistical methods .......................................................................................14 3. Results..................................................................................................................15 3.1. Identification of studies................................................................................15 3.1.1. Trial flow...................................................................................................15 3.1.2. Quality assessment ..................................................................................17 3.2. Effects of illicit recreational drugs upon sleep ..........................................19 3.2.1. Cocaine ....................................................................................................19 3.2.1.1. Study characteristics......................................................................... 19 3.2.1.2. Preclinical studies ............................................................................. 19 3.2.1.3. PSG studies of cocaine administration and withdrawal..................... 21 3.2.1.4. Meta-analysis of objective sleep measures during acute and subacute cocaine withdrawal......................................................................................... 30 3.2.1.5. Studies measuring subjective effects of cocaine upon sleep ............ 33 3.2.1.6. Sleep effects of prenatal cocaine exposure ...................................... 40 3.2.1.7. Overview over effects of cocaine upon sleep.................................... 44 3.2.2. 3,4-Methylenedioxymethamphetamine (MDMA; “Ecstasy”) and 3,4- Methylenedioxy-N-ethylamphetamine (MDE; “Eve”) ......................................... 45 3.2.2.1. Study characteristics......................................................................... 45 3.2.2.2. Preclinical studies ............................................................................. 46 3.2.2.3. PSG studies of MDMA/MDE intake................................................... 46 3.2.2.4. Studies assessing subjective effects of ecstasy upon sleep ............. 49 3.2.2.5. Overview over sleep effects of ecstasy............................................. 52 3.2.3. D-Lysergic acid diethylamide (LSD) .........................................................53 3.2.3.1. Study characteristics......................................................................... 53 3.2.3.2. Preclinical studies ............................................................................. 53 3.2.3.3. PSG studies of LSD ingestion........................................................... 57 3.2.3.4. Overview over effects of LSD upon sleep ......................................... 60 3.2.4. Cannabis ..................................................................................................60 3.2.4.1. Study characteristics......................................................................... 60 3.2.4.2. Preclinical studies ............................................................................. 61 3.2.4.3. Studies measuring objective sleep effects of cannabis in humans ... 67 3.2.4.4. Studies assessing subjective sleep effects of cannabis.................... 77 3.2.4.5. Effects of gestational cannabis exposure upon sleep ....................... 87 VI 3.2.4.6. Overview over sleep effects of cannabis........................................... 89 3.3. Effects of sleep disturbances upon vulnerability to substance use ........90 3.3.1. Study characteristics ................................................................................90 3.3.2. Impact of sleep disturbances upon vulnerability to subsequent onset of drug abuse ........................................................................................................ 91 3.3.3. Predictive value of sleep disturbances for relapse ...................................97 4. Discussion ...........................................................................................................99 4.1. Principal findings and their implications ....................................................99 4.1.1. Impact of illicit recreational drugs upon sleep...........................................99 4.1.1.1. Cocaine............................................................................................. 99 4.1.1.2. MDMA and MDE ............................................................................. 103 4.1.1.3. LSD................................................................................................. 104 4.1.1.4. Cannabis......................................................................................... 105 4.1.2. Effects of sleep disturbances upon propensity for drug abuse ...............107 4.2. Limitations of this review ...........................................................................109 5. Summary ............................................................................................................112 6. Zusammenfassung............................................................................................113 7. References .........................................................................................................114 VII Abbreviations CBD cannabidiol d day DB double-blind DSM-IV Diagnostic and Statistical Manual of Mental Disorders, fourth edition EA early abstinence EEG electroencephalogram EMG electromyogram EOG electrooculogram h hour HIV human immunodeficiency virus i.v. intravenous (route of administration) LA late abstinence LSD lysergic acid diethylamide MDE methylenedioxyethamphetamine MDEA =MDE (methylenedioxyethamphetamine) MDMA methylenedioxymethamphetamine