Characterization of the Prosocial and Prosexual Effects of GHB

Multimodal Characterization of the Prosocial and Prosexual Effects of GHB Assessing Behavior, fMRI, EEG, and Neuroendocrine Mechanisms

The purpose of this study is to determine whether gamma-Hydroxybutyrate (GHB) has prosocial and prosexual effects in healthy male participants, and to characterize these putative effects via behavioral tests, functional magnetic resonance imaging (fMRI), electroencephalography (EEG), and neuroendocrine parameters. The investigators predict that GHB in fact has prosocial and prosexual effects which can be neurobiologically characterized using the assessed methods. Such effects would be of high interest for the treatment of mental disorders which involve impairments of social interaction and sexual function such as major depression or autism.

Introduction Gammahydroxybutyrate (GHB) is an endogenous short-chain fatty acid and discussed as a neurotransmitter (Bessman and Fishbein, 1963) with high affinity to specific GHB (Benavides et al., 1982; Snead, 2000) and α4βδ-gamma-Aminobutyric acid (GABA)A receptors (Absalom et al., 2012) that also binds with lower affinity to GABAB receptors (Engberg and Nissbrandt, 1993). It is internationally used as standard treatment for narcolepsy with cataplexy (Alshaikh et al., 2012), and in some European countries for alcohol withdrawal and craving (Keating, 2014). Additionally, recent randomized controlled studies showed therapeutic effects in fibromyalgia (Spaeth et al., 2013). Anecdotal reports from GHB abusers indicate mood enhancing, prosocial and prosexual effects of the drug (Sumnall et al., 2008), which were not objectively assessed so far. Impaired social decision making is a behavioral finding in depression (Pulcu et al., 2014), that is related to social withdrawal symptoms. Moreover, sexual dysfunction is both a symptom of depression and an adverse effect of most antidepressant medications (Kennedy and Rizvi, 2009), with a deteriorating impact on quality of life measures. Due to its unique pharmacologic effects on sleep, daytime vigilance, pain, and social interaction, GHB was recently proposed as experimental therapeutic for the treatment of depression (Bosch et al., 2012). Study Aims A) Investigating the putative prosocial effects of GHB in humans B) Investigating the putative prosexual effects of GHB in humans C) Investigating the neuroendocrine mechanisms of putative prosocial and prosexual effects of GHB in humans D) Investigating electrophysiological effects of GHB in decision-making in humans E) Investigating the functional neurobiology of GHB and its putative prosexual effects in humans Study Design A) The effects of GHB on social cognition, sexual arousal, neuroendocrine parameters, and EEG measures in healthy subjects: GHB (20 mg/kg p.o.) was tested in 16 healthy males, using a randomized, placebo-controlled, cross-over design. Subjective effects on mood were assessed by visual analogue scales (VAS) and the GHB Specific Questionnaire (GSQ). Prosocial behavior was examined by the Charity Donation Task, the Social Value Orientation test, and the Reciprocity Task. We assessed reaction time and motor performance using the Delayed Matching to Sample and the Reaction Time tasks from the Cambridge Neuropsychological Test Automated Battery (CANTAB). We assessed social cognition using the Multifaceted Empathy Task (MET) and the Movie for the Assessment of Social Cognition (MASC). We assessed memory using a German version of the Rey Auditory Verbal Learing Task. Sexual arousal was assessed using the Sexual Arousal and Desire Inventory (SADI), sexual perception was assessed using a self-designed Sexual Arousal Task (SAT). Furthermore, the investigators assessed GHB effects on brain electrophysiological activity using electroencephalography (EEG) and a flanker task for the assessment of error-related negativity. Blood plasma levels of GHB, oxytocin, testosterone, progesterone, dehydroepiandrosterone (DHEA), cortisol, aldosterone, and adrenocorticotropic hormone (ACTH) were determined. B) The effects of GHB on neuronal networks and sexual arousal in healthy subjects - an fMRI study: The investigators performed a characterization of the putative prosexual effects of GHB (35 mg/kg vs. placebo p.o.) in 19 healthy participants. Questionnaires (VAS, SADI, GSQ) were used to assess subjective aspects. Brain reactivity towards erotic vs. neutral pictures of persons, as well as resting state connectivity and arterial spin labelling (ASL) was investigated with functional magnetic resonance imaging (fMRI).

Changes in sexual arousal after GHB challenge compared to placebo (Sexual Arousal and Desire Inventory [SADI], Sexual Arousal Task [SAT], brain reactivity towards erotic vs. neutral pictures ([fMRI-Task])

Changes in social cognition and behavior after GHB challenge compared to placebo (Charity Donation Task, Social Value Orientation test, Reciprocity Task, Multifaceted Empathy Task [MET], Movie for the Assessment of Social Cognition [MASC])

Testosterone, DHEA, cortisol, aldosterone, ACTH, progesterone, oxytocin plasma levels after GHB challenge compared to placebo

Brain activity in fMRI after GHB challenge compared to placebo (Picture-Task, Resting State Connectivity, ASL)

Inclusion Criteria: Healthy male subjects. Exclusion Criteria: Any Axis-I DSM-IV psychiatric disorder, any form of addiction or regular illegal drug use (lifetime use >5 occasions) with exception of occasional cannabis use, a lifetime history of GHB use, a neurological disorder or head injury, clinically relevant medical diseases, a family history of schizophrenia or bipolar disorder, and any use of prescription drugs.

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