Alcohol Intoxication Clinical Trial
Official title:
Neurosteroids and Acute Alcohol Intoxication in Humans
1. The major aims are to assess: (1) the relationship of basal and alcohol-induced
neurosteroid and GABA levels to the degree of acute alcohol intoxication in healthy male and
female volunteers; and (2) the effect of acute pregnenolone administration on the degree of
acute alcohol intoxication in these same volunteers. Specific hypotheses are:
- Baseline serum levels of pregnenolone, pregnenolone sulfate (PS),
dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEA-S) will be inversely correlated
with the magnitude of acute behavioral responses to alcohol (sedation, anxiolysis,
amnesia, psychomotor impairment and intoxication). That is, higher baseline levels of
these neurosteroids will be associated with lessened behavioral responses to alcohol.
- Baseline serum levels of allopregnanolone, tetrahydrodeoxycorticosterone (THDOC),
androstanediol, androsterone and GABA will be directly correlated with the magnitude of
acute behavioral responses to alcohol. That is, higher baseline levels of these
substances will be associated with heightened behavioral responses to alcohol.
- Acute alcohol ingestion, compared to placebo ingestion, will increase serum levels of
allopregnanolone and THDOC and plasma levels of GABA and will decrease plasma levels of
PS. (Effects on levels of other neurosteroids are not specifically predicted based on
animal data but will be examined in an exploratory manner.)
- Acute alcohol-induced increases in serum levels of allopregnanolone and THDOC and in
plasma levels of GABA will be directly correlated with the magnitude of acute
behavioral responses to alcohol. Acute alcohol-induced decreases in serum levels of PS
will be directly correlated with the magnitude of acute behavioral responses to
alcohol. Correlations between alcohol-induced changes in other neurosteroids and
changes in behavior are not specifically predicted but will be examined in an
exploratory manner.
- Pregnenolone, compared to placebo, pre-treatment will antagonize the acute effects of
alcohol on the behavioral measures.
2. BACKGROUND Neurosteroid Responses to Alcohol Administration: Alcohol likely interacts
with the brain GABA-A receptor complex via two distinct manners: a direct effect (Grobin et
al 1998), and an indirect effect, which is secondary to alterations in levels of endogenous
GABA-A receptor-active neurosteroids or in levels of GABA itself (Morrow et al 1999).
Indeed, alcohol's effects on neurosteroid and GABA levels may represent a novel and
important mechanism of alcohol's actions (Morrow et al 1999). Acute alcohol administration
significantly increases cerebral cortex (700%) and circulating (600%) levels of
allopregnanolone, a potent GABA-A receptor agonist neurosteroid, in male rats (Morrow et al
1999). The magnitude of the observed alcohol-induced increase in allopregnanolone levels is
sufficient to enhance GABA'ergic neurotransmission and to exert anxiolytic, sedative and
anticonvulsant effects. Indeed, alcohol-induced increases in cerebral cortex
allopregnanolone levels are significantly correlated with alcohol's hypnotic effects in rats
(VanDoren et al 2000), and the time course of alcohol-induced increases in cerebral cortex
allopregnanolone levels correlates well with many of alcohol's behavioral effects (VanDoren
et al 2000); (Morrow et al 1999). Alcohol's effects on other neurosteroids have been poorly
studied, although preliminary data suggest that alcohol dramatically lowers brain levels of
PS (a GABA-A receptor antagonist neurosteroid) (Corpechot et al 1983) and increases brain
levels of THDOC (a GABA-A receptor agonist neurosteroid) (Barbaccia et al 1999) in rats. In
the latter study, THDOC and allopregnanolone levels were increased to a significantly
greater extent in alcohol-preferring, compared to non-preferring rats, supporting a role of
these neurosteroids in modulating alcohol's reinforcing effects (Barbaccia et al 1999) and
in determining individual susceptibility to alcoholism. Regarding levels of GABA itself,
acute alcohol administration raises total brain GABA levels in rats (Kulonen 1983) and
raises plasma GABA levels in normal humans (Bannister et al 1988) (however, see: (Moss et al
1990)), although the acute behavioral correlates of these changes have not been
well-characterized. Also, interactions between GABA changes and changes in neurosteroid
levels have been poorly characterized. These data suggest that alcohol-induced changes in
allopregnanolone (and perhaps PS, THDOC, other neurosteroids and GABA) levels are important
contributors to alcohol's behavioral actions in rodents. Surprisingly, to our knowledge, no
studies have yet assessed the effects of acute alcohol administration on neurosteroids in
humans and the relationship of these biochemical effects to alcohol's behavioural effects,
and few have assessed alcohol's effects on GABA levels.
Pharmacological Manipulation of Neurosteroid Levels Alters the Behavioral and Biological
Effects of Alcohol and Other Sedative-Hypnotics: Pregnenolone and PS block the "anxiolytic"
effect of alcohol in mice (Melchior and Ritzmann 1994), and these steroids, as well as DHEA
and DHEA-S (which are GABA-A receptor antagonist/ inverse agonist neurosteroids), block the
memory-impairing effect of alcohol in mice (Melchior and Ritzmann 1996). PS pre-treatment
also significantly attenuates alcohol-induced sedation, hypnosis and incoordination in rats,
whereas these alcohol effects are potentiated by pre-treatment with allopregnanolone
(Czlonkowska et al 2000). In rats, PS also blocks sedation/hypnosis induced by barbiturates
(Majewska et al 1989) and benzodiazepine-induced long-term electrophysiological depression
(Akhondzadeh and Stone 1998). Pre-treatment of male rats with allopregnanolone also
increases the reinforcing effects of alcohol (Janak et al 1998). This is understandable,
since GABA-A receptor agonists typically facilitate voluntary ethanol consumption in
animals, and since GABA-A receptor inverse agonists typically curtail ethanol consumption
(reviewed in: (Grobin et al 1998)). These findings are consistent with a GABA-A receptor
agonist effect of allopregnanolone and with an antagonist effect of pregnenolone, PS, DHEA
and DHEA-S. In addition to direct antagonist effects, PS influences GABA-A receptor affinity
and number in a manner opposite to that seen with alcohol (Majewska 1988). No studies in
humans, to our knowledge, have followed up on these findings in animals by examining the
effects of pharmacological neurosteroid manipulation on behavioral responses to acute
alcohol ingestion. However, we have previously found that pregnenolone pre-treatment
significantly antagonizes certain acute effects of benzodiazepines (which also act directly
at the GABA-A receptor complex) in healthy humans (Meieran et al in review, 2002). In that
study, we found that pregnenolone significantly attenuated diazepam's sedative effects
(Meieran et al in review, 2002), consistent with pregnenolone's role as a GABA-A receptor
antagonist/ inverse agonist.
;
Allocation: Randomized, Endpoint Classification: Pharmacodynamics Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Basic Science
Status | Clinical Trial | Phase | |
---|---|---|---|
Terminated |
NCT04192448 -
Men, Mood, and Attention Study: Examination of Alcohol, State Anger, and Emotion Regulation Sexual Aggression
|
N/A | |
Completed |
NCT04230460 -
Cannabis Impairment Detection Application (CIDA)
|
N/A | |
Completed |
NCT00515294 -
Acute and Residual Effects of Caffeinated Beer
|
Phase 2 | |
Recruiting |
NCT05779774 -
WayToServePlus: Improving Responsible Alcohol Service Ph II
|
N/A | |
Completed |
NCT03449095 -
Understanding Alcohol Reward in Social Context
|
N/A | |
Completed |
NCT02861807 -
Mindfulness-Based Intervention and Transcranial Direct Current Brain Stimulation to Reduce Heavy Drinking
|
N/A | |
Completed |
NCT01783223 -
Prevalence of Chronic Inebriates to the Emergency Department and Suitability for Sobering House Services
|
||
Completed |
NCT01688245 -
A Text Message Behavioral Intervention to Reduce Alcohol Consumption in Young Adults
|
N/A | |
Completed |
NCT05028413 -
Evaluating Perceived Fitness to Drive While Intoxicated
|
N/A | |
Not yet recruiting |
NCT06419647 -
Tracking Mood: The Effects of Daily Mood Tracking VAS on Alcohol Consumption in Adult Heavy Drinkers
|
N/A | |
Recruiting |
NCT05701865 -
Biphasic Effects of Acute Alcohol Intoxication on Bystander Intervention
|
N/A | |
Recruiting |
NCT05757089 -
Efficacy of the Dietary Food Supplement ALCOFILTRUM in Alleviating Alcohol Hangover Symptoms
|
N/A | |
Recruiting |
NCT04912492 -
Promoting Prosocial Bystander Behavior in Intoxicated Men: Evaluation of RealConsent2.0
|
N/A | |
Active, not recruiting |
NCT04564599 -
The Rise of Ride Sharing Companies and Trends in Impaired Driving Accidents
|
||
Not yet recruiting |
NCT04229732 -
Trials of Ventilation Assisted Substance Elimination Via the Lung - Ethanol (VASEL - Ethanol)
|
N/A | |
Recruiting |
NCT06065657 -
Effect of Nutritional Ketosis on Alcohol Metabolism
|
Phase 2/Phase 3 | |
Recruiting |
NCT03242161 -
Development of LabPatch-alcohol as a Noninvasive Skin Patch to Detect Blood Alcohol Concentrations
|
Early Phase 1 | |
Recruiting |
NCT04931095 -
The Impact of Oral Cannabis Administration and Co-Administration of Alcohol on Impairment
|
Phase 1 | |
Active, not recruiting |
NCT03467191 -
Behavioral Alcohol Responses (BAR) Study
|
Early Phase 1 | |
Recruiting |
NCT06264791 -
Stress-motivated Alcohol Use as a Value-based Decision-making Process
|
N/A |