Pregnenolone for Chronic Traumatic Brain Injury
Recruiting in Palo Alto (17 mi)
+1 other location
Age: 18+
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Christine Marx, MD
Prior Safety Data
Trial Summary
What is the purpose of this trial?This trial is testing whether pregnenolone can help improve mental and physical health in veterans with long-term brain injuries. Participants will take pregnenolone daily for a period of time. The study aims to see if pregnenolone is effective in improving health outcomes and to find the best safe dose.
Will I have to stop taking my current medications?
The trial does not require you to stop taking your current medications if they are for stable and well-controlled conditions, like hypertension. However, you cannot change psychiatric or pain medications during the study or in the two weeks before joining. Some medications, like prednisone, are not allowed as they could affect the study results.
What evidence supports the effectiveness of pregnenolone as a drug for chronic traumatic brain injury?
Pregnenolone has shown potential in reducing sedation effects when used with diazepam, a medication affecting the brain, and has been studied for its role in modulating alcohol intake in animal models. However, its direct effectiveness for chronic traumatic brain injury is not clearly established in the provided research.
12345Is pregnenolone generally safe for humans?
Pregnenolone has been generally well-tolerated in studies with humans, showing no significant negative effects on mood, memory, sleep quality, or well-being. It appeared safe and well-tolerated in patients with mood and substance-use disorders, although it may increase certain risks in specific conditions, such as facilitating neuronal damage in animal models exposed to hypoxia.
24567How is the drug pregnenolone unique for treating chronic traumatic brain injury?
Pregnenolone is unique because it is a neurosteroid that can modulate brain receptors like GABA(A), potentially affecting mood and cognition, which might be beneficial for brain injury recovery. Unlike other treatments, it has been studied for its effects on mood and cognitive functions in various conditions, suggesting it might offer novel benefits for brain injury patients.
24567Eligibility Criteria
This trial is for OEF/OIF/OND-era U.S. Military Veterans aged 21-65 with a history of mild TBI since 2001, who can read English and consent to the study. They must not plan to change psychiatric or pain meds during the study, have no recent psychotropic interventions, and if female and able to become pregnant, must use birth control.Participant Groups
The trial tests whether pregnenolone improves psychological health, physical function, cognition, PTSD symptoms, and pain in veterans with chronic TBI compared to a placebo over eight weeks. It also examines biological effects of pregnenolone and its optimal safe dose.
2Treatment groups
Active Control
Placebo Group
Group I: PregnenoloneActive Control1 Intervention
Group II: PlaceboPlacebo Group1 Intervention
Find A Clinic Near You
Research locations nearbySelect from list below to view details:
Durham VA Health Care SystemDurham, NC
Duke University School of MedicineDurham, NC
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Who is running the clinical trial?
Christine Marx, MDLead Sponsor
References
Pregnenolone and ganaxolone reduce operant ethanol self-administration in alcohol-preferring p rats. [2021]Neuroactive steroids modulate ethanol intake in several self-administration models with variable effects. The purpose of this work was to examine the effects of the long-acting synthetic GABAergic neurosteroid ganaxolone and the endogenous neurosteroid pregnenolone, a precursor of all GABAergic neuroactive steroids, on the maintenance of ethanol self-administration in an animal model of elevated drinking-the alcohol-preferring (P) rats.
Chronic pregnenolone effects in normal humans: attenuation of benzodiazepine-induced sedation. [2019]Pregnenolone is the major steroid precursor in humans. It is also a "neurosteroid" and possesses intrinsic behavioral and brain effects in animals, affecting the GABA(A) and other receptors. In two preliminary studies, we sought to characterize its tolerability and psychotropic effects in humans. In Study 1, 17 normal volunteers received pregnenolone and placebo for 4 weeks each (15 mg PO per day x2 weeks followed by 30 mg PO per day x2 weeks, vs. placebo x4 weeks) in a within-subject, double-blind, cross-over design, with a 4 week drug-free washout period separating the two arms. Subjects' behavioral responses were assessed at the beginning and end of the 4-week pregnenolone arm and the 4-week placebo arm. Pregnenolone was generally well-tolerated but, by itself, had no significant effects on mood, memory, self-rated sleep quality or subjective well-being. In Study 2, 11 subjects from Study 1 received a single dose of diazepam (0.2 mg/kg PO) immediately following completion of Study 1 in order to assess, in a between groups design, the impact of 4-weeks' pre-treatment with pregnenolone (N=5) vs. placebo (N=6) on the acute sedative, amnestic and anxiolytic effects of this benzodiazepine. Pregnenolone-pretreated subjects showed significantly less sedation following diazepam (p
Effects of cytochrome P450 inhibitors and of steroid hormones on the formation of 7-hydroxylated metabolites of pregnenolone in mouse brain microsomes. [2019]Hydroxylations of pregnenolone (PREG) at the 7 alpha- and 7 beta-positions have been reported in numerous murine tissues and organs and responsible cytochrome P450 (CYP) species await identification. Using thin layer chromatography and gas chromatography-mass spectrometry, we report identification of 7 alpha-hydroxy-PREG and 7 beta-hydroxy-PREG metabolites produced in mouse brain microsome digests and kinetic studies of their production with apparent KM values of 0.5 +/- 0.1 microM and 5.1 +/- 0.6 microM for 7 alpha- and 7 beta-hydroxylation respectively. Investigation of CYP inhibitors and of steroid hormone effects on both 7 alpha- and 7 beta-hydroxylations of PREG showed that: (i) different CYP were involved in 7 alpha- and 7 beta-hydroxylation of PREG because solely 7 alpha-hydroxylation was extensively inhibited by metyrapone, alpha-naphthoflavone, ketoconazole and 3 beta-hydroxysteroids, (ii) CYP 1A2, 2D6, 2B1 and 2B11 were not responsible for 7 alpha- and 7 beta-hydroxylation of PREG because respective specific inhibitors furafylline, quinidine and chloramphenicol triggered no inhibition, (iii) CYP 1A1 was responsible for only part of the 7 beta-hydroxylation of PREG because use of alpha-naphthoflavone, which inhibits specifically CYP 1A1, did not suppress entirely 7 beta-hydroxylation, while ketoconazole, metyrapone and antipyrine, which do not inhibit CYP 1A1, decreased part of the 7 beta-hydroxylation, (iv) 7 alpha-hydroxylation of PREG may be shared with other 3 beta-hydroxysteroids such as isoandrosterone and 5-androstene-3 beta,17 beta-diol which were strong inhibitors, but not with dehydroepiandrosterone which was a non-competitive inhibitor as weak as 3-oxosteroids, and (v) 7 beta-hydroxylation of PREG was not markedly changed by other steroids. Taken together, these findings will be of use for identification of the CYP species responsible for 7 alpha- and 7 beta-hydroxylation of PREG and for studies of their activities in brain.
Assessment of pregnenolone effects on alcohol intake and preference in male alcohol preferring (P) rats. [2014]Neuroactive steroids can modulate a variety of neurobehavioral functions via the GABAergic system. This study was conducted to determine the importance of the neurosteroid pregnenolone on the regulation of alcohol intake. The effects of acute and chronic administration of pregnenolone on alcohol intake were assessed in alcohol preferring (P) rats. The rats were injected i.p. with the vehicle or pregnenolone (25, 50 or 75 mg/kg) and their alcohol and water intake were recorded at 2, 4, 6 and 24 h. Also, the chronic effects of 50 mg/kg (i.p.) pregnenolone on alcohol intake were determined. Our results show that although the main effect of i.p. injection of pregnenolone in reducing alcohol intake was not quite significant compared with the vehicle, pregnenolone at 75 mg/kg significantly (P
Differential effect of dehydroepiandrosterone and its steroid precursor pregnenolone against the behavioural deficits in CO-exposed mice. [2019]The neuroactive steroids pregnenolone (3beta-hydroxy-5-pregnen-20-one) and dehydroepiandrosterone (DHEA, 3alpha-hydroxy-5-androstene-17-one) are negative allosteric modulators of the GABA(A) receptors and positive modulators of acetylcholine, NMDA and sigma(1) receptors. Pregnenolone was recently shown to potentiate the neuronal damage induced by excessive glutamate in cell culture models, whereas dehydroepiandrosterone was reported to present some neuroprotective activity. The in vivo relevance of these effects was investigated in mice submitted to an hypoxic insult, the repeated exposure to carbon monoxide (CO) gas, a model that leads to neurodegeneration in the CA(1) hippocampal area and learning deficits. Recording spontaneous alternation behaviour in the Y-maze assessed short-term memory and long-term memory was examined using a passive avoidance task. After exposure to CO, mice showed a progressive deterioration of their learning ability, reaching significance after 3 days and being maximal after 7 days. Pregnenolone administered before CO significantly facilitated the hypoxia-related deficits, which could be measured 1 day after CO and appeared maximal after 3 days. Dizocilpine blocked the deficits in vehicle- and pregnenolone-treated CO-exposed animals, showing that pregnenolone selectively facilitated the NMDA receptor-dependent excitotoxicity. Dehydroepiandrosterone blocked the appearance of the CO-induced deficits, even after 7 days. Interestingly, the sigma(1) receptor antagonist N, N-dipropyl-2-(4-methoxy-3-(2-phenylethoxy)phenyl)ethylamine (NE-100) failed to affect the dehydroepiandrosterone-induced protection, showing the lack of involvement of sigma(1) receptors. Cresyl violet-stained sections of the mouse hippocampal formation showed that the neurodegeneration observed in the CA(1) area after exposure to CO was augmented by pregnenolone and blocked by dehydroepiandrosterone. These results show that pregnenolone and dehydroepiandrosterone, although being similarly involved in modulating the excitatory/inhibitory balance in the brain, do not equally affect the extent of excitotoxic insults.
Pregnenolone for cognition and mood in dual diagnosis patients. [2013]Mood and substance-use disorders are both associated with cognitive deficits. Patients with mood and substance-use disorders have poorer cognition than patients with only a mood disorder. Pregnenolone may have beneficial effects on mood and cognition. In a proof-of-concept investigation, 70 participants with bipolar disorder or recurrent major depressive disorder and history of substance abuse/dependence (abstinent for > or =14days prior to enrollment) were randomly assigned to receive pregnenolone (titrated to 100mg/day) or placebo for 8weeks. Participants were assessed using the Mini International Neuropsychiatric Interview, Hamilton Rating Scale for Depression (HRSD), Young Mania Rating Scale (YMRS), Rey Auditory Verbal Learning Test (RAVLT), Trail Making Test (TMT-B), and Stroop Test. Mood was assessed bi-weekly, while cognition was evaluated at baseline, and weeks 4 and 8. Groups were compared using a random regression analysis that used all of the available data. The pregnenolone group showed trends toward greater improvement, relative to placebo, on the HRSD and YMRS. A post hoc analysis of completers found a statistically significant reduction in HRSD scores with pregnenolone as compared to placebo. Pregnenolone appeared to be safe and well tolerated. Findings suggest that pregnenolone use may be associated with some improvement in manic and depressive symptoms, but not cognition in depressed patients with a history of substance use. Larger trials examining the impact of pregnenolone on mood in more narrowly defined populations may be warranted.
Does Pregnenolone Adjunct to Risperidone Ameliorate Irritable Behavior in Adolescents With Autism Spectrum Disorder: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial? [2023]Pregnenolone is a neurosteroid with modulatory effects on γ-aminobutyric acid neurotransmission. Here, we aimed to evaluate the effectiveness and safety of pregnenolone add-on to risperidone in adolescents with autism spectrum disorders (ASD).