11 replies to this topic

[gizmobrain]

I am currently trying to figure out if my ADD-like symptoms can be nailed down to NMDA hypoactivity. After reading a bit, I decided to pick up some Pregnenolone in order to find out what results it would have. After not finding good results, I decided to re-read through some of my research again... and apparently I didn't read too closely because I just realized that Pregnenolone has very different effects than Pregnenolone Sulfate.

Pregnenolone and its sulfate, like DHEA and its sulfate and progesterone, belong to the group of neurosteroids that are found in high concentrations in certain areas of the brain, and are synthesized there. Neurosteroids affect synaptic functioning, are neuroprotective, and enhance myelinization. Pregnenolone and its sulfate ester are under investigation for their potential to improve cognitive and memory functioning.^[2] Pregnenolone is also being considered as a potential treatment for schizophrenia.^[3]
Pregnenolone has been shown to act as a positive allosteric modulator of the GABA_A receptor with slightly less potency than allopregnanolone (its 3α,5α-isomer).^[4] Accordingly, it has anxiolytic effects in animals, similarly to other neurosteroids like allopregnanolone and tetrahydrodeoxycorticosterone (THDOC).^[1]
Interestingly, unlike pregnenolone, pregnenolone sulfate is a negative allosteric modulator of the GABA_A receptor^[5] as well as a positive allosteric modulator of the NMDA receptor.^[6] In addition, it has been shown to activate the transient receptor potential M3 (TRPM3) ion channel in hepatocytes and pancreatic islets causing calcium entry and subsequent insulin release.^[7]

Mol Pharmacol. 1991 Sep;40(3):333-6.
Pregnenolone sulfate: a positive allosteric modulator at the N-methyl-D-aspartate receptor.

Wu FS, Gibbs TT, Farb DH.

Source

Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Massachusetts 02118.

Abstract

The N-methyl-D-aspartate (NMDA) receptor is believed to play a major role in learning and in excitotoxic neuronal damage associated with stroke and epilepsy. Pregnenolone sulfate, a neurosteroid, specifically enhances NMDA-gated currents in spinal cord neurons, while inhibiting receptors for the inhibitory amino acids glycine and gamma-aminobutyric acid, as well as non-NMDA glutamate receptors. This observation is consistent with the hypothesis that neurosteroids such as pregnenolone sulfate are involved in regulating the balance between excitation and inhibition in the central nervous system. PMID:1654510

"Pregnenolone has been shown to act as a positive allosteric modulator of the GABAA receptor. [...] Interestingly, unlike pregnenolone, pregnenolone sulfate is a negative allosteric modulator of the GABAA receptor as well as a positive allosteric modulator of the NMDA receptor."

I've been taking 25mg of Pregnenolone for the past 5 days and have not had positive results.

2 Questions:

1. Am I reading this right that Pregnenolone Sulfate would boost NMDA activity?

2. Does anyone know of a source for this besides the overly expensive chemical synth companies?

Edited by zrbarnes, 22 July 2012 - 06:06 PM.

[gizmobrain]

Heck, even better:

Proc Natl Acad Sci U S A. 2001 Nov 20;98(24):14033-7.
The synthetic enantiomer of pregnenolone sulfate is very active on memory in rats and mice, even more so than its physiological neurosteroid counterpart: distinct mechanisms?

Akwa Y, Ladurelle N, Covey DF, Baulieu EE.

Source

Institut National de la Santé et de la Recherche Médicale U488, Stéroides et Système Nerveux, 80 Rue du Général Leclerc, 94276 Le Kremlin-Bicêtre Cedex, France. yakwa@kb.inserm.fr

Abstract

The demonstration that the neurosteroid pregnenolone sulfate (PREGS) is active on memory function at both the physiological and pharmacological levels led to us examining in detail the effects of the steroid on spatial working memory by using a two-trial recognition task in a Y-maze, a paradigm based on the natural drive in rodents to explore a novel environment. Dose-response studies in young male adult Sprague-Dawley rats and Swiss mice, after the postacquisition intracerebroventricular injection of steroid, showed an U-inverted curve for memory performance and indicated a greater responsiveness in rats compared with mice. Remarkably, the synthetic (-) enantiomer of PREGS not only also displayed promnesiant activity, but its potency was 10 times higher than that of the natural steroid. Intracerebroventricular coadministration experiments with DL-2-amino-5-phosphonovaleric acid, a competitive selective antagonist of the N-methyl-D-aspartate receptor, abolished the memory-enhancing effect of PREGS, but not that of the PREGS enantiomer, evoking enantiomeric selectivity at the N-methyl-d-aspartate receptor and/or different mechanisms for the promnestic function of the two enantiomers. PMID:11717462

Eur Neuropsychopharmacol. 2011 Feb;21(2):211-5. Epub 2010 Oct 30.
Pregnenolone sulfate and its enantiomer: differential modulation of memory in a spatial discrimination task using forebrain NMDA receptor deficient mice.

Petit GH, Tobin C, Krishnan K, Moricard Y, Covey DF, Rondi-Reig L, Akwa Y.

Source

Centre National de la Recherche Scientifique, Neurobiologie des Processus Adaptatifs (UMR7102), Université Pierre et Marie Curie, Paris, France.

Abstract

This study examined the role of forebrain N-methyl-D-aspartate receptors (NMDA-Rs) in the promnesiant effects of natural (+) pregnenolone sulfate (PREGS) and its synthetic (-) enantiomer ent-PREGS in young adult mice. Using the two-trial arm discrimination task in a Y-maze, PREGS and ent-PREGS administration to control mice increased memory performances. In mice with a knock-out of the NR1 subunit of NMDA-Rs in the forebrain, the promnesiant effect of ent-PREGS was maintained whereas the activity of PREGS was lost. Memory enhancement by PREGS involves the NMDA-R activity in the hippocampal CA1 area and possibly in some locations of the cortical layers, whereas ent-PREGS acts independently of NMDA-R function.
Copyright © 2010 Elsevier B.V. and ECNP. All rights reserved. PMID:21036556

Interesting. Looks like the synthetic enantiomer of pregnenolone sulfate acts on a different receptor. So maybe we will focus on that at a different time.

Edited by zrbarnes, 22 July 2012 - 06:25 PM.

[gizmobrain]

So this was something that I had thought maybe was the case:

Neuroscience. 2011 Sep 15;191:78-90. Epub 2011 Jul 1.
Pregnenolone as a novel therapeutic candidate in schizophrenia: emerging preclinical and clinical evidence.

Marx CE, Bradford DW, Hamer RM, Naylor JC, Allen TB, Lieberman JA, Strauss JL, Kilts JD.

Source

Duke University Medical Center, Durham, NC, USA. marx0001@mc.duke.edu

Abstract

Emerging preclinical and clinical evidence suggests that pregnenolone may be a promising novel therapeutic candidate in schizophrenia. Pregnenolone is a neurosteroid with pleiotropic actions in rodents that include the enhancement of learning and memory, neuritic outgrowth, and myelination. Further, pregnenolone administration results in elevations in downstream neurosteroids such as allopregnanolone, a molecule with neuroprotective effects that also increases neurogenesis, decreases apoptosis and inflammation, modulates the hypothalamic-pituitary-adrenal axis, and markedly increases GABA(A) receptor responses. In addition, pregnenolone administration elevates pregnenolone sulfate, a neurosteroid that positively modulates NMDA receptors. There are thus multiple mechanistic possibilities for pregnenolone as a potential therapeutic agent in schizophrenia, including the amelioration of NMDA receptor hypofunction (via metabolism to pregnenolone sulfate) and the mitigation of GABA dysregulation (via metabolism to allopregnanolone). Additional evidence consistent with a therapeutic role for pregnenolone in schizophrenia includes neurosteroid changes following administration of certain antipsychotics in rodent models. For example, clozapine elevates pregnenolone levels in rat hippocampus, and these increases may potentially contribute to its superior antipsychotic efficacy [Marx et al. (2006a) Pharmacol Biochem Behav 84:598-608]. Further, pregnenolone levels appear to be altered in postmortem brain tissue from patients with schizophrenia compared to control subjects [Marx et al. (2006c) Neuropsychopharmacology 31:1249-1263], suggesting that neurosteroid changes may play a role in the neurobiology of this disorder and/or its treatment. Although clinical trial data utilizing pregnenolone as a therapeutic agent in schizophrenia are currently limited, initial findings are encouraging. Treatment with adjunctive pregnenolone significantly decreased negative symptoms in patients with schizophrenia or schizoaffective disorder in a pilot proof-of-concept randomized controlled trial, and elevations in pregnenolone and allopregnanolone post-treatment with this intervention were correlated with cognitive improvements [Marx et al. (2009) Neuropsychopharmacology 34:1885-1903]. Another pilot randomized controlled trial recently presented at a scientific meeting demonstrated significant improvements in negative symptoms, verbal memory, and attention following treatment with adjunctive pregnenolone, in addition to enduring effects in a small subset of patients receiving pregnenolone longer-term [Savitz (2010) Society of Biological Psychiatry Annual Meeting New Orleans, LA]. A third pilot clinical trial reported significantly decreased positive symptoms and extrapyramidal side effects following adjunctive pregnenolone, in addition to increased attention and working memory performance [Ritsner et al. (2010) J Clin Psychiatry 71:1351-1362]. Future efforts in larger cohorts will be required to investigate pregnenolone as a possible therapeutic candidate in schizophrenia, but early efforts are promising and merit further investigation. This article is part of a Special Issue entitled: Neuroactive Steroids: Focus on Human Brain.
Published by Elsevier Ltd. PMID:21756978

I wonder then if it would be best to take the pregnenolone before bed so that hopefully pregnenolone sulfate levels would be higher in the morning. I have no idea how long it takes. I must find more science...

[Picard]

What were the outcomes of this research trek? I'd love to hear about them.

[dear mrclock]

i have made thread about this long ago trying to discuss the differences between pregnenolone and the sulfate version, differences and various bioavaiable characteristics and to this day, im still confused. nobody could ever explain or care to, or know to.

[normalizing]

zrbarnes, any updates ? i cannot also find sulfate version anywhere. only the chemical companies can synthesize it. im confused as to why the sulfate version is not fucking sold anywhere ! also i found out, actually the allopregnenolone is the active version of pregnanolone and it is the one having the most research done which includes; growth of neurons and protection, reversal brain damage, memory and learning etc. YET AGAIN nowhere to be found for sell !! meanwhile, the basic pregnenolone is sold everywhere for the pathetic amount of 6 to 12 bucks. speaks quite clearly how useful it is !

anyone has any clue how to find the actual active versions of that powerful neurosteroid and/or why it is so that its almost impossible for the consumers to get a hold of it ??

[YoungSchizo]

zrbarnes, any updates ? i cannot also find sulfate version anywhere. only the chemical companies can synthesize it. im confused as to why the sulfate version is not fucking sold anywhere ! also i found out, actually the allopregnenolone is the active version of pregnanolone and it is the one having the most research done which includes; growth of neurons and protection, reversal brain damage, memory and learning etc. YET AGAIN nowhere to be found for sell !! meanwhile, the basic pregnenolone is sold everywhere for the pathetic amount of 6 to 12 bucks. speaks quite clearly how useful it is !

anyone has any clue how to find the actual active versions of that powerful neurosteroid and/or why it is so that its almost impossible for the consumers to get a hold of it ??

Pregnenolone Sulfate Sodium Salt is unfortunately not that cheap (Don't know if the Sodium Salt is the right one though)..

It is also very interesting for schizophrenics! Group buy? :P

I'm on the cheap Pregnenolone, it reversed the "muscle growth damage" Zyprexa has causes due to chronic use of 7-8 years. Even when I was off it for 1,5 year I could not make any progress, on Preg however I finally make quite some noticeable progression (like I was used to back in the days)!

Edited by YoungS, 29 November 2013 - 02:52 PM.

[normalizing]

wow 20 dollars for 25 mg. are those people nuts ? and i never heard of pregnenolone and relation to muscle growth, you sure you didnt take other stuff too in combination ? also, do you notice anything cognitive wise when you were taking the cheap shit pregnenolone ? i know we need the other forms for cognitive enhancement, too bad nobody will form a group buy....

[YoungSchizo]

wow 20 dollars for 25 mg. are those people nuts ? and i never heard of pregnenolone and relation to muscle growth, you sure you didnt take other stuff too in combination ? also, do you notice anything cognitive wise when you were taking the cheap shit pregnenolone ? i know we need the other forms for cognitive enhancement, too bad nobody will form a group buy....

There are lots off chemicals for that price that we can use to self-medicate and get a better treatment then what's possible at the psych, however, guess the production costs are high and/or the pharma's are lined up to monetize those chems!! (I'll bet on the last one)

Nope, didn't take anything else, my regime for 5/6 months was:
Rivotril 1,5mg
Mirtazapine 30mg
Sarcosine 2/3grams
Pregnenolone 50mg for months (now I'm taking 200mg)
Omega 3's 1000mg
Men Multivitamin
(Last two weeks I gone on a diet and added a lot of stuff to recover/gain muscle's faster)

Well, I didn't knew it either, I started with Preg in the hopes to counteract the cognitive decline from (schizophrenia and) Rivotril, unfortunately it isn't potent enough to counteract Rivotril. Don't know if it would have enhanced cognition without Rivotril, in schizophrenia trials it did (on the bottom of the page, left and right there are more study's with Preg).. Though, all of a sudden, just on 50mg, it enhanced my mood, motivation, endurance, muscle firmness and gaining muscle mass (I wasn't even on a diet). The past 3 years that I work-out again I bulk (protein) dieted 3 times, those 3 times the only thing I gained was (a lot of) FAT, I didn't even gain with weight-lifting.. (I think my muscle mass has increased 4-5-6KG in just those 5/6 months, I'll have to measure it though, but this was impossible for 3 years and if people at the gym say you became friggin' lean and muscular then I'm not making shit up/dreaming..!

The body decide in which hormones it turns Preg, so I guess it's paying off in low cortisol, high testosterone etc. (don't know for sure, didn't get tested or something) because I exercise/work-out hard. Btw, Pregnenolone is considered a prohormone and is used by (some) bodybuilders..

Edited by YoungS, 30 November 2013 - 03:44 AM.

[normalizing]

i still cannot find pregnenolone sulfate sold anywhere for the casual consumer's access. any ideas why is that? as someone mentioned in this thread, it does seem most positive studies were done with pregnenolone sulfate, so the other cheaper type of pregnenolone is mostly filler it seems.

[YoungSchizo]

i still cannot find pregnenolone sulfate sold anywhere for the casual consumer's access. any ideas why is that? as someone mentioned in this thread, it does seem most positive studies were done with pregnenolone sulfate, so the other cheaper type of pregnenolone is mostly filler it seems.

 You're from China man, if you don't have a cheap source, I guess no one will have one 

[normalizing]

and yet, i still cannot find the sulfate form. from the studies, it is the only form to help boost dopamine and yet, why do we have the undisclosed unreliable version widely sold and available??