Pregnenolone

links: Steroid Hormones Neurosteroid reference:

Pregnenolone (P5) #

“A couple of times I saw men who were not quite suicidal, but extremely depressed, talking about quitting their job and just giving up, and they both happened to be sitting in a dark corner of the room with a glass of wine, wanting to retreat, even within the room as well as from life in general. And, thinking about the old bayonet studies and such, I put a pinch of pregnenolone in their wine; and within about 15 minutes, in both cases, they were grinning and talking about projects and went back to work and were just as happy as they could ever be.”

Increases dopamine release/response to Morphine in rat nucleus accumbens R
Anti-Cancer.
Improves joint mobility in arthritis, tissue elasticity in lungs, and eyesight.
Improves function of the thyroid and other glands.
Enhances memory and mood (calms emotions, increased resilience) skin (improves circulation), normalizes aldosterone, and lowers estrogen. Peat
The most potent inhibitor of the stress signal. RPF
Activates TRPM1/3 channels.
Interferes with TLR4 activation.
CB1 negative allosteric modulator.
- Pregnenolone Can Protect the Brain from Cannabis Intoxication
Excitatory neurosteroids [DHEA] and PGL at physiological concentrations participate in the inhibition of cortical neuronal degeneration elicited by staurosporine and glutamate, whereas the most potent positive modulator of GABA-A receptor - Allopregnanolone - has no effect. R
FSH-induced aromatase activity in porcine granulosa cells: non-competitive inhibition by non-aromatizable androgens
- Preg and Progesterone were inhibitory, but T was stimulatory.

Neuro #

Pregnenolone itself doesn’t do much, but pregnenolone sulfate does exhibit cognitive/memory enhancing, antidepressant, anxiogenic, and proconvulsant effects.
Potent negative allosteric modulator of GABA-A; weak positive allosteric modulator of NMDAR.
- To a lesser extent, acts as a negative allosteric modulator of AMPAR, Kainate Receptor and Glycine receptors.
- Subtype-dependence of N-methyl-d-aspartate receptor modulation by pregnenolone sulfate
  - Shown previously how P-S potentiates A>B and inhibits C$\approx$D: Inhibition of the NMDA response by pregnenolone sulphate reveals subtype selective modulation of NMDA receptors by sulphated steroids
  - the structure of the extracellular loop between the third and fourth transmembrane domains of the NR2 subunit is a key determinant for the PS effects
  - Acts at 2 distinct binding sites.
  - - Interesting stuff in A: it initially inhibits the current, and then when it unbinds,
  - 20-oxo-5β-Pregnanolone-S (3α5βS) inhibits the responses.
  - responses induced by NR1A/NR2A and -NR2B receptors are potentiated five- to eight-fold more by pregnenolone sulfate than responses of NR2C and NR2D.
Hypothalamic pregnenolone mediates recognition memory in the context of metabolic disorders
- Acute obesogenic diet administration in mice impaired recognition memory due to defective production of pregnenolone in the hypothalamus.
- POMC neurons have a far superior neuroSteroidogenesis capacity than AgRP neurons.
- loss of Stard1 in POMC neurons impaired recognition memory performance in the face of normal metabolic and energy balance status. These findings indicate that inadequate neurosteroid production by POMC neurons is fundamentally implicated in cognition, but it is dispensable for energy homeostasis control
The neurosteroid pregnenolone promotes degradation of key proteins in the innate immune signaling to suppress inflammation
- Promotes ubiquination of TLR2/TLR4 adaptor protein TIRAP and TLR2 in Macrophages and microglia, and suppressed TLR2/TLR4-mediated IL-6 and TNF-α secretion.
Brain distribution and behavioral effects of progesterone and pregnenolone after intranasal or intravenous administration
Nanomolar Concentrations of Pregnenolone Sulfate Enhance Striatal Dopamine Overflow In Vivo
Stabilizes Microtubules and stimulates assembly. RPF
- Pregnenolone binds to microtubule-associated protein 2 and stimulates microtubule assembly Binds to MAP2. (Pregnenolone sulfate does not)

LTP #

Pregnenolone sulfate enhances long‐term potentiation in CA1 in rat hippocampus slices through the modulation of N‐methyl‐D‐aspartate receptors
- Neuroactive steroid pregnenolone sulphate inhibits long-term potentiation via activation of alpha2-adrenoreceptors at excitatory synapses in rat medial prefrontal cortex.
  - PREGS inhibited induction of LTP in the Medial Prefrontal Cortex and had no influence on NMDA
PREGS induces LTP in the hippocampal dentate gyrus of adult rats via the tyrosine phosphorylation of NR2B coupled to ERK/CREB [corrected] signaling
- Total p-ERK levels increased but not levels of ERK. This is thanks to the calcium influx in NMDAR, and this is important for plasticity:
- Which number on tyrosine NR2B? Not sure
May have interactions with nACh receptors as well.
Steroid pregnenolone sulfate enhances NMDA-receptor-independent long-term potentiation at hippocampal CA1 synapses: role for L-type calcium channels and sigma-receptors

Supplementation #

Peat has said that literally every source on the market today is unsafe for one reason or another.

70-80% oral bioavailability.
Men/women age 30 produce ~30-50mg/day. A dose of 300mg acts for a week. Dosing actually improves the body’s ability to produce its own pregnenolone. But high doses such as >100 inhibit androgens/DHT?
- We produce 5% as much in old age than we do in our youth - as is the case with DHEA and progesterone.
30-50mg for DHEA+progesterone pthway, while 100-150 is more like mainly in the way of progesterone.

Intranasal #

@Intranasal pregnenolone increases acetylcholine in frontal cortex, hippocampus, and amygdala-Preferentially in the hemisphere ipsilateral to the injected nostril (Fazari et al. 2019)
Brain distribution and behavioral effects of progesterone and pregnenolone after intranasal or intravenous administration (Ducharme et al., 2011)
- ~23% entered the blood. Brain levels were about two fold lower after intranasal administration.
  - From 10 to 60 minutes, Brain: 35 ± 2.6 -> 45 ± 18
  - Serum 3.7 -> 7.6
- (Inj/g = percent of amount administered.) All this really asserts is preg’s affinity for brain regions.
- 200pg was the goldilocks zone for memory enhancement, while 1fg or 200ng were without effect. They weighed 0.025 - 0.03kg, so that’s 0.00015pg/kg. HED = 0.0000229995pg/kg = 20 fucking femtograms of pregnenolone. I probably get more than that by just happening to be inhaling when I open the jar.
Promnestic effects of intranasally applied pregnenolone in rats
- 0.187 or 0.373 mg/kg = 0.056 or 0.112 mg = HED 2.1 or 4.2 mg.
- - C depicts how much time they spent in previous reward platforms as opposed to the new ones - this is a measure of relearning or whatever.

Solution #

Solubility in DMSO is 22mg/mL.
It’s $10 for a whopping 5g on botany.bio

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