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5α-Dihydroprogesterone (5α-DHP) - Pro-hormone And Neurosteroid For R&D

Discussion in 'IdeaLabs' started by haidut, Nov 23, 2016.

  1. Quality

    Quality Member

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    http://sci-hub.cc/10.1016/j.neuroscience.2008.09.003

    INTRANASAL ADMINISTRATION OF PROGESTERONE INCREASES DOPAMINERGIC ACTIVITY IN AMYGDALA AND NEOSTRIATUM OF MALE RATS

    "There is evidence for a modulatory action of PROG and its metabolites on the activity of type A GABA (GABAA), the N-methyl-D-aspartate (NMDA), nicotinic acetylcholine (nACh) and sigma 1 (1) receptors (Schumacher et al., 2000, 2007b)."

    Study showed the different routes of administration of progesterone (inlcuding intranasal) and elevations of dopamine in the amygdala (raised dopamine there).
     
  2. OP
    haidut

    haidut Member

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    That's pretty interesting, thanks for posting. The HED used were not that high. For intranasal progesterone, the HED was 0.3mg/kg and for subcutaneous was 0.6mg/kg. Both routes increased dopamine to the same extend but the intranasal route did so at half the dose compared to s.c. Also, the effects for s.c. route on dopamine was delayed (i.e. it started about 90min after administration) but achieved higher sustained levels than intranasal.
     
  3. Andman

    Andman Member

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    remember him writing on the pfs thread that once you have pfs, taking a progestin (according to him) like finasteride will actually fix the symptoms. until you stop taking it, that is.
     
  4. OP
    haidut

    haidut Member

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    Well, in the case of 5a-DHP it is hard to say if it is his theory that is correct or simply 5a-DHP increasing allopregnanolone levels (which are known to be tanked by finasteride). The neurosteroid issue is only part of the PFS problem. As I posted in other threads, there are reports on finasteride causing liver and GI damage (and possibly physical nerve damage). So, if one or more of these is common side effect then progesterone (and progestins may help) but I would not take finasteride to stay symptom-free. Might as well use a higher dose progesterone as it should be much safer aside from the anti-androgenic effects.
     
  5. Quality

    Quality Member

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    Not a problem, would be interesting to see what would happen after the 240mins of monitoring concentrations, for example if the rats would get a temporary drop in dopamine levels.
    Anyways it seems that if this would be possible in a nasal spray, once/twice daily dosing would be sufficient, considering after 240mins dopamine levels are still more than quadrupled.

    Im not sure if intranasal administration would have a more brain specific effect, but it might.
     
  6. Quality

    Quality Member

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    Another one with potential 'proof' of the efficiacy of progesterone on lowering serotonin (5ht1a specific). This study was done in health men and with brain scans:

    Progesterone Level Predicts Serotonin-1A Receptor Binding in the Male Human Brain
    https://sci-hub.cc/https://doi.org/10.1159/000328432

    ..............blablablabla.................................We found that P levels explained up to 65% of the variability in 5-HT 1A receptor binding (see online suppl. tables 3–5). Multiple linear regression analyses, including P plasma level, age and radiochemical variables as predictors revealed a strong negative effect of P on the 5-HT 1A receptor binding ( fig. 1 ) in the amygdala ( R2 = 0.46, p = 0.0069), retrosplenial cortex ( R2 = 0.65, p = 0.0063) and orbitofrontal cortex ( R2 = 0.41, p = 0.0147);

    Low serotonin levels are well linked to romance, especially early stages of love.
    I feel as if progesterone might shift the libido in males from primal (T/DHT dominance driven) to affectionate/romantic (low serotonin/craving).

    I made a post about a year ago or so about vitex agnus castus, some of you might still remember it, I had intense feelings of desire (I have to admit I felt as if I was desperate and vulnerable while on vitex and craving for being with women).
    FYI: It had annoying side effects on me such as flaring up of red zits/acne like stuff, only on my abdomen though it was very weird, not on my face. I got scared as hell of that and abruptly stopped it, vitex definatly builded up in my system so to speak, so the longer I used it the stronger the effect became on me.

    Now some of you might argue... vitex pffffff.... some bull**** herb for women.
    Well I have found multiple sources indeed backing up what im saying:

    ___________________________________________________________________________________________________________________
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    Possible Modulation of the Anexiogenic Effects of Vitex Agnus-castusby the Serotonergic System
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3586884/

    Results
    Oral administration of vitex (100, 200, 300 mg/kg) for two weeks induced an anxiogenic-like effect which was shown through specific decreases in the percentages of open arm time (OAT %) and open arm entries (OAE %). Intra-TV infusion of 5HT1A receptor agonist, 8-OH-DPAT (5, 10 and 25 ng/rat) increased OAT% and OAE%, indicating anxiolytic–like behavior. However, injection of 5HT1A receptor antagonist NAN190 (0.25, 0.5 and 1 µg/rat) produced anxiogenic-like behavior. The most effective dose of 8-OH-DPAT (10 ng/rat), when co-administered with vitex (100, 200, 300 mg/kg), attenuated the anxiogenic-like effects of vitex significantly. Injection of the less effective dose of NAN190 (0.5 µg/rat), in combination with vitex (100, 200, 300 mg/kg), potentiate anxiogenic effects of vitex.
    - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
    In other words it potentiated the effect of the 5ht1a antagonist, opposed the effect of the 5ht1a agonist, seems to me an easy conclusion that vitex modulates/potentiates the efficiacy of the 5ht1a autoreceptor.
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    Gynecological efficacy and chemical investigation of Vitex agnus-castus L. fruits growing in Egypt.
    https://www.ncbi.nlm.nih.gov/pubmed/18415863

    Abstract
    ....blablablabla.............. The extract induced significant increase in the uterine weight of ovariectomized rats at two dose levels comparable to that of control group. The percentages of the total average number of scores were increased significantly too. Significant increases in plasma progesterone and total estrogens levels were shown at the two dose levels when compared to that of control group. On the other side, the extract induced significant reduction in luteinizing and plasma prolactin hormones.
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    Pharmacological activities of Vitex agnus-castus extracts in vitro.
    https://www.ncbi.nlm.nih.gov/pubmed/11081988

    Abstract
    The pharmacological effects of ethanolic Vitex agnus-castus fruit-extracts (especially Ze 440) and various extract fractions of different polarities were evaluated both by radioligand binding studies and by superfusion experiments. A relative potent binding inhibition was observed for dopamine D2 and opioid (micro and kappa subtype) receptors with IC50 values of the native extract between 20 and 70 mg/mL. Binding, neither to the histamine H1, benzodiazepine and OFQ receptor, nor to the binding-site of the serotonin (5-HT) transporter, was significantly inhibited. The lipophilic fractions contained the diterpenes rotun-difuran and 6beta,7beta-diacetoxy-13-hydroxy-labda-8,14-dien . They exhibited inhibitory actions on dopamine D2 receptor binding. While binding inhibition to mu and kappa opioid receptors was most pronounced in lipophilic fractions, binding to delta opioid receptors was inhibited mainly by a aqueous fraction. Standardised Ze 440 extracts of different batches were of constant pharmacological quality according to their potential to inhibit the binding to D2 receptors. In superfusion experiments, the aqueous fraction of a methanolic extract inhibited the release of acetylcholine in a concentration-dependent manner. In addition, the potent D2 receptor antagonist spiperone antagonised the effect of the extract suggesting a dopaminergic action mediated by D2 receptor activation. Our results indicate a dopaminergic effect of Vitex agnus-castus extracts and suggest additional pharmacological actions via opioid receptors.
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    Another example of me responding well to a progesterenic substance is the herb Damiana which has phyto-progesterone activity:

    Estrogen and progestin bioactivity of foods, herbs, and spices.
    https://www.ncbi.nlm.nih.gov/pubmed/9492350

    ...........The six highest ER-binding herbs that are commonly consumed were soy, licorice, red clover, thyme, tumeric, hops, and verbena. The six highest PR-binding herbs and spices commonly consumed were oregano, verbena, tumeric, thyme, red clover and damiana.

    Stimulating property of Turnera diffusa(=Damiana) and Pfaffia paniculata extracts on the sexual behavior of male rats
    http://sci-hub.cc/10.1007/s002130050913
    So, from our present data, it would appear that the plant extracts used in this study, which selectively improve the sexual behavior of sluggish/impotent rats, while being ine¤ective in potent rats, might act mainly by increasing central noradrenergic and dopaminergic tone, and possibly (indirectly) oxytocinergic transmission.

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    According to above studies:

    * vitex increased progesterone levels
    * vitex lowered prolactin levels
    * vitex decreased lh levels (can be bad I suppose)
    * vitex lowered serotonin (5ht1a) levels (aggression,jealousy,craving,romance)
    * vitex increased dopaminergic activity through d2 receptors

    The best way to describe how I felt on vitex was like a depressed wounded vulnerable animal desperate to reproduce before his lights go out. I was definatly very far out of balance on vitex.
    Note: the effects get more pronounced over time, it definatly took me over a week to get this feeling 'creep up' on me.

    * damiana acts upon progesterone receptors
    * damiana is pro-libido in males

    Damiana gave me that lazy horny desperate type of libido where you just want to sit in your chair and let a woman ride you while you keep on drinking your beer.


    TL;DR:

    I think its save to assume that for me personally (and most likely other males who lack the drive for romantic type of sex) that progesterone can be beneficial, how much of that effect is due to downstream effect on allopregnanolone we might never find out, but there are definatly benefits to reap.

    Note: Im not promoting vitex use at all, im just highlighting my experience with it and atleast for me personally I think progesterone raising substances (most likely pure progesterone would be best) will be beneficial for my lack of affection and to tone down the need to dominate women and people at work.
     
  7. OP
    haidut

    haidut Member

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    Thanks for this, these are great finds. The especially intriguing effect is the antagonism on 5-HT1A, as some forum members swear that this is the most effective antidepressant pathway. Anything that antagonizes 5-HT1 is expected to raise dopamine, which is what the other studies you quoted found as these herbs either contains a natural progesterone or a flavonoid that can activate the PR.
    Hey, @Brooks Esq. you may want to look at this.
     
  8. Quality

    Quality Member

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    Your welcome,
    Im quite positive that brain specific PR ligands (or even intranasal progesterone?) could have the potential to treat apathy/indifference, by lowering serotonin in the amygdala thereby increasing amygdala reactivity, both good and bad as this will amplify both how one perceives emotional positive aswell as negative experiences.

    No surprise that alcohol withdrawal/hangovers also lower serotonin in the amygdala with a somewhat similar mechanism as progesterone.

    Contribution of Noradrenaline, Serotonin, and the Basolateral Amygdala to Alcohol Addiction: Implications for Novel Pharmacotherapies for
    AUDs

    https://www.intechopen.com/books/re...eral-amygdala-to-alcohol-addiction-implicatio

    There are others forums and website where tons of people swear by the fact that the day after binge drinking they are temporary yet completely cured by their apathy and anhedonia (asd,adhd,pfs,pssd), this is because their amygdalas have under-excitability by default (either drugs induced by ssri's, finasteride or genetically born this way), during the hangover their amygdala reactivity shoots up and brings them up to proper amygdala reactivity allowing them in a temporary fully hedonic state.
    And with the projections from the amygdala to the NAc, back online comes their reward system.
    Many people with pfs and pssd induced sexual dysfunction do not only report a lack of attaction to the oposite sex, but report a lack of passion for life basically.

    This also explains why alcoholics and emotional sensitive people get extremely anxious/panic attacks during withdrawal as their allready hyperactive amygdalas go into overdrive during withdrawal, resulting in.... you guessed it, grabbing another drink in an attempt to raise serotonin in their amygdala. I wouldnt be surprised if alcoholics have high progesterone levels naturally, atleast in their brains.

    Also with regards to my previous post about the brain scan they did to healthy human men, the p = 0.0069 is just damn impressive considering its in healthy men, can only imagine what an effect this might give in men who have elevated levels of serotonin in their amygdala.
     
  9. Andman

    Andman Member

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    @Quality
    awesome info thanks a lot
    this stuff hits right home for me..in my younger years i was def. the 2nd case you describe - very emotional (both in good and bad ways) which led me down a path to alcohol, drugs, medication etc. - nowadays im mr. apathy/disinterest personified, trying to get out of that.

    besides hangovers, one thing that kicked my symptoms completely for ~2 days was CBD..which has potent 5ht1a actions, although not sure if agonist or antagonist..i was using very low does too, like 1-2 drops of a cheap 5% oil i got for 10 bucks on amazon!

    edit: Also, there are quite a few user reports of pregnenolone enhancing emotional experiences, both good and bad - might be because of prog conversion?
     
  10. Quality

    Quality Member

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    According to what Ive read CBD oil has a biphasic effect on anxiety.

    The anxiolytic action of CBD may be mediated by 5-HT1A receptors, as it displaces the agonist [3H]8-OHDPAT from the cloned human 5-HT1A receptor in a concentration-dependent manner and exerts an effect as an agonist at the human 5-HT1A receptor in signal-transduction studies (Russo et al, 2005). Additionally, CBD injected into the dorsolateral periaqueductal gray of rats produced anxiolytic-like effects in the elevated plus-maze and elevated T-maze, and these effects were prevented by a 5HT1A receptor antagonist (Soares et al, 2010; Campos and Guimaraes, 2008).

    My guess is by using CBD oil you were also hitting the 5ht1a auto-receptor, this gave you temporary relieve untill your brain compensated for that decreasing the auto-receptor after 2 days.

    SSRI's work somewhat similar AFAIK, this is why those with MDD (low serotonin type of depression) temporarily get worse the first 2 weeks of starting SSRI treatment where the autoreceptor gets activated and serotonin levels in the brain drop even lower untill the body compensates by shutting down its autoreceptors. Yet those who experience apathy/indifference SSRI's usually only work the first 2 weeks and loses effiacy after that.
    I would dare even go even that far that people with apathy/indifference have alot of the oposite responses to serotoninergic drugs as MDD.

    Cannabidiol Reduces the Anxiety Induced by Simulated Public Speaking in Treatment-Naïve Social Phobia Patients

    CDP-choline might be beneficial to you (I know it is to me):

    Effects of cytidine-5' diphosphocholine on norepinephrine, dopamine and serotonin synthesis in various regions of the rat brain.
    Effects of cytidine-5' diphosphocholine on norepinephrine, dopamine and serotonin synthesis in various regions of the rat brain. - PubMed - NCBI

    Abstract
    Administered intravenously to rats, CDPcholine, significantly increases the level and the synthesis rate of dopamine, and the level of tyrosine in the corpus striatum (maximum effect for 50 mg/kg, one hour after administration). CDPcholine decreases the level of serotonin and tryptophan and the synthesis rate of serotonin in the midbrain + hypothalamus and in the brain stem. The increase of the striatum dopamine level and the decrease of the brain stem and midbrain serotonin level are correlated with the recognized antiparkinson and neurostimulant action of this nucleotide.

    Regarding cdp-choline's bioavailability, according to wikipedia it has 90% oral bioavailability.

    Im starting to think that most people with apathy/indifference may benefit from low dose anxiogenic, to put the amygdala back online, in their case it would not even be consider anxiogenic as it brings their amygdala reactivity back to normal levels.
    Caffeine/coffee can also be anxiogenic, yet it is used/abused (however you want to put it) by people all around the world.

    In fact a recent study showed that caffeine increased oxytocin...

    Caffeine inhibits hypothalamic A1R to excite oxytocin neuron and ameliorate dietary obesity in mice.
    Caffeine inhibits hypothalamic A1R to excite oxytocin neuron and ameliorate dietary obesity in mice. - PubMed - NCBI
     
  11. Joeyd

    Joeyd Member

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    Have many people reported anxiety? I can't find these comments. I've taken 5adhp 3 times before now, but I just took 5 drops with some k2 and got quite bad anxiety. No idea why
     
  12. amaranthine

    amaranthine Member

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    @Joeyd I don't know, was a pretty long time ago I wrote that. I would've just been referring to people commenting in this thread though, and skimming through it again, seems that it's a generally positive consensus but some people do suffer some side effects. Dhair said he suffered agitation and that was probably what I meant as it's on the same page as my original post
     
  13. Joeyd

    Joeyd Member

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    @haidut ive had this problem of inflamed, iritated red eyes for a while now. It seems like h1 antihistamines seem to cause it, like doxylamine succinate and diphenhydramine seem to cause it. Maybe it causes eye dryness and then the red eye inflammation follows.

    anyway, ive noticed that your 5aDHP seems to resolve this. I take about 5 drops before bed, i wake up with almost clear white eyes, no inflammation at all. Do you have any idea which pathway its acting on to affect this? thanks
     
  14. OP
    haidut

    haidut Member

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    That's strange, as antihistamines are supposed to help with red eyes (due to inflammation). Maybe your red eye was due to either high BP or lactate and 5a-DHP lowered one/both somehow and this helped?? Really not sure, but these are the other common causes of red eyes.
    Anyways, thanks for the feedback!
     
  15. johnsmith

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    The first time subject used this, there was a remarkable improvement in eye sight. Subject was a Pansterone/Androsterone user prior, but tried to switch to 5a-dhp, but switched back to Pansterone after a month. 5a-dhp didnt seem to be a sufficient replacement for Pansterone. Subject is curious to try this at the same time as Pansterone, or within the same day. Or maybe one day a week.

    Its hard to gauge the effects of 5a-dhp because subject suspects withdrawal symptoms (for lack of a better word) from Pansterone set in when Pansterone is stopped.

    5a-dhp dose used was 2-6 drops, once a day. Most often used orally.
     
  16. Makrosky

    Makrosky Member

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    I can confirm this works also with intranasal pregnenolone. Of course I don't know if the biochemical reactions are the same than those of the study but it feels like it : anxiolytic and slightly dopaminergic feeling (elevated mood, focus, motivation).
     
  17. Andman

    Andman Member

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    oh man my rats gotta try that haha. just straight preg powder or dissolved in a spray bottle?
     
  18. Makrosky

    Makrosky Member

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    Healthnatura pure preg powder. Just a small pinch. Not dissolved or anything. I don't know how safe it is but works very good. Other forum users have done that with b vitamins.
     
  19. Joeyd

    Joeyd Member

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    I think 5aDHP might also be helping to reduce my hangovers. Any idea why that might be?
     
  20. Joeyd

    Joeyd Member

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