Glycine Strongly Upregulates 5-alpha Reductase (5-ar) Activity

A.R

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Better digestion mainly (and its consequences), if it improves absorption of nutrients that could be a nice benefit too. Tyw mentioned its use, I don't think he saw it as a digestive aid but rather a way to eliminate pathogens (don't quote me on that). Tarmander uses it, he posted information in his log and on the gbolduev Q and A thread. m_arch had reported good digestion with it.
Thank you
 
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This is study is a great find in my opinion. It is well known that conditions like depression and dementia are associated with reduced levels of the neurosteroid allopregnanolone. A few of the successful SSRI drugs like Prozac have the "side effect" of increasing levels of allopregnanolone in the brain. Several other drugs that increase brain levels of allopregnanolone are currently in clinical trials for depression, dementia, anxiety, and even schizophrenia. Furthermore, allopregnanolone is capable of increasing metabolism by activating the bile acid "receptor" as described in this thread.
How Pregnenolone And Progesterone Raise Metabolism | Ray Peat Forum

On the flip side, drugs like Finasteride and some other anti-androgens lower allopreganolone by inhibiting 5-AR. All in all, raising levels of allopregnanolone appears to be highly beneficial and lowering its levels can lead to everything from depression to the dreaded post-Finasteride syndrome.

Allopregnanolone is a steroid derived from progesterone through the action of the enzyme 5-AR. Another steroid derived through the activity of 5-AR is of course DHT. DHT also has strong anti-depressant and pro-metabolic effects. Furthermore, upregulated 5-AR helps with deactivation and excretion of cortisol and estrogen.
This study found that even physiological concentrations of glycine both raised levels of allopreganolone in the brain AND upregulated activity of 5-AR. If true, this immediately makes glycine a potent, dirt-cheap OTC anti-depressant and a powerful androgenic stimulator. Considering the effects of other amino acids like taurine on steroidogenesis, a combination of glycine and taurine would be a great way to upregulate sagging steroid production (especially in the brain), while simultaneously lowering estrogen and cortisol. I know some people here also cross-post on the hair loss and post-Finasteride forums, so it would be good to see what folks over there think about that as well.

Regulation of neurosteroid allopregnanolone biosynthesis in the rat spinal cord by glycine and the alkaloidal analogs strychnine and gelsemine. - PubMed - NCBI

"...But concerning glycine, no report had until now investigated the possible control of neurosteroid biosynthesis, particularly 3,5-THP secretion, by pharmacological agents of the glycinergic system. Therefore, the present work constitutes the first demonstration indicating that glycine, acting through Gly-R, stimulates 3,5-THP production in the rat SC. Applications of graded micromolar concentrations of glycine generally involved in glycinergic neurotransmission (Legendre, 2001; Kirsch, 2006) induced a dose-dependent increase of 3,5-THP biosynthesis in the rat SC. Furthermore, this paper also shows that gelsemine, a structural analog of strychnine, is a positive regulator of 3,5-THP formation in the SC."


"...Therefore, it appears that the chloride ion influx induced by glycine or gelsemine via Gly-R activation may indirectly cause an intracellular pH modification allowing the stimulation of 5-reductase and/or 3-HSOR activity in spinal nerve cells. In support of this hypothesis, we observed that at certain concentrations (1 uM and 35 uM), glycine strongly enhanced 5-reductase activity leading to increased amounts of [3H]5-DHP. Other concentrations of glycine (70 uM and 140 uM) mainly accelerated 3-HSOR activity and the elevated speed of 3-HSOR enzymatic reaction generating high amounts of [3H]3,5-THP did not allow identification of the transient increase of the intermediate steroid ([3H]5-DHP) level 3 h after the incorporation of [3H]PROG into SC slices."

"...Glycine and the neurosteroid 3,5-THP are known to regulate several important neurophysiological processes such as pain and anxiety (Akwa et al., 1999; Patte-Mensah et al., 2004a, 2005, 2006; Zeilhofer, 2005; McCool and Chappell, 2007; Pellicer et al., 2007). The neuroactive steroid 5-DHP also exhibited neuroprotective properties in various experimental models (for review, Roglio et al., 2007). Therefore, even though further studies are required to specify gelsemine effects in vivo, the fact that gelsemine exerts a potent stimulatory action on 5-DHP and 3,5-THP biosynthesis suggests that gelsemine and medicine produced from Gelsemium sempervirens may be interesting compounds to investigate for therapies of neuropathological disorders evoked by disturbances of the central inhibitory transmission."

Now of course everybody wants to know what dose of glycine would have that effect. The study shows that the effective glycine concentrations were in the range 1 uM - 35 uM. The glycine concentrations in the brain are about 100 times lower than in plasma. This means, a plasma concentration in the range 100uM - 3,500uM is needed. As I posted in another study on glycine below, an oral dose of 4.6g glycine achieves about 900uM, so for simplicity let's say 5g achieves 1,000uM (1mM).
Aging in human mitochondria fully reversed by glycine | Ray Peat Forum

This mean that oral glycine doses in the range of 500mg - 16g are needed to achieve the effective concentration in the brain. The effect is dose-dependent, so the higher the glycine dose the more effective it is on allopregnanolone and 5-AR activity. Now, taurine seems to upregulate the rest of the steroidogenic pathways as the study below indicate.
Taurine increases testicular function in aged rats by inhibiting oxidative stress and apoptosis. - - NCBI
Taurine reverses endosulfan-induced oxidative stress and apoptosis in adult rat testis. - PubMed - NCBI

If glycine indeed upregulates 5-AR then combining glycine with taurine and adding DHEA/pregnenolone (if needed) should have a dramatic positive effect on mental health, cognition, and steroid profile that are so negatively affected by hypothyroidism and aging in general.

Furthermore, in light of the ability of niacinamide to lower cortisol, oppose estrogen, and increase androgenic expression and DHT signalling, adding niacinamide to the glycine/DHEA combo should make it even more potent.
Niacinamide Is Androgenic And Increases Dht Effects/signaling | Ray Peat Forum
Niacinamide Is Anti-estrogenic | Ray Peat Forum
Niacinamide Lowers Cortisol | Ray Peat Forum

haidut, do you think it is accurate to say if you were affected by a 5ar2 inhibitor, that magnesium is something that would be lost very quickly? i appear to be a constant state of high stress, however, that is combined with a fast loss of magnesium. it makes sense to say that if pregenenlone is low, then progesterone is low, then that would automatically assume that thyroid function is low and that is losing magnesium? it appears i need to do supplementing of 400mg of magnesium per day, along with kale broths each day, just to maintain some form of magnesium. if i miss even one day, i appear to get strong estrogen symptoms like puffy nipples which i'm trying to piece together what is causing what.

it seems like the high stress is causing the loss of minerals, but who knows what other minerals are being lost on top of that, which i think plays into the whole PFS dilemma.
 
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haidut

haidut

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haidut, do you think it is accurate to say if you were affected by a 5ar2 inhibitor, that magnesium is something that would be lost very quickly? i appear to be a constant state of high stress, however, that is combined with a fast loss of magnesium. it makes sense to say that if pregenenlone is low, then progesterone is low, then that would automatically assume that thyroid function is low and that is losing magnesium? it appears i need to do supplementing of 400mg of magnesium per day, along with kale broths each day, just to maintain some form of magnesium. if i miss even one day, i appear to get strong estrogen symptoms like puffy nipples which i'm trying to piece together what is causing what.

it seems like the high stress is causing the loss of minerals, but who knows what other minerals are being lost on top of that, which i think plays into the whole PFS dilemma.

Low 5-AR expression results in less de-activation of cortisol as 5-AR is one of the crucial pathways for that. Under the influence of higher cortisol, more magnesium will be lost since cortisol can activate the mineralocorticoid receptors (MR) just like aldosterone, which results in sodium retention at the expense of magnesium/potassium.
 
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Low 5-AR expression results in less de-activation of cortisol as 5-AR is one of the crucial pathways for that. Under the influence of higher cortisol, more magnesium will be lost since cortisol can activate the mineralocorticoid receptors (MR) just like aldosterone, which results in sodium retention at the expense of magnesium/potassium.

well that makes absolute perfect sense. i absolutely have high cortisol that i cannot get down. i managed to get it down once via light and pregenenlone together, but i haven't been able to replicate it since. sigh, well i'll keep up with the glycine and gelatin, maybe it will come down. using pregnenlone, back on my magnesium again, glycine, gelatin, cascara, 100grams of protein a day, anything else you can think of lol? thyroid i think causes the stress reaction to go up. but maybe pregenenlone and thyroid together could be different.

the only other thing i can think of if doing all of this together doesn't get the ball rolling is unfortuantely to drop sugar. while i know sugar is "healthy", in a state where cortisol isn't controlled, sugar appears to bring up the stress response. i have once been able to rid of the stress via only eating gelatin, as in literally only eating gelatin at every meal and dropping all sugar. which i don't know is doing more good than bad long term, but what other option do i really have at this point ha.

do u think it is permanently down regulated? i dont think so, because if pregenenlone is low, which it is, if you manage to get the cortisol low enough, i'd imagine the pregnenlone would eventually regenerate. but i dont know what is keeping the stress there. it seems like the low pregenenelone is keeping the cortisol out of control. or is it the "x-factor" finasteride keeping 5ar2 inhibited which is causing the problem?

i feel maybe progesterone was too strong with finasteride, suppressing testosterone too far, pushing pregnenelone down too low, and not be able to bring the loop back due to the low magnesium, from the pregnenelone drop, causing strong endotoxin buildup in the gut from no magnesium being able to move bowel movements, keeping cortisol elevated. but i'm not sure if it can come back around again full circle, any stressful event renables the loop back again, like working out, walking, masturbating, having sex, etc.
 
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haidut

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well that makes absolute perfect sense. i absolutely have high cortisol that i cannot get down. i managed to get it down once via light and pregenenlone together, but i haven't been able to replicate it since. sigh, well i'll keep up with the glycine and gelatin, maybe it will come down. using pregnenlone, back on my magnesium again, glycine, gelatin, cascara, 100grams of protein a day, anything else you can think of lol? thyroid i think causes the stress reaction to go up. but maybe pregenenlone and thyroid together could be different.

the only other thing i can think of if doing all of this together doesn't get the ball rolling is unfortuantely to drop sugar. while i know sugar is "healthy", in a state where cortisol isn't controlled, sugar appears to bring up the stress response. i have once been able to rid of the stress via only eating gelatin, as in literally only eating gelatin at every meal and dropping all sugar. which i don't know is doing more good than bad long term, but what other option do i really have at this point ha.

do u think it is permanently down regulated? i dont think so, because if pregenenlone is low, which it is, if you manage to get the cortisol low enough, i'd imagine the pregnenlone would eventually regenerate. but i dont know what is keeping the stress there. it seems like the low pregenenelone is keeping the cortisol out of control. or is it the "x-factor" finasteride keeping 5ar2 inhibited which is causing the problem?

i feel maybe progesterone was too strong with finasteride, suppressing testosterone too far, pushing pregnenelone down too low, and not be able to bring the loop back due to the low magnesium, from the pregnenelone drop, causing strong endotoxin buildup in the gut from no magnesium being able to move bowel movements, keeping cortisol elevated. but i'm not sure if it can come back around again full circle, any stressful event renables the loop back again, like working out, walking, masturbating, having sex, etc.

Usually, the mos common reason for high cortisol in males is low thyroid, chronic stress, heavy drinking, chronic infection, or poor sleeping habit. In that order. Not sure how much you have investigated each of these angles but that's what I would focus on.
 

Wagner83

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Usually, the mos common reason for high cortisol in males is low thyroid, chronic stress, heavy drinking, chronic infection, or poor sleeping habit. In that order. Not sure how much you have investigated each of these angles but that's what I would focus on.
Do you have any tips to determine and treat chronic infections?
 
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haidut

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Do you have any tips to determine and treat chronic infections?

In chronic infections, usually WBC will be slightly elevated or very near the top of the range. RBC may also be elevated, if the infection is somewhere in the GI tract. RBC tend to rise in endotoxemia. TNF is also elevated in many chronic infections and I think there is now a newer test for procalcitonin, which is appretnly very sensitive for a bacterial infection of some sort. Maybe @Dan Wich can find a lab that offers that test to consumers but I know LabCorp does and a doctor can order it for you. Hopefully, it is available a-la-carte as well.
Procalcitonin - Wikipedia
 
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Someone made the following statement on the PFS board:

"Glycine is an inhibitory neurotransmitter in the central nervous system, especially in the spinal cord, brainstem, and retina. When glycine receptors are activated, chloride enters the neuron via ionotropic receptors, causing an Inhibitory postsynaptic potential (IPSP). Strychnine is a strong antagonist at ionotropic glycine receptors, whereas bicuculline is a weak one. Glycine is a required co-agonist along with glutamate for NMDA receptors. In contrast to the inhibitory role of glycine in the spinal cord, this behaviour is facilitated at the (NMDA) glutamatergic receptors which are excitatory.[20] The LD50 of glycine is 7930 mg/kg in rats (oral),[21]and it usually causes death by hyperexcitability.

This is why chloride is so important. and that is why PFS people @TubZy felt terrible on gelatin . Since without chloride glycine is only excitatoryGlycine is an inhibitory neurotransmitter in the central nervous system, especially in the spinal cord, brainstem, and retina. When glycine receptors are activated, chloride enters the neuron via ionotropic receptors, causing an Inhibitory postsynaptic potential (IPSP). Strychnine is a strong antagonist at ionotropic glycine receptors, whereas bicuculline is a weak one. Glycine is a required co-agonist along with glutamate for NMDA receptors. In contrast to the inhibitory role of glycine in the spinal cord, this behaviour is facilitated at the (NMDA) glutamatergic receptors which are excitatory.[20] The LD50 of glycine is 7930 mg/kg in rats (oral),[21]and it usually causes death by hyperexcitability.

This is why chloride is so important. and that is why PFS people felt terrible on gelatin . Since without chloride glycine is only excitatory."

Any merit to this claim? I have worried about excitotoxicity, as some people claim to get headaches from gelatin. I tend to get wild dreams which bother me at night.
Very interesting about the chloride. My chloride is low and I read on a chemo therapy website that one of the side effects of Accutane is low HCL.
 

sladerunner69

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Very interesting about the chloride. My chloride is low and I read on a chemo therapy website that one of the side effects of Accutane is low HCL.

Thanks, I had forgot about this quote. I am still waiting for it to be more thoroughly addressed here. I wonder if glycine is in fact excitotoxic and the cause of migraines which some have reported after consuming gelatin or glycine?
 
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Thanks, I had forgot about this quote. I am still waiting for it to be more thoroughly addressed here. I wonder if glycine is in fact excitotoxic and the cause of migraines which some have reported after consuming gelatin or glycine?
I don’t think it would be in normal doses.
 
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Glycine can be excitatory, not toxic. Anything that promotes GABA in general can be in theory excitatory for some. Other factors like chloride are crucial in how a cell behaves when inhibited. It can go either way.
 
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Glycine can be excitatory, not toxic. Anything that promotes GABA in general can be in theory excitatory for some. Other factors like chloride are crucial in how a cell behaves when inhibited. It can go either way.
I think the toxicity is pretty high
 

Jon2547

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I don't think glycine is excitatory. But I base this off of my own experience:
I've very susceptible to the effects of MSG. And I haven't had a diet soda in 20 years.
However, eating a little too much beef gelatin can cause a reaction (probably due to the glutamic acid?). But I've been using both regular Glycine and DMG in copious amounts over the last 11 to 12 years or so and have always had good experience with it.

For frame of reference, I can't even eat sandwich breads because of the GLUten, it used to give me pains all over. I don't eat bread anymore for the most part.
 

kaybb

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I don't think glycine is excitatory. But I base this off of my own experience:
I've very susceptible to the effects of MSG. And I haven't had a diet soda in 20 years.
However, eating a little too much beef gelatin can cause a reaction (probably due to the glutamic acid?). But I've been using both regular Glycine and DMG in copious amounts over the last 11 to 12 years or so and have always had good experience with it.

For frame of reference, I can't even eat sandwich breads because of the GLUten, it used to give me pains all over. I don't eat bread anymore for the most part.
About the pain from gluten, did you feel it the day you ate the gluten or did it take a few days?
 

Jon2547

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About the pain from gluten, did you feel it the day you ate the gluten or did it take a few days?
Its felt that day, usually about three or four hours later.
 

AndrogenicJB

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My original point wasn't exactly succinct, what I meant however, was that gelatin doesn't seem to give me that elusive DHT boost like shellfish does. I am forever seeking the eternal path of DHT increase. And I have much experience and wisdom to share from my jounrey along this road.
What has worked the best for dht release
 

AndrogenicJB

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Please share your journey and results if you please :) perhaps in a seperate thread. This is one of my great goals as Well. For me eating three oysters at The same time of taking ~1 mg DHEA + 2mg preg seems to do The trick for a short time
What ahs worked the best
 

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