Research: Finasteride, GABA-A and mental/anxiety problems

Mew · May 25, 2018, 5:49am

Came across this 2003 thread from a hairloss forum, the user “Moeman” pulled together a bunch of research about Finasteride’s effects on GABA-A, anxiety and mental function. Have a read through, it only further confirms what some of us experienced - brain fog.

hairlosshelp.com/forums/mess … SGDBTABLE=

I have pasted his words verbatim below, in case that forum goes offline there will be a record here.

MOEMAN’s post:

Notes

This is a followup to my initial post asking for feedback on the mental/emotional side effects of finasteride. Someone on HLH mentioned a possible link between GABA, mental function and finasteride. I followed up with some research. This is what I could piece together- i don’t want to be alarmist but as far as I’m concerned it’s not positive news…

Why is this a concern to me… as i mentioned i have felt a little cloudy mentally for sometime… i’m a professional, finished my undergraduate degree at a decent university with a 3.9 GPA, high school with a 97% average… i thought i’d do an IQ test yesterday to give me an idea of whether i was just imagining this… I scored 105 (roughly consistent on 3 different tests). Lots of things can affect your IQ and i’m not necessarily attributing it all or at all to finasteride but my subjective decline seemed to onset with my use of proscar. (FYI i’m in otherwise good health and on no other medications, and use no illicit drugs… the rare toke aside)

Even for those who haven’t noticed any negative effects- read the summary at least. It’s important to know how finasteride impacts on your central nervous system.

Disclaimer
I do not have any particular expertise in the subject material I present here so take it with a grain of salt. Any feedback would be appreciated.

Summary- this might initially seem overly technical but it’s not that hard to follow.

DOC, an adrenal steroid whose synthesis is enhanced during stress, undergoes sequential metabolic reduction by 5a-reductase and 3-hydroxysteroid oxidoreductase to form 5-dihydrodeoxycorticosterone (DHDOC) and allotetrahydrodeoxycorticosterone (THDOC), a GABAa receptor-modulating neurosteroid with anticonvulsant properties.1

As you’re aware, finasteride (propecia/proscar) blocks 5-reductase.

So, apparently, finasteride by decreasing DHDOC and THDOC levels inhibits the effect of GABA. What does this mean to you? GABA is the most prevalent inhibitory neurotransmitter in the CNS (Central Nervous System ie. your brain). It is somewhat counter intuitive to think that inhibiting the effect of GABA (which is itself an inhibitory neurotransmitter) could have a negative impact on mental function… but the following good analogy has been made…

“It’s like New York City or Boston during a blackout,” Leventhal said, describing what would happen if neurons weren’t restricted to specific responses. “With all the gating mechanisms like the stoplights out, you’d think traffic would move faster. But it doesn’t.” 6

What do scientists believe GABA’s function impacts on- There are 3 GABA receptors A, B, and C… GABA A has anxiolytic functions (ie. anti anxiety… FYI valium acts by stimulating GABA receptors)… GABA B affects memory and mood,… GABA C- unknown… Other higher brain functions (eg. visual recognition, understanding language, memory, mental decline in the elderly, and possibly learning) are linked to GABA but I’m still researching- and unsure if they’re linked to A or B… This is pertinent because thus far the studies i’ve reveiwed have focused on the relation between GABA A and finasteride… it isn’t a far jump to think that these same neurosteroids finasteride impacts on would also affect GABA B but I haven’t been able to determine that as of yet… I will update you when I learn more.

References

The following are excerpts from different articles:

GABA

a)Higher brain functions, such as visual recognition or understanding language, require the processing of information in the brain but decline as people get older. This decline appears to be due to a reduction in a neurotransmitter called GABA, say researchers.

Macaque monkeys, with an age equivalent to 90-years in humans, were not as sharp as their younger counterparts in visual tests despite having perfect eyesight. But when they were given drugs to increase levels of GABA in the brain they improved vastly, say the team.

Delivering GABA calms the neurons down and they become more selective, says neuroscientist Audie Leventhal, at the University of Utah School of Medicine, who led the study. “They look the same as they did 20 years ago,” he says.

Importantly, this suggests that mental decline could be easily treated, says Leventhal. “The fact is all the cells are still there and functioning, it’s a transmitter problem - it’s treatable,” he told New Scientist.2

b)Neurosteroids (ie. DHDOC and THDOC) also are capable of interacting directly with GABAa receptors, albeit at high concentration. Of clinical significance, neurosteroids have been demonstrated to have anxiolytic (anti anxiety), hypnotic, anesthetic, and anticonvulsant effects,and have been implicated as having a role in memory enhancement, behavioral actions, and neuroprotection…

In an elegantly designed set of experiments, Reddy and Rogawski showed that the stress-induced neurosteroid DOC is capable of positively modulating GABAAreceptors through its metabolites DHDOC and THDOC.3

c)pharmacological modulation of GABAa-receptor efficacy with exogenous agents (e.g., benzodiazepines and -carbolines) is known to occur through allosteric mechanisms that modulate the effectiveness (positive and negative) of GABA at this receptor. The most potent endogenous modulators are 5 alpha-reduced steroids. Production of these steroids was attenuated in adult rats with systemic injection of Finasteride, a competitive substrate for 5-reductase.4

d)Introduction
GABA == ?-aminobutyric acid (Neuroscience, p110)
Identified in the 1950s. (Neuroscience, p111)
It is a neurotransmitter: it is released from presynaptic terminal buttons into the synaptic cleft in response to action potentials. (Neuroscience, p111)
GABA is the most prevalent inhibitory neurotransmitter in the CNS. (Neuroscience, p110) Although in the spinal cord about half of inhibitory neurons use glycine instead. (Neuroscience, p112)

Role
Curtis & Watkins (1959) showed that GABA had an inhibitory effect on neurons: it inhibits the ability of neurons to fire action potentials (Neuroscience, p119)

Altered GABA function or degeneration of GABAergic neurons leads to many disorders: (MNP, p154-155)
Epilepsy
Huntington disease
Tardive dyskinesias
Alcoholism
Sleep disorders
Enhancement of GABAergic function is a highly effective method for treating some types of anxiety and epilepsy. (MNP, p155) 5

e)Biological Explanation of Anxiety

Inactivity of GABA neurotransmitter:

Normal person: There is a dangerous or anxiety-provoking stimulus à neurons fire impulses that increase excitability and anxiety à excited neurons send messages to other neurons through feedback loop to release GABA neurotransmitter à GABA neurotransmitter is released and binds to receptors of the excited neurons à GABA is an inhibitory neurotransmitter that inhibits the excitability of the neurons à anxiety is reduced
Person with anxiety: There are problems with the feedback loop or amount of GABA released à not enough GABA binds to the receptors of the excited neurons à excited neurons continue firing à person remains in prolonged state of anxiety.7

Footnotes

Question…

a)Is the GABA B receptor modulated by the neurosteroids that finasteride impacts on or just GABA A?

Mew · May 25, 2018, 5:52am

Some more insights from another hairloss site, some guy’s own synthesis of information:

hairsite7.com/m586dutas26/_d … 000236.htm

5 alpha-reductase inhibitors and mental health…scary
From: Scared
Date: 7/28/2002
Time: 10:24:17 AM
Remote Name: 193.219.1.37

"I’ve been using finasteride (proscar cut into roughtly 1.25mg quarters) now for about four to five months. I can’t tell yet if it is helping my hair, which is not suprising given this short duration.

I have experienced few if any sexual side effects, except that maybe I’m not as consistently horny as I used to be. That isn’t entirely a bad thing. However, despite the intact sex life, I must admit I’ve felt a bit more moody on it than I used to feel. I thought maybe it was just my imagination, but then one night I went to a party and had a couple beers. I don’t drink very often and my tolerance is not all that high these days. I was suprised to notice that I didn’t really feel drunk. I had two more beers. At this point I should have had a lampshade on my head, but instead I felt only slightly buzzed. Another night I went out to eat with my girlfriend and, after a couple drinks, felt next to nothing. At least, I didn’t feel that kind of relaxing high that alcohol can give you. All I felt was a bit red in the face.

I didn’t think much of it at the time, but on a hunch, I got on the internet, wondering if finasteride might affect the way EtOH is metabolized or something.

Much to my suprise, I did find a connection between finasteride and alcohol. It would appear that alchohol causes an increase in the production of a “neurosteroid” called allopregnanolone. Allopregnanolone binds to a certain receptor in your brain, the GABA(A) receptor. GABA(A) is a receptor for a neurotransmitter called GABA (short for gamma aminobutyric acid). GABA is one of the major inhibitory neurotransmitters, and is implicated in many anxiety disorders and depression. Certain anti-anxiety drugs like valium bind to GABA’s recpetor too. Allopregnanolone is an “allosteric enhancer” of the GABA(A) receptor. That means it helps the receptor do it’s job better. Specifically, it intensifies the effects of GABA by making it much easier for GABA to “turn on” the receptor. So, when you drink alcohol, more allopregnanolone gets produced, GABA is thus made more potent, and you feel relaxed and happy.

Here’s the deal: Allopregnanolone is a metabolite of progesterone. Guess what is one of the enzymes responsible for converting progesterone to allopregnanolone: Yep, 5-alpha reductase. In other words, just like it inhibits the conversion of testosterone to DHT, finasteride blocks the conversion of progesterone to allopregnanolone.

It gets worse: Just before menstruation, the levels of progesterone in a woman’s body drop dramatically. This leads to a corresponding drop in allopregnanolone, which leads to…PMS! That’s right, one of the reasons women get moody and anxious before they get their period is because they’re experienceing allopregnanolone withdrawl. Contrary to what many think, men also make progesterone, and men also depend on allopregnanolone for the proper functioning of GABA in their brains.

Needless to say, I have been doing a lot of reading about this, and I’m a bit alarmed. I knew going into it that finasteride could maybe effect erections or my sex drive, but nobody said it could make me depressed or anxious too. But there is clear scientific evidence out there that finasteride can have some profound effects on the way your brain works. Most specifically, it will effect the way your brain reacts to stress: stress causes increases in the production of allopregnanolone, and allopregnanolone production in the cerebral cortex is greatly inhibited by finasteride. Some people are even considering giving finasteride to alcoholics to help them get off the sauce: Since finasteride deprives you of the relaxing reward of drinking, there’s less of an incentive to drink!

I work as a biologist. The studies on this subject have been published in some very reputable journals, like The Proceedings of the National Academy of Sciences, The Journal of Neuroscience, Brain Research, etc.

Just follow this link:

ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed

Type in the blank “finasteride” and “allopregnanolone” and see what you turn up. Scientists use finasteride as a tool in the lab to study behavior in rats, like their response to alcohol or stress. Loss of allopregnanolone even makes rats more prone to seizures when treated with certain drugs. I’m not making any of this up.

My feelings upon reading all this stuff: Oh f**k! I really don’t know what I should do at this point. My emotional state has only been mildly affected, I would say, and I can’t really say I’ve experienced any significant impact on my life. But the fact is, this drug does more than just just stop you from losing your hair (maybe). It turns out there are a lot of steroid hormones in your body, and many of them are converted by 5-alpha reductase. All of these hormones have a purpose, and I just have to wonder what the long-term effects of monkeying around with them might be. If all finasteride did was inhibit DHT, I probably could ignore it, since my sex life is fine. But I’m not so sure any of us should ignore some of its other effects. We should at least be fully informed as to what this drug does to our bodies.

Mew · May 25, 2018, 5:52am

2nd post from above user:

hairsite7.com/m586dutas26/_d … 00023c.htm

5 alpha-reductase inhibitors and mental health. Vol. 2
From: Scared
Date: 7/28/2002
Time: 2:33:12 PM
Remote Name: 193.219.1.37

"I hate to say it, but it gets worse.

There’s another neurosteroid that is affected by finasteride. It’s called allotetrahydrodeoxycorticosterone (long name…call it THDOC for short). It is a metabolite of deoxycorticosterone (DOC), an adrenal stress hormone. Part of the body’s “stress response” is to produce corticosteroids like DOC, which has lots of differente effects relevant to “fight or flight”. Anyway, DOC is coverted through two steps (the final step relying on 5-alpha reductase) into THDOC, which has a similar function to allopregnanolone: It is an enhancer of GABA signaling. So, when you are confronted with a stressor, your body releases corticosteroids, you get a jolt from that, and then at least one of them, DOC, is converted into a relaxing neurosteroid.

I think the implication of this is clear: Finasteride may interfere with your body’s ability to produce an emotional calm after a stressor. If one is experiencing a lot of turmoil in one’s life, I just have to wonder if taking finasteride makes it harder to cope with it.

The details of this study can be found here:

ncbi.nlm.nih.gov/entrez/quer … t=Abstract

There’s another troubling study here:

ncbi.nlm.nih.gov/entrez/quer … t=Abstract

In this study, rats were subjected to physical stress, or treated with an anxiogenic drug. In both cases, finasteride potentiated the response to anxiety in the brains of these rats, by lowering allopregnanolone levels.

Damn, damn, damn.

I didn’t want to believe it, but I’m starting to become more and more convinced: This stuff may literally not be good for your mental health. There are more and more studies each month and they all tell the same story: finasteride is essentially an anxiogenic drug in both biochemical and behavioral animal models. It’s reasonable to conclude it could have the same effect in humans, since these animal models are used to screen drugs for their potential anxiolytic or antidepressant properties. I’m deeply concerned now, and I don’t know what the best response should be."

r_u_going_bald · May 25, 2018, 5:53am

The last 3 years I have been dealing with anxiety/depression, the past year I have been going the natural way and taking amino acids to raise my neurotransmitters. I have taken 4 neurotransmitter tests to see if my levels are rising and every test showed my gaba transmitter has never raised into the normal levels. This might be the propecia that I have been on for 10 years. Thanks for the post.

Mew · May 25, 2018, 5:54am

Info on GABA levels and relationship to depression:

clinchem.org/cgi/reprint/40/2/296.pdf

r_u_going_bald · May 25, 2018, 5:54am

So what r u saying most people with low Gaba are mentally ill

Mew · May 25, 2018, 5:54am

It’s just interesting to note that based on this study, they conclude that low GABA levels may pre-dispose someone to depressive or other mood disorders.

Abstract:

y-Aminobutyric acid b, an inhibitory neurotransminer
that serves about one-third of brain neurons, is
involved in the development of depression and in the
treatment of depression and mania with pharmacological
therapy. [/b]

Brain activity of GABA may be conveniently measured
in plasma, and changes in plasma concentrations
of GABA reflect brain GABA activity.

Plasma concentrations
of GABA are signfficantly lower than control values
in about one-third of patients with major depressive disorder;
concentrations are also low in patients with mania
and in bipolar patients who are depressed.

These low
concentrations of GABA appear to persist after recovery
from depression and are not increased by treatments that
improve depressive symptoms. Follow-up studies suggest
that GABA concentrations remain relatively constant
over at least 4 years. Additionally, preliminary data suggest
that low plasma GABA is a familial marker of mood
disorders in a subset of patients.

Despite the difficultyof
demonstrating that a particular biochemical measure is a
true genetic trait marker for vulnerability for development
of an illness, the accumulated data suggest that low
plasma GABA may represent a biological marker of vulnerability
for development of various mood disorders.

r_u_going_bald · May 25, 2018, 5:54am

Mew
Do you know any supplements or anything that can raise the Gaba levels

ithappens · August 25, 2021, 10:55am

funny you should say this and we’re here talking about it. GABA is basically the overall neurosteroid that allows for the entire brain system to function properly, i.e. allo-pregnenolone etc produces it. I wouldnt say im mentally ill as much as emotionally numb to everything, and physically exhausted. I’ve been having muscle twitches from hell too recently so it’s all very interesting. Any drug that somehow raises GABA levels which they are trying to come out with would be extremely beneficial but the problem with that is anything that directly affects GABA alcohol, marijuana, and GHB etc would send the user into a drunken/high sort of state. Anyway, they’re putting me on xyrem so I should finally get some needed deep sleep but the effect on GABA is far less potent than real ghb.

peres · August 25, 2021, 10:55am

Alcohol also? That could explain why I had 2 days of recovery to pre-fin state after I drunk a lot at the party

r_u_going_bald · August 25, 2021, 10:56am

Ithappens what is xyrem, and do you have any relief with it.

ithappens · May 25, 2018, 5:54am

Xyrem is sodium oxybate (the salt crystals of GHB). It basically is a medication used for narcolepsy and cataplexy. It’s suppose to work is a similar manner to that of real ghb, sending the user into a deep stage 3 and 4 sleep for a period of time etc. I have not taken it yet I just recently had it prescribed, and will have to wait to be approved for it, and get it as it is a highly controlled thing here. Problem is real pure GHB would be far more powerful and work a lot better while Xyrem is so weak it just sort of gets you by. Also i’m not sure how effective xyrem is on increasing GABA compared to real GHB.

r_u_going_bald · May 25, 2018, 5:54am

Is ghb illegal and the the other one and can you become addicted to it.

ithappens · May 25, 2018, 5:54am

yes here in the US it is ILLEGAL unfortunately and yes when abused and taken multiple times throughout the day GHB can become addictive. However, and I do stress when taking daily small amounts at night just for sleep there seems to be some very beneficial properties. There is no evidence to suggest either way that when taken properly and not abused GHB is or isn’t addictive, as many users who have taken it in controlled doses over the years claim it isn’t. As with xyrem there is little chance at all for addiction just based on my own personal opinion and observations. It is far less stronger than real GHB and many from every doctor I talked to and user etc when taken at the prescribed nightly amount there is little to chance of addiction. However, the problem remains Xyrem probably won’t be strong enough to tickle this situation in terms of deep sleep and GH release, real GHB is most likely a far better option, in my opinion.

NameChange · May 25, 2018, 5:54am

ithappens: hopefully that helps you. If it does, is it a medication that has to be taken for life? You are lucky you live in the US, here in Scandinavia I will probably have difficulties getting even clomid before trying TRT.

ithappens · May 25, 2018, 5:54am

Onni I honestly hope it helps too. I realize that you may have a hard time getting on xyrem as i think i read somewhere it is still in the process of being released throughout europe. However, in europe GHB/GBL is still very much bought and sold in the drug trade and I have no doubt that if you looked hard enough you could find some or the ingredients to make your own. Here in the US though the stuff has literally been removed from the streets as it is a scheduled 1 substance, you get caught with this and you’re probably gonna go to jail. I asked a few of my shadier friends over the past year about it, and basically and I quote from one of them “you have a better chance of finding heroin”. Anyway, as far as taking it for life I dunno. Xyrem is far less powerful than true GHB so it may not even work, but the bottom line is i need it to help with deep sleep so hopefully i can recover and lead a somewhat normal life. I just hope it at least works and i can take it from there.

Mew · May 25, 2018, 5:56am

Neuroactive Steroids in Schizophrenia

ww1.cpa-apc.org:8080/Publication … bbo-RP.pdf

For those experiencing “dementia” or feelings of mania while on Finasteride, this article may provide some insight.

Looks like our old friends, the neuroactive steroids Allopregnanlone (3a, 5a-THP), Tetrahydrodeoxycorticosterone (3a, 5a-THDOC) and GABA-A are interfered with when it comes to schizophrenia. There is a diagram in this paper illustrating where 5AR comes into play.

Of course, Finasteride blocks Allopregnanolone and THDOC production thanks to blockade of 5AR-reduction of these metabolites, so they can no longer act properly on GABA-A while the drug is taken.

As well, the authors mention antipsychotic drugs which can be used to boost Allopregnanlone and THDOC: olanzapine, and clozapine. However, these are only mentioned in passing – taking such medications may be extremely dangerous, as mechanisms of action are not fully known and overdose can possibly lead to death or other problems.

nlm.nih.gov/medlineplus/drug … 01213.html

en.wikipedia.org/wiki/Olanzapine