Hi all—
It’s been a long while since I have posted here (roughly 8 months), and it’s now been exactly a year since I discontinued finasteride (which I had taken at 1 mg for 3.5 months). If I’m going to be honest, I had a pretty lousy experience on this site; I encountered a lot of negativity, incredulity, dismissiveness, and sententiousness around the few posts I made doing some perfunctory speculation about our collective condition. This, in conjunction with the general (and understandable) defeatism and fatalism by most member, mostly left me feeling far worse any time I ventured on the site. So, I eventually decided I wouldn’t come back, and that has mostly been for the better. Though I will say the past year has been the worse of my life, and that the decision to initially take finasteride has unequivocally been the worst decision I’ve ever made. I’ve debated writing anything here at all—and I’ll likely just post this and not view any of the comments—but I feel that I have some responsibility to share my positive outcome with both those looking for hope and for those who many want to pursue the therapies I did.
Now onto the positive: I’m recovered after a year of real pain and anguish and in addition I know the exact biochemical mechanism underpinning my unique problem. Now, I know that there are disparate symptomologies when it comes to finasteride discontinuation, and I’m not making any blanket statements about quick fixes, cures, or other problems outside of how my symptoms evinced. I hope this is sufficiently hedged such that it is clear that I’ve only done research and pursued treatment specific to my unique experience. Though I won’t go i to detail about the different therapies and tests I pursued, I’ve now seen 6 neurologists, two neuro-ophthalmologists, a neuro-endocrinologist, and several other specialty doctors. I’ve done every type of EEG and electrophysiological test on my eyes, MRI’s, spinal taps; I have also tried many medications largely to no appreciable avail. My final diagnosis—and one that is congruent with all my symptoms and the available research—is the development of pathological, chronic allopregnanolone tolerance. I will explicate more on this below. I will also make a note that I do have a background/degrees in biochemistry if only to add some ethos to this post.
In general, I suffered from many of the commonplace neurological symptoms: headache mostly manifesting as pressure behind the eyes in the frontal cortex region, debilitating insomnia, saccadic eye movement intrusions when attempting to read and to fixate, shaking visual fields, cognitive block, some hyper-adrenergic feelings, heightened anxiety, and generalized dizziness without a rotational, vertiginous component. At their height, my symptoms made me contemplate suicide on an hourly basis (though not as a result of any adduced depression but rather as a way to escape the pain), and I even wrote notes to those closest to me while holding out hope that they would never require delivery. I will note that I have not experienced sexual side effects beyond the attenuated libido of the sleep deprived, so I can unfortunately provide no guidance with this common symptom.
I was initially inclined to believe that I was suffering some ablation in my production of allopregnanolone as all of my symptoms are directly tied to its neurological effects (reduction of anti-saccadic eye movement), sedation, etc (https://en.wikipedia.org/wiki/Allopregnanolone). This theory has borne out false as two separate CSF fluid tests have indicated adequate 5α-sterol production within my CNS, in serological tests, and in urinary tests. I pursued many other avenues of testing in service of many other plausible theories underpinning my symptoms, such as the de-methylation theory I’ve seen countenanced here and various other logical possibilities, with no ultimately no evidential basis that any of these were the ultimate cause.
The fifth neurologist with whom I consulted at Mayo Clinic suggested I look into thalamus and thalamus-relay cell conditions (such as some forms of epilepsy) as many of my symptoms appeared reflective of disfunction in the ventral-posteriomedial nucleus and the reticular formation of the thalamus, areas controlling reduction in intrusive eye movements, visual cortex relay, sleep-wake cycles, and indeed even conscious awareness (https://en.wikipedia.org/wiki/Reticular_formation). This presentiment proved exactly correct: a further test of my CSF indicated a significant downregulation of δ subunit-containing GABA(a) receptors. Without being too technical, these are the GABA(a) receptor unit subtypes that are most commonly expressed in the relay neurons of the thalamus, and they mediate the extra-synaptic tonic GABA conductance necessary for neural inhibition of the various cortices under their control. This paper delineates the various changes produced to GABA(a)—and very likely GABA(c-rho) receptors most densely found in the human retina—that occur after chronic exposure to elevated ALLO concentrations (with pregnancy as a substantiator of this):
In effect, after chronically inhibiting 5α-sterol, the receptors for these ligands and positive allosteric modulators increase in expression and density as one would expect. Upon disinhibition, ALLO levels rise acutely and stay elevated (at least seemingly elevated to my body’s new set point after finasteride treatment) and fomented a quick and substantial downregulation of the receptors most responsive to ALLO positive allosteric modulation. This is similar to a sudden usage of large doses of benzodiazepines (albeit this is a flawed analogy given how they activate entirely separate GABA subunits) and the concomitant development of rapid tolerance (via rapid downregulation of δ subunit-containing GABA(a) receptors). Unfortunately for us, in the ALLO agonizes more homeostatically important receptors that mediate tonic inhibition in our most crucial of neural circuitry: thalamic reticular formations. As such, our bodies seem unable to equilibrate or to so slowly when our sleep and anti-inflammatory pathways are so irreparably disrupted.
As an aside, I’ll include as many of the studies/papers that are relevant to this post as I can, but I’m liable to omit something, so please do your research if you believe you are in the same boat as me. Now, regarding specific GABA(a) subunit composition in the extra-synaptic and peri-synaptic space, a few subtypes are solely expressed, specifically α4βδ’s. In this study on the effects of sub-chronic finasteride treatment (which many of you are familiar), “GABA-A receptor subunits (i.e., a decrease of alpha 4 and beta 3 mRNA levels in the cerebral cortex) were detected” of the mice in the withdrawal arm of the study:
This is congruent with the widespread down regulation of α4β3δ GABA(a) receptor subunit in my CSF reports, and further suggests that at the level of mRNA regulation, I developed a paucity of these crucial receptor types which are potentiated and modified by ALLO more potently than any other receptor type. Further evidence of this is that the ALLO tolerance paper which I previously cited found a similar down regulatiuon of the GABA-A receptor α4 subunit and the expression of the α4 subunit mRNA in the ventral-posteriomedial nucleus of the thalamus.”
So, what to do? My specific situation has been distilled to marked downregulation of α4β3δ GABA(a) receptor subunits in my thalamic relay neurons, my cortex, and likely my hippocampus (and probably many other brain regions that are beyond discernment). So I began researching GABA(a) receptor upregulating substances ad nauseum. I also have looked into GABA(b) receptor up regulators too, as even though they are structurally and functionally different there is good evidence that GABA(b) agonism potentiates GABA(a) tonic conductance while simultaneously upregulating various neuro-steroid concentrations (https://www.jneurosci.org/content/33/9/3780).
This study delineates the mechanism of regulation of α4βδ GABAR Expression (https://www.frontiersin.org/articles/10.3389/fncir.2013.00135/full), and is worth reading. Here is the upshot from my notes:
Expression of α4βδ controlled by:
-mRNA expression up-regulated by NMDA activation (inotropic glutamate receptors - needs glycine and glut)
-“GABA alone does not increase receptor expression (it’s only a partial agonist of these receptors), but other high efficacy agonists, such as gaboxadol (THIP) and β-alanine, are able to increase surface expression of the receptor, an effect mediated by protein kinase C-δ” (seems like this is only acute - chronic admin leads to tolerance buildup)
-Brain-derived neurotrophic factor (BDNF) plays a role in the activation of the α4 promoter and increasing delta subunit expression (via TrbK activation; agonists: Amitryptiline & 7,8 DHflavone!) - Niacin appears to upregulate BDNF and tropomyosin receptor kinase B (TrkB) expression as well.
-apparently gabapentin increases expression of these receptors of δ subunit-containing GABAA receptors (https://www.ncbi.nlm.nih.gov/pubmed/30878595). (This is probably subject to withdrawal, however, and is dose-dependent)
As a general rule, it is advisable to avoid full agonists of these receptors as they might aid in the short term but will further lead to down-regulation of the receptors (https://www.ncbi.nlm.nih.gov/pubmed/8246917). As referenced above, “β-alanine and taurine are full agonists at these receptors” [α4βδ].
I’d like to qualify my statements again and say this improvement has only been specific to my personal condition, and I’m unsure if it’s extrapolatable. I’m just reporting what has provided me improvement given my specific case and am not claiming that this is the root cause for all here.
The most important things that have led to my recovery (which is completely independent from time progress as my windfall in improvement was about 2 months ago and was a departure from my terrible trajectory) are these:
-Intermittent Fasting (I initially tried keto, but it did not seem too efficacious for me; rather, 22 hour intermittent fasting protocol has wrought significant improvement. There exists good research into the neurotrophic-boosting benefit of this as well as its glutamate-induced toxicity attenuating effects)
-Mg BHB (an exogenous keto to aid in the fasting)
-Bacopa Monnieri (this is arguably the most important supplement I’ve taken; this study-- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3306740/ – finds that this herb/nootropic normalizes all GABAR deficiencies in epileptic rats, a condition that mimics my own)
-Caffeine (although potentially aggravating in the short-term, leads to “GABAA receptor density is increased by 65%”- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3437321/)
-Curcumin (seemed to aid me greatly with general neuroinflammation)
Here are various other non-essential supplements I’ve tried and the reasoning from my notes:
-*Kava (increases Gaba receptor density - doesn’t seem to bind directly to gaba r though - https://www.ncbi.nlm.nih.gov/pubmed/27332705 - the degree of enhancement was greater at α4β2δ!)
-Black Seed Oil/ Nigella sativa (reduce NO; promote GABA signaling; good for brain injury, etc.)
-Uridine Monophosphate (increase NGF/neuroplasticity & improve delta sleep - seems better to take in morning)
-Exogenous Ketones (MG BHB)
-Fasoracetam (up regulate gaba b - this, in turn, unregulates allo synthesis)
-PQQ (neuro inflammation & sleep)
-Lemon Balm (Gaba breakdown inhibitor - might cause baba r down reg)
-Panax Ginseng (glutamate toxicity - apparently acts similar to a neurosteroid)
-Lithium (potent neuro protectant) - watch out for SS w ami
-Vinpocetine (neuro protectant) - side effect = insomnia, though
-Phosphatidylserine (neuro protectant/ memory aid + reduces cortisol)
-Resveratrol (anti-inflammatory - Neuron growth, etc.)
-Curcumin (need this w bioperine to aid absorption)
-Magnesium Citrate 1200 mg daily (glycine is a co activator of NMDAR)
-Vitamin D3 (2,000 IU)
-Taurine (GABA full agonist @ α4βδ - issues w agonist tolerance)
-SkullCap (gaba a agonist/PAM - probably not a good idea w tolerance)
-Zinc (seems that it binds at the alpha-beta subunit site to antagonize GABA a - probably not a good idea)
-Emoxypine (apparently similar to NAC - neurotropic and anti-inflammatory specific to hangovers; also, epilepsy treatment) - although it’s just a P-5-P homolog
-Afobazole (Russian drug - neurotrophic increase, etc.)
-Saffron (more research needed)
-Etifoxine (drug — up neurosteriod synthesis - idk about this one)
-Magnolia Bark (up regulate certain alpha subunit GABA R’s) - I have a little bit in Relora
-Beta-alanine (full agonist of delta-subunit contenting Gaba a receptors - probably tolerance issue)
-7,8 DHFlavone (TrkB receptor agonist - to promote BDNF to promote increased extra synaptic Gaba expression)
I’d like to note that none of these are entirely necessary but may be an avenue to pursue, but what has benefitted me the most is fasting and Bacopa. Here is the list of medication that I have tried and have seen no appreciable benefit from:
-Trazodone
-Baclofen
-Gabapentin (though this did greatly aid with sleep, it exacerbated daytime headaches)
-Amitriptyline
-Atenolol
My best wishes to everyone here, and I hope this is of help to someone.