Can anyone make sense of this to explain to a layperson?

[[cs...]]

I received a few questions on benzodiazaphines, Neurosteroids and tolerance,as well as how neurosteroids affect GABAa receptors.  I have not done much research on  this ADDENDUM yet. I wanted to provide some of the information I have in this subject right now,  for those who are interested….

 

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Some notes on Neurosteroids

 

Some of the neurosteroid metabolic pathways are a bit involved, so this diagram below will be helpful in interpreting the information below.

 

Neurosteroid pathways

 

https://www.frontiersin.org/files/Articles/16748/fendo-03-00010-HTML/image_m/fendo-03-00010-g001.jpg

 

Source

 

https://www.frontiersin.org/articles/10.3389/fendo.2012.00010/full

 

  Neurosteroids not only bind to the synaptic GABAa receptors but also to the extrasynaptic GABAa receptors, preferentially to the δ subunit receptors, with very high affinity. If you recall from an earlier ADDENDUM, the extrasynaptic receptors play a large part in tonic inhibition, which is sort of like a steady state low level inhibition, that is instigated by low levels of extracellular GABA.  It has many purposes in the neural circuitry in the brain, such as reducing the probability that an action potential fires off in neurons, in a sense tempering or calming down the excitatory aspect of the neuron.  Preferential binding to δ subunits causing tonic inihibition can have opposite effects when the binding is to an interneuron as opposed to a principal neuron, as illustrated in the figure below.  The binding of a neurosteroid to an interneuron will cause less GABA to be released to the principal neuron, thus disinhibiting (exciting) it, whereas the binding of the neurosteroid to the principal neuron will inhibit the principal neuron.  Thus, clinical studies are very difficult to interpret sometimes. The effects of the neurosteroid(s) on the inhibitory circuitry of portions of the brain that are being studied, relative to physiological function can often be complex and even somewhat perplexing

 

https://www.frontiersin.org/files/Articles/64757/fncir-08-00003-HTML/image_m/fncir-08-00003-g001.jpg

 

 

The Neurosteroids preferentially bind to the δ extrasynaptic receptors, and act as positive allosteric modulators (PAMs) on these GABAa receptors.  They also bind to synaptic receptors as well, as a  PAM.  Extrasynaptic receptors  effect the membrane potential of the post synaptic neuron, in such a way that this steady state inhibitory conductance prevents excessive excitatory potentials in the post synaptic neuron.  In fact, extrasynaptic knockout mice(mice that have selectively removed subunit extrasynaptic receptors) are more prone to seizures and have a lower seizure threshold.  Once again, these studies are very difficult to interpret, because in knocking out specific subunits, there are compensatory intracellular processes in place that often upregulate or sensitize  different and other subunit GABAaR populations as part of a homeostatic response to the knockout.  There are newer more modern genetic (antibody) techniques for handling these types of clinical studies, but this subject area is beyond the scope of this module.

 

The neurosteroids bind between α and  β subunits , but the GABAA receptors are very sensitive to neurosteroids if a δ subunit is present . The binding site is the same site as endogenous GABA, which is also between the α and β subunits.

 

In addition, as we saw in an earlier ADDENDUM with alcohol, Neurosteroids, as a PAM , do change the extrasynaptic and synaptic subunit distribution .(references below) There are changes most notably in α4 and δ extrasynaptic GABAa receptors, and tonic inhibition is affected accordingly. (Reference below).  Thus, just because a PAM does not bind to the same site as benzodiazaphines (between the α and γ subunits), it does not mean that the PAM cannot produce changes in the GABAa receptor subunit clustering configuration that affect these subunits or affect GABAaR trafficking adversely.  Furthermore, the intracellular processes involved in such processes  are complex and not always consistent across various PAMs.  The mechanisms behind general and local anesthetics as PAMs are not entirely clear, but some anesthetics (like propofol) are thought to bind primarily to the β3 subunit of the GABAaR.  In β3 knockout mice, these very powerful anesthetics have very little effect.  Nonetheless they do affect the GABAaRs in a manner similar to other PAMs and can potentiate the negative effects that benzodiazaphines have on the GABAa receptor, just like the other PAMS.

 

One reason causing the apparent inconsistency in our understanding of the neurosteroid GABAa receptor interaction, in particular , is that it is brain region and neuron type specific.

Benzodiazaphines appear to affect neurosteroid synthesis and metabolism, through peripheral benzodiazaphine binding sites called TSPOs (mentioned in the dementia paper as well) , as well as by inhibiting some isoenzymes that are directly involved in neurosteroid synthesis. (References below) Enzymes are catalysts to a substrate production of the end product. Thus, some endogenous  neurosteroid production is reduced when taking benzodiazaphines chronically.  However, when acting through the TSPO mechanisms, neurosteroid production appears to be increased or enhanced. 

The former (the reduction in neurosteroid synthesis )could account for the exogenous neurosteroid therapeutic benefits that are seen in managing withdrawal and tolerance from benzodiazaphines.(see reference below).  Because neurosteroid metabolism and synthesis can be reduced with chronic benzodiazaphines administration, the neurosteroid levels could be one of many causes for tolerance development. 

 

Using Neurosteroids as an adjunctive therapy during benzodiazaphine withdrawal is contraindicated for the same reasons that have been cited for other PAMs.  Some of these have been discussed previously in the context of benzodiazaphines. (Downregulation, changes in subunit synaptic and extrasynaptic clustering, changes in phosphorylation and endocytosis of synaptic receptors, etc….). The studies cited below do show improvement in the withdrawal symptoms, but the studies were relatively short at 21 days.

 

  It's important to note that there are excitatory and inhibitory neurosteroids.  See the wiki link below.

Neurosteroids profoundly affect stress homeostasis, and physical and  psychological well being during pregnancy, ovarian cycle, and postpartum .  One mechanism is through their profound effects on synaptic and extrasynaptic GABAa receptors.

 

 

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Technical information

 

 

https://en.m.wikipedia.org/wiki/Neurosteroid

 

 

 

Inhibitory neurosteroids

 

 

Quote

These neurosteroids exert inhibitory actions on neurotransmission. They act as positive allosteric modulators of the GABAA receptor(especially δ subunit-containing isoforms), and possess, in no particular order, antidepressant, anxiolytic, stress-reducing, rewarding,[10]prosocial,[11] antiaggressive,[12] prosexual,[11] sedative, pro-sleep,[13] cognitive and memory-impairing,[citation needed] analgesic,[14] anesthetic, anticonvulsant, neuroprotective, and neurogenic effects.[3]

Major examples include the pregnanes allopregnanolone (brexanolone), pregnanolone (eltanolone),(dm123: note: not the same as pregenolone) and tetrahydrodeoxycorticosterone(THDOC), the androstane 3α-androstanediol, and the cholestane cholesterol.[15][16]

 

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Excitatory neurosteroids

 

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These neurosteroids have excitatory effects on neurotransmission. They act as potent negative allosteric modulators of the GABAAreceptor, weak positive allosteric modulators of the NMDA receptor, and/or agonists of the σ1 receptor, and mostly have antidepressant, anxiogenic, cognitive and memory-enhancing, convulsant, neuroprotective, and neurogenic effects.[3]

Major examples include the pregnanes pregnenolone sulfate (PS), epipregnanolone, and isopregnanolone (sepranolone), the androstanes dehydroepiandrosterone (DHEA; prasterone), and dehydroepiandrosterone sulfate (DHEA-S; prasterone sulfate), and the cholestane 24(S)-hydroxycholesterol (NMDA receptor-selective; very potent).[17]

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Other neurosteroids including corticosteroids, prgenenolone, progesterone, estradiol need to be considered.

 

 

Quote

Certain other endogenous steroids, such as pregnenolone,[21] progesterone,[22][23] estradiol,[5] and corticosterone are also neurosteroids. However, unlike those listed above, these neurosteroids do not modulate the GABAA or NMDA receptors, and instead affect various other cell surface receptors and non-genomic targets. Also, many endogenous steroids, including pregnenolone, progesterone, corticosterone, deoxycorticosterone, DHEA, and testosterone, are metabolized into (other) neurosteroids, effectively functioning as so-called proneurosteroids.

 

 

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neurosteroids and hormone homeostasis in the DG (a region of the the hippocampus )

 

Source:

Front. Neural Circuits, 03 February 2014 | https://doi.org/10.3389/fncir.2014.00003

The impact of tonic GABAAreceptor-mediated inhibition on neuronal excitability varies across brain region and cell type

Vallent Lee and Jamie Maguire

 

https://www.frontiersin.org/articles/10.3389/fncir.2014.00003/full

Quote

 

In addition to potenti- ating the effects of GABA on GABAARs, steroid hormones and neurosteroids have also been shown to alter the expression of GABAA R subunits. GABAA R subunit expression patterns change throughout the ovarian cycle. .

 

 

At times of the cycle when levels of progesterone and progesterone-derived neurosteroids, such as 3α,5α-THP (allopregnanolone), are increased, expression of the GABAAR δ subunit and tonic inhibition is increased in DGGCs, whereas levels of the γ2 subunit decrease (Maguire et al., 2005). .  It has been demonstrated that the ovarian cycle-associated changes in GABAAR subunit expression in the dentate gyrus is dependent on neurosteroid synthesis (Maguire and Mody, 2007).

Changes in GABAAR subunit expression have also been demonstrated during pregnancy and the postpartum period. Elevations in neurosteroid levels in the brain and plasma during pregnancy (Concas et al., 1998; Follesa et al., 1998) are accompanied by a downregulation of GABAAR γ2 and δ subunits in the dentate gyrus, resulting in a decrease in both tonic and phasic inhibition (Maguire and Mody, 2008; Maguire et al., 2009). . It has been proposed that the downregulation of GABAAR subunit expression during preg- nancy is a compensatory mechanism to offset the massive increase in neurosteroid levels during pregnancy which can act to poten- tiate GABAergic inhibition (Maguire et al., 2009; Maguire and Mody, 2009). (dm123:Postpartum depression and anxiety ?)

 

Consistent with this theory, the increased hip- pocampal excitability in slices from pregnant mice was restored to virgin levels upon the addition of allopregnanolone (Maguire et al., 2009; Maguire and Mody, 2009). These results suggest that homeostatic mechanisms exist to balance GABAAR expres- sion with fluctuating hormone levels, which likely functions to maintain an ideal level of neuronal excitability (Maguire and Mody, 2009).

 

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Neurosteroids and acute stress homeostasis in the DG (cells in the hippocampus)

 

Quote

 

Neurosteroid-mediated changes in GABAAR sub- unit expression in the dentate gyrus have also been demonstrated following acute stress. Acute stress can rapidly increase the level of stress hormones like THDOC, and acute restraint stress has been demonstrated to upregulate the GABAAR δ subunit and increase tonic inhibition in DGGCs (Maguire and Mody, 2007). This GABAAR regulation was shown to be dependent on neu- rosteroidogenesis (Maguire and Mody, 2007; Sarkar et al., 2011), demonstrating dynamic regulation of GABAARs in the dentate gyrus under conditions of altered neurosteroid levels (for review see Ferando and Mody, 2012).

 

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https://en.m.wikipedia.org/wiki/Tetrahydrodeoxycorticosterone

 

 

 

 

Sex Differences in Neurological Diseases

 

 

http://www.sciencedirect.com/topics/neuroscience/steroid-hormone

 

Farida Sohrabji*, ... Doodipala Samba Reddy*, in Sex Differences in the Central Nervous System, 2016

 

Quote

Conclusions

Steroid hormone and neurosteroids are believed to play a key role in the sex-specific forms of epilepsies and gender-related seizure susceptibility. Menstrual and stress-related fluctuations in seizures may be related to alterations in brain neurosteroid levels. In addition to neurosteroid fluctuations, there is emerging evidence that plasticity in GABA-A receptor subunits could play a role in the enhanced seizure susceptibility in gender-specific forms of epilepsy such as catamenial epilepsy. Such neuroendocrine changes can result in reduced inhibition, resulting in enhanced excitability, which, among other effects, predisposes to catamenial seizures. A neurosteroid replacement therapy has been suggested as a rational treatment strategy for management of catamenial epilepsy.

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Estrogens and seizures

 

https://en.m.wikipedia.org/wiki/Catamenial_epilepsy

 

 

Quote

 Estradiol represents the most prolific estrogen ligand receptor in the female body, particularly in non-pregnant females, and is a more effective activator of estrogen receptor function than estrone or estriol. Estradiol directly increases NMDA mediated receptors of glutamate activity at the neuronal membrane. Through this mechanism hippocampal pyramidal neurons CA1 are excited, and a repetitive firing response is induced.[7]  Dendritic spine density on CA1 hippocampal pyramidal cells is dependent upon estradiol levels, showing a direct correlation during normal fluctuations during the menstrual cycle. Estradiol has been shown to apply its effects on dendritic spine density of hippocampal cells by using a mechanism that requires activation of NMDA receptors.[8] Furthermore, Herzog postulates that, “estradiol may thus further increase excitatory input to the CA1 neurons.” [9] Through many animal models, as well as human-use of estrogen-based hormone replacement therapy, estrogens have been seen to increase the excitability of neurons, leading to a decreased seizure threshold. In female adult rat experimental trials, the limbic seizure threshold fluctuates inversely to estradiol levels during the estrous cycle.

 

 Estriol is known to inhibit GABA and to promote kindling and epileptiform discharges.[10] Estriol is only produced in significant quantities during pregnancy via placental aromatization of fetal androgen, however it can also be synthesized in smaller quantities (non-pregnancy) in the liver by hydroxylation of estrone.

 

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Neurosteroids and tolerance development

 

 

https://www.hindawi.com/journals/aps/2012/416864/

 

Quote

4.4.3. Mechanism 6: Neurosteroids

There is ample and convincing evidence that neurosteroids are endogenous allosteric regulators that interact with GABAA receptors to modulate both tonic (extrasynaptic) and phasic (synaptic) inhibition (for reviews, see [150, 151]). [ ]Also, acute or chronic neurosteroid treatment may change GABAA receptor subunit expression, especially extrasynaptic α4 and δ subunits [151]. In light of the plasticity-inducing actions of neurosteroids on inhibitory signaling, long-term enhancement of the GABA system with benzodiazepines may in turn evoke changes in the neurosteroids system such as changes in neurosteroid synthesis and metabolism, although classical benzodiazepines may differ in their potency to cause such changes [152].

 

In support, ovariectomy attenuated the development of tolerance to the anticonvulsant actions of diazepam [153]. Moreover, co-administration of the neurosteroids allopregnanolone or pregnenolone (but not dehydroepiandrosterone) prevented the development of tolerance after chronic treatment with either triazolam and diazepam [154]. Adding to the complexity of the putative involvement of neurosteroids in benzodiazepine tolerance, factors such as GABAA receptor subunit composition, phosphorylation mechanisms, and ((extra)synaptic) localization—which are all factors that were already found to be involved in tolerance development—influence the specific dynamics of neurosteroid activity.

 

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Ref 151

 

M. B. Herd, D. Belelli, and J. J. Lambert, “Neurosteroid modulation of synaptic and extrasynaptic GABAA receptors,” Pharmacology and Therapeutics, vol. 116, no. 1, pp. 20–34, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus

Quote

Certain naturally occurring pregnane steroids act in a nongenomic manner to potently and selectively enhance the interaction of the inhibitory neurotransmitter GABA with the GABAA receptor. Consequently such steroids exhibit anxiolytic, anticonvulsant, analgesic, sedative, hypnotic, and anesthetic properties. In both physiological and pathophysiological scenarios, the pregnane steroids may function as endocrine messengers (e.g., produced in the periphery and cross the blood–brain barrier) to influence behaviour. However, additionally “neurosteroids” can be synthesised in the brain and spinal cord to act in a paracrine or autocrine manner and thereby locally influence neuronal activity. Given the ubiquitous expression of the GABAA receptor throughout the mammalian central nervous system (CNS), physiological, pathophysiological, or drug-induced pertubations of neurosteroid levels may be expected to produce widespread changes in brain excitability. However, the neurosteroid/GABAAreceptor interaction is brain region and indeed neuron specific. The molecular basis of this specificity will be reviewed here, including (1) the importance of the subunit composition of the GABAA receptor; (2) how protein phosphorylation may dynamically influence the sensitivity of GABAA receptors to neurosteroids; (3) the impact of local steroid metabolism; and (4) the emergence of extrasynaptic GABAA receptors as a neurosteroid target.

 

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Ref 152

N. Usami, T. Yamamoto, S. Shintani et al., “Substrate specificity of human 3(20)α-hydroxysteroid dehydrogenase for neurosteroids and its inhibition by benzodiazepines,” Biological and Pharmaceutical Bulletin, vol. 25, no. 4, pp. 441–445, 2002. View at Publisher · View at Google Scholar · View at Scopus

 

https://www.jstage.jst.go.jp/article/bpb/25/4/25_4_441/_pdf

 

Quote

 

 

In this report, we compared kinetic constants and products in the reduction of the neurosteroids, 3α, 5α-tetrahydroprogesterone (3α,5α-THP) and 3α,5α-tetrahydrodeoxycorticosterone (3α,5α-THDOC), and their precursors, 5α-dihydroprogesterone (5α-DHP), 5α-dihydrodeoxycorticosterone (5α-DHDOC) and progesterone, by three isoenzymes (AKR1C1, AKR1C2 and AKR1C3) of human 3α-hydroxysteroid dehydrogenase. AKR1C1 efficiently reduced 3α,5α-THP, 5α-DHP and progesterone to their 20α-hydroxy metabolites, and slowly converted 5α-DHDOC to 3α,5α-THDOC. AKR1C2 exhibited low 20-ketoreductase activity for 3α,5α-THP and moderate 3-ketoreductase activity for 5α-DHP and 5α-DHDOC. 3α,5α-THDOC was not reduced by the two isoenzymes. No significant activity for the steroids was detected with AKR1C3. The results suggest that AKR1C2 is involved in the neurosteroid synthesis, but AKR1C1 decreases the neurosteroid concentrations in human brain by inactivating 3α,5α-THP and eliminating the precursors from the synthetic pathways. In addition, we found that the several benzodiazepines inhibited the three isoenzymes noncompetitively with respect to the substrate. Although cloxazolam was a potent and specific inhibitor of AKR1C3, diazepam, estazolam, flunitrazepam, medazepam and nitrazepam, that inhibited AKR1C1 and AKR1C2, may influence the neurosteroid metabolism.

 

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Ref 153

 

M. A. Wilson and R. Biscardi, “Effects of gender and gonadectomy on responses to chronic benzodiazepine receptor agonist exposure in rats,” European Journal of Pharmacology, vol. 215, no. 1, pp. 99–107, 1992. View at Publisher · View at Google Scholar · View at Scopus

 

Quote

 

Gonadal steroid hormones on their derivatives have been shown to modulate the GABA receptor complex and GABA-mediated responses in a manner similar to the benzodiazepines. The present study examines if hormonal status modulates the development of tolerance and/or the neural adaptations in GABAA receptors associated with chronic benzodiazepine exposure. Anticonvulsant effects of diazepam were compared in groups of male, female, orchidectomized, and ovariectomized rats following acute (3 day) and chronic (3 week) exposure to diazepam-filled silastic implants. Results indicated that hormonal status did not significantly modify either the neural levels of drug resulting from the diazepam implants or the diazepam-induced increases in bicuculline seizure thresholds following acute (3 day), exposure. Unlike males and gonad-intact females, ovariectomized rats continued to display elevated seizure threshold (dm123: more inhibitory conductance)values due to the diazepam released from the implants even after chronic diazepam exposure.This suggests that the tolerance to benzodiazepine actions observed in male and intact female rats was prevented by ovariectomy. Analysis of the anticonvulsant effects of additional challenge doses of diazepam in chronic diazepam-treated rats paradoxically suggested that benzodiazepine tolerance developed in all hormone groups. The discrepancies between these two tests of anticonvulsant tolerance may be related to the divergent neural GABAA receptor adaptations seen between hormone groups. Ovariectomized rats displayed a reduction in GABA IC50 values for [3H]bicuculline-thiocyanate binding in cortex following chronic diazepam exposure that was not observed in males or intact females. These results suggest that the diminution of ovarian steroid hormones may modulate the neural GABAergic changes associated with the development of tolerance to benzodiazepine actions during chronic agonist exposure.(dm123: i.e., less down regulation or desensitization of the GABAa receptor and/or less estrogen like seizure(excitatory) promoting neurosteroids)

 

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Ref 154

 

D. S. Reddy and S. K. Kulkarni, “Neurosteroid coadministration prevents development of tolerance and augments recovery from benzodiazepine withdrawal anxiety and hyperactivity in mice,” Methods and Findings in Experimental and Clinical Pharmacology, vol. 19, no. 6, pp. 395–405, 1997. View at Google Scholar · View at Scopus

 

Quote

 

Neurosteroids are potent and specific modulators of the GABAA receptors which regulate the neuronal activity through diverse neurotransmitter mechanisms. In the present study we investigated the effects of concomitant treatment with various neurosteroids on the development of tolerance and recovery from withdrawal anxiety and hyperactivity to chronic benzodiazepines. Long-term treatment of mice with full allosteric modulator (triazolam 0.25 mg/kg/day for 8 days) or selective allosteric modulator (diazepam 20 mg/kg/day for 21 days) of GABAA receptor induced tolerance to behavioral sedation on actimeter and anxiolytic effects on plus-maze, and produced a marked withdrawal anxiety and hyperactivity syndrome upon abrupt cessation of treatment, respectively. Concomitant progesterone (10 mg/kg, s.c.), a neurosteroid precursor, of 4'-chlordiazepam (0.25 mg/kg, i.p.), a mitochondrial diazepam binding inhibitor (DBI) receptor (MDR) ligand, prevented the development of tolerance and significantly augmented the recovery from withdrawal-induced anxiety and hyperlocomotion to diazepam. When administered alone for 21 days, neither progesterone nor 4'-chlordiazepam produced any per se effects on actimeter or plus-maze when tested on post-withdrawal days. Coadministration of neurosteroid allopregnanolone (AP) (0.25 and 0.5 mg/kg), or pregnenolone sulfate (PS) (2 mg/kg), but not dehydroepiandrosterone sulfate (2 mg/kg), abolished the development of tolerance and attenuated withdrawal-induced anxiety and hyperlocomotion due to triazolam, without producing any per se behavioral effects when tested at 1 and 2 days after the last injection. Coadministration of flumazenil (5 mg/kg), progesterone (10 mg/kg), 4'-chlordiazepam (0.25 mg/kg), hydrocortisone (100 mg/kg) or nifedipine (2 mg/kg) also prevented the development of tolerance and suppressed the triazolam withdrawal syndrome. However, pretreatment with PK11195 (2 mg/kg), a MDR partial antagonist, reversed the effects of 4'-chlordiazepam on triazolam tolerance and recovery from chronic triazolam. When injected simultaneously, nifedipine, a Ca2+ channel antagonist, potentiated the progesterone- and 4'-chlordiazepam-induced attenuation of triazolam tolerance and withdrawal behavior. These findings suggest that coadministration of neurosteroids allopregnanolone, pregnenolone sulfate and progesterone, and MDR ligand 4'-chlordiazepam prevents the development of tolerance to benzodiazepines and augments the recovery from chronic benzodiazepines. These results indicate that coadministration of neurosteroids may facilitate discontinuation of benzodiazepines in long-term therapy.

 

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Benzodiazaphines and neurosteroid synthesis

 

http://journal.frontiersin.org/article/10.3389/fncir.2014.00003/full

 

Quote

 

 

Benzodiazepines may influence neurosteroid metabolism by virtue of their actions on translocator protein (TSPO; "peripheral benzodiazepine receptor").[59] The pharmacological actions of benzodiazepines at the GABAA receptor are similar to those of neurosteroids. Factors which affect the ability of individual benzodiazepines to alter neurosteroid levels may depend upon whether the individual benzodiazepine drug interacts with TSPO.

 

Some benzodiazepines may also inhibit neurosteroidogenic enzymes reducing neurosteroid synthesis.[60]

 

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Ref 59.

 

  In this interesting study we see that for some benzodiazaphines , both the action on TSPOs and Neurosteroids is relevant for anitseizure effects, whereas in other benzodiazaphines like clonazepam, the TSPO binding has no effect on its anitseizure properties.  I am guessing this might be because clonazepam seems to have additional mechanisms on the action potential, including it’s effecfs on Voltage gated sodium and calcium channels.  These effects might make the TSPO binding effect negligible in the context of its powerful antiseizure properties.

 

Dhir A, Rogawski MA (April 2012). "Role of neurosteroids in the anticonvulsant activity of midazolam". British Journal of Pharmacology. 165 ( 8 ): 2684–91. PMC 3423249  . PMID 22014182. doi:10.1111/j.1476-5381.2011.01733.x.

 

 

Quote

 

Midazolam is a short-acting benzodiazepine that is widely used as an i.v. sedative and anticonvulsant. Besides interacting with the benzodiazepine site associated with GABAA receptors, some benzodiazepines act as agonists of translocator protein (18 kDa) (TSPO) to enhance the synthesis of steroids, including neurosteroids with positive modulatory actions on GABAA receptors. We sought to determine if neurosteroidogenesis induced by midazolam contributes to its anticonvulsant action.

Midazolam (500–5000 mg·kg-1, i.p.) caused a dose-dependent increase in seizure threshold. Pretreatment with the neurosteroid synthesis inhibitors finasteride, a 5a-reductase inhibitor, and a functional TSPO antagonist PK 11195, reduced the anticonvulsant action of midazolam. The anticonvulsant action of midazolam was enhanced by the neurosteroidogenic drug metyrapone, an 11b-hydroxylase inhibitor. In contrast, the anticonvulsant action of clonazepam (100 mg·kg-1) was reduced by finasteride but not by PK 11195, indicating a possible contribution of neurosteroids unrelated to TSPO.

 

Enhanced endogenous neurosteroid synthesis, possibly mediated by an interaction with TSPO, contributed to the anticonvulsant action of midazolam. Enhanced neurosteroidogenesis may also be a factor in the actions of other benzodiazepines,(dm123: for example clonazepam )even those that only weakly interact with TSPO.

 

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Ref 60 (cited earlier as well in an earlier section)

 

 

Usami N, Yamamoto T, Shintani S, Ishikura S, Higaki Y, Katagiri Y, Hara A (April 2002). "Substrate specificity of human 3(20)alpha-hydroxysteroid dehydrogenase for neurosteroids and its inhibition by benzodiazepines" (pdf). Biological & Pharmaceutical Bulletin. 25 (4): 441–5. PMID 11995921. doi:10.1248/bpb.25.441.

 

https://www.jstage.jst.go.jp/article/bpb/25/4/25_4_441/_pdf

 

 

Quote

 

In this report, we compared kinetic constants and products in the reduction of the neurosteroids, 3a,5a- tetrahydroprogesterone (3a,5a-THP) and 3a,5a-tetrahydrodeoxycorticosterone (3a,5a-THDOC), and their pre- cursors, 5a-dihydroprogesterone (5a-DHP), 5a-dihydrodeoxycorticosterone (5a-DHDOC) and progesterone, by three isoenzymes (AKR1C1, AKR1C2 and AKR1C3) of human 3a-hydroxysteroid dehydrogenase. AKR1C1 effi- ciently reduced 3a,5a-THP, 5a-DHP and progesterone to their 20a-hydroxy metabolites, and slowly converted 5a-DHDOC to 3a,5a-THDOC. AKR1C2 exhibited low 20-ketoreductase activity for 3a,5a-THP and moderate 3-ketoreductase activity for 5a-DHP and 5a-DHDOC. 3a,5a-THDOC was not reduced by the two isoenzymes. No significant activity for the steroids was detected with AKR1C3. The results suggest that AKR1C2 is involved in the neurosteroid synthesis, but AKR1C1 decreases the neurosteroid concentrations in human brain by inacti- vating 3a,5a-THP and eliminating the precursors from the synthetic pathways. In addition, we found that the several benzodiazepines inhibited the three isoenzymes noncompetitively with respect to the substrate.

 

Although cloxazolam was a potent and specific inhibitor of AKR1C3, diazepam, estazolam, flunitrazepam, medazepam and nitrazepam, that inhibited AKR1C1 and AKR1C2, may influence the neurosteroid metabolism.

 

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[[li...]]

DM123,

 

Quick question. I did not study all of the theory above in detail (!), but I wondered if testosterone would affect GABAA.

 

https://www.ncbi.nlm.nih.gov/pubmed/20551294 suggests that is does, indeed indirectly. I did not look at interneurons and such.

Would this be a mechanism why young men would recover more quickly ? It seems plausible.

[[cs...]]

DM123,

 

Quick question. I did not study all of the theory above in detail (!), but I wondered if testosterone would affect GABAA.

 

https://www.ncbi.nlm.nih.gov/pubmed/20551294 suggests that is does, indeed indirectly. I did not look at interneurons and such.

Would this be a mechanism why young men would recover more quickly ? It seems plausible.

 

Hi liberty, yes it does. There are several Neurosteroids that are synthesized from testosterone , as well as other pro Neurosteroids.  It's  part of the next segment. See the post below..    The testosterone part is at the end, if you want to skip ahead.....

 

I'm not sure if it's why young men recover more quickly, but it's a great question....

[[cs...]]

EDIT add:  added a few more reference links on 10/2/17 as well as information on DHEA-S under the testosterone section

 

  Neurosteroid metabolic pathways : from Proneurosteroids to Neurosteroid GABAaR and NMDAR activity

 

A bit of a rant….

~from the movie A Few Good Men:

Jessup:” I'll answer the question. You want answers?

Kaffee: “I think I'm entitled!

Jessup:” You want answers?!

Kaffee: “I want the truth!

Jessup: “You can't handle the truth!”

https://en.m.wikiquote.org/wiki/A_Few_Good_Men

 

 

I think we are all entitled to the truth.  Sometimes when we find out the truth, we get angry.  I’m presenting the truth about Neurosteroids and proneurosteroids, because I’ve been adversely affected by them personally, and because I want everyone to realize how marvelously complex our physiology is in this area.  In doing so, perhaps some may reconsider taking an exogenous  neurosteroid “prescribed” to them by a “practitioner” simply because the physiology and chemistry is so complex.  Both the practitioner and the patient really don’t know what they are getting into. The body maintains and seeks homeostasis no matter what.  Compensatory mechanisms that occur with exogenous neurosteroid use often have unintended and unforeseen consequences.  Honestly, I have nothing against naturopaths, “functional practitioners”, and the like.  I do question their knowledge, and in some cases their ethics and integrity when I see how loosely Neurosteroids and their corresponding proneurosteroids are “prescribed”.  Do monetary incentives  come into play?  I think sometimes they do….I know there are some good chiropractors , licensed acupuncturists, and naturopaths that have good intentions, but these are far and few between.  Part of the problem is greed and patient turnover, and the other part of the problem is simply a lack of respect and knowledge for the incredibly complex physiology and biochemistry involved in this area.  There are so many false stories on the internet about “functional physiology” when it comes to Neurosteroids.

 

  I use the term “practitioner” rather loosely, because most of these people come from all walks of life, and very few of them are actually medical doctors.  I am by no means implying that an MD is the superior clinician and practitioner, but I’ve just observed that many of the people irresponsibly prescribing these proneurosteroids and Neurosteroids are not physicians or MDs, and are, in fact,  people from other walks of life with all kinds of strange certifications and degrees.

 

Do I have all the answers? Far from it.  The more I learn, the less I know, and the more appreciation I have for our natural physiological processes.  In layman’s terms, I have found that it’s best to leave things alone when it comes to Neurosteroids .  I say this from my own personal experience, as well as from the perspective of the clinical studies posted in the earlier post above, and new post below.  It’s said simply out of awestruck humility.  The material below, I hope, will put this thought into a literal clinical context.  It’s  just focused on one very very small area of Neurosteroids: their effects on GABAaRs and NMDARs.  And even at this small level, it’s still quite overwhelming.  So much so, that the below is just a high level summary.

 

Unless one has genetic endocrine or hormonal  issues(like Addison’s, for example ), hypopituitarism, is post menopausal, or has had a hysterectomy, Neurosteroids should be used with reticent caution…..especially when used with benzodiazaphines. This is a biased opinion, of course, and the data below is presented rather one dimensionally, from the perspective of NMDA and GABAa receptor modulation.  In this respect, nonetheless, I hope it’s something that will be useful to members of this forum, and serve as a cautionary note.

 

In retrospect, one has to be careful about making bad choices.  When faced with “adrenal fatigue”, one can enter into a very perilous and treacherous path, guided by naturopaths,  chiropractors (functional practitioners), LAcs ,and even an MDs. “Adrenal fatigue” is a marketing term.  It truly does exist, but it is in essence HPA dysfunction, and it has nothing to do with Addisonian-autoimmune-adrenal destruction of the cortex or dysfunction of the adrenal gland itself..  In most cases, the hypothalamus starts to severely dysregulate after an extended period of extreme stress and lack of sleep.  The exact causative agent is often very very elusive.  I can tell you that it’s a very real phenomenon.

 

Is hydrocortisone warranted in severe cases?  Yes, perhaps for a few months, but definitely not for a few years.  Is 30 mg of hydrocortisone a proper dose? Perhaps for the first few weeks, but no longer than 8 weeks. Do I personally think that 30 mg is a trivial physiological dose? Not a chance.  It’s a very powerful hormone.  I see 30 mg on the thyroid forums being touted as a physiological dose and I cringe.  Yes, it’s physiological, but in the sense that it is a COMPLETE 24 hour physiological replacement dose for  someone with Addison’s disease!

 

 

Is DHEA warranted?  No.  It’s an excitatory neurosteroid. (It’s sold over the counter in the USA). Even if it is warranted, the typical 25-50 mg/day sold over the counter is a huge dose.  A practitioner  who “prescribes” it for adrenal fatigue, or along with benzodiazaphines has no clue what they are doing. 

 

Is pregnenolone necessary?(it’s over the counter as well in the USA!).  Absolutely unequivocally not!  Exogenous Pregnenolone, as we will see, is truly a “jack in the box”.  You really don’t know what Neurosteroids you will end up with. It’s like  playing Russian roulette with your excitatory and inhibitory receptors.  The complexity is captured in part by the diagram below.  It’s not a complete diagram by any means.  Nor does it indicate all of the enzymatic processes that are involved.  It also doesn’t account for physiological homeostatic and compensatory processes in the body when an very powerful exogenous hormone is dumped into the body, especially if it’s the “mother hormone” pregnenolone .  Furthermore, it doesn’t capture the temporal aspects of natural neurosteroid production, nor brain specific variations in their activity on the receptors that we will discuss.  If I dump a whole bunch of pregnenolone into my body all at the same time, the body will compensate, and it won’t be straightforward.  Functional practitioners like to simplify things: if I put x amount of hormone y into a person, given the metabolism diagram, they will end up with an increase in neurosteroid z.  In real life the body doesn’t work that way, unless you are truly metabolically or genetically deficient in the hormone or neurosteroid.  Even in this case, the temporal aspects of dosing become a challenge, as well as other things like enzyme levels, and a transient homeostatic adjustment of the other hormones to accommodate the corrected deficiency.  How does one even maintain a bio-identical temporal rhythm of the hormone given that most of these practitioners don’t even consider or know the half life of the administered neurosteroid or hormone? 

 

In short, unless the practitioner is measuring every single neurosteroid and proneurosteroid in that diagram, and unless he or she knows what the level of those enzymes are, all at a given point in time, prescribing pregnenolone and some of the other proneurosteroids (listed below)is completely reckless.  If one is truly deficient, as noted above, then that’s a different situation.

 

And what about the “pregnenolone steal” that occurs with adrenal fatigue, whereby the pregnenolone serum levels are drained to very low levels by being shunted to support cortisol synthesis during phase II of adrenal fatigue.  This is a functional medicine term.  It’s not in the clinical literature.  I'm not sure what to make of it.  Benzodiazaphines, as we all know, will suppress ACTH and hypothalamic activity.  The benzodiazaphines can in fact, incite adrenal issues. I’ve run across several stories of people “hitting the wall” after a few years on benzodiazaphines, only to be told that they have adrenal fatigue, at which point they are offered various neurosteroids. Please take caution.

Here is the truth (note, many  of these neurosteroids are potent PAMs or NAMs)…

 

 

 

Proneurosteroids

 

From Wikipedia:

https://en.m.wikipedia.org/wiki/Neurosteroid

Quote

 

Certain other endogenous steroids, such as pregnenolone,[21] progesterone,[22][23] estradiol,[5] and corticosterone (dm123: no footnote, this needs to be verified) are also neurosteroids. However, unlike those listed above, these neurosteroids do not modulate the GABAA or NMDA receptors, and instead affect various other cell surface receptors and non-genomic targets.

 

Also, many endogenous steroids, including pregnenolone, progesterone, corticosterone (dm123: needs a footnote and verification), deoxycorticosterone, DHEA (dm123: see newly added references below on this) , and testosterone, are metabolized into (other) neurosteroids, effectively functioning as so-called proneurosteroids.

End quote

 

 

Note corticosterone is  included.  Is this  a  “mysterious” link between hydrocortisone and Neurosteroids or hydrocortisone as a PAM?  Corticosterone as a proneurohormome needs more research.  It’s a topic for another discussion.

  One take away from this post is, please be careful with neurosteroid hormone therapy and benzodiazaphines.  We will focus on three of these proneurosteroids below: deoxycorticosterone, testosterone, and progesterone, the so called Big Three

 

Neurosteroid metabolic pathways

 

 

 

Quote

Neuroactive steroids are produced in peripheral organs, includ- ing testes, ovaries, adrenal glands, lung, and liver, but can cross the blood–brain barrier and be metabolized in the brain. Fur- ther, neurosteroids are produced de novo in the brain. Whether of peripheral or central origin, all neuroactive steroids are derived from cholesterol. The transport of cholesterol to the inner mito- chondrial membrane, mediated by steroidogenic acute regula- tory protein (StAR), is the rate-limiting step in steroidogenesis (Stocco and Clark, 1996). At the inner mitochondrial mem- brane, the enzyme P450 side-chain cleavage transforms cho- lesterol to pregnenolone.(dm123: precursor to all neuroactive steroids)

Neuroactive steroids with activity at GABAA receptors are metabolites of the precursor steroids deoxy- corticosterone, progesterone, testosterone, and androstenedione( dm123: precursor  to testosterone )(Figure 1 below).

End quote

 

 

https://en.m.wikipedia.org/wiki/11-Deoxycorticosterone

 

Source:

Front. Endocrinol., 31 January 2012 | https://doi.org/10.3389/fendo.2012.00010

Neurosteroid influences on sensitivity to ethanol

Christa M. Helms, David J. Rossi and Kathleen A. Grant

 

https://www.frontiersin.org/articles/10.3389/fendo.2012.00010/full

 

https://www.frontiersin.org/files/Articles/16748/fendo-03-00010-HTML/image_m/fendo-03-00010-g001.jpg

 

Quote

Figure 1. Neurosteroids modulating GABAergic neurotransmission are produced by the precursor steroids deoxycorticosterone (3α,5α-THDOC, allotetrahydrodeoxycorticosterone), progesterone (3α,5α-P, allopregna-nolone; 3α,5β-P, pregnenolone; 3β,5α-P, epiallopregnanolone; 3β,5β-P, epipregnanolone), and testosterone (3α,5α-A, androsterone; 3α,5β-A, etiocholanolone) via the sequential actions of reductase and hydroxy-steroid dehydrogenase enzymes. Ellipses highlight steroids known to influence sensitivity to the behavioral or endocrine effects of ethanol. Alcohol dehydrogenase and 3α-hydroxysteroid dehydrogenase require common co-factors. Sulfotransferase enzymes adding a sulfate group rapidly alter the pharmacological activity of neurosteroids. DHDOC, dihydrodeoxycortico-sterone; HSD, hydroxysteroid dehydrogenase; NADPH, nicotinamide adenine dinucleotide phosphate-oxidase; NADH, nicotinamide adenine dinucleotide; scc, side-chain cleavage; StAR, steroidogenic acute regulatory protein.

End quote

 

 

 

 

Precursors and their Neurosteroids: Their effects on GABAaRs and NMDARs

 

a.Deoxycorticosterone

 

1. Tetrahydrodeoxycorticosterone or allotetrahydrocorticosterone 3α,5α-THDOC. 

 

Potent PAM of GABAaR

 

https://en.m.wikipedia.org/wiki/Tetrahydrodeoxycorticosterone

 

http://www.jneurosci.org/content/22/9/3795.long

https://www.ncbi.nlm.nih.gov/pubmed/16325348

 

 

b.Progesterone

 

 

1. Allopregnanolone, also known as 5α-pregnan-3α-ol-20-one or 3α,5α-tetrahydroprogesterone (3α,5α-THP) or simply 3 α, 5 α-P.

 

Potent PAM of GABAaR

https://en.m.wikipedia.org/wiki/Allopregnanolone

 

 

2. Allopregnanolone sulfate

 

NAM of NMDA receptor

 

3. 3α,5β-P, pregnanolone (note: error in original citation, above; they listed as pregnEnolone, an entirely different neurosteroid , note letter “a” and letter “e”. Pregnenolone is the “mother hormone” and does not directly modulate the receptor but it is the master proneurosteroid….)

 

Pregnanolone, also known as eltanolone (INN), as well as 3α,5β-tetrahydroprogesterone (3α,5β-THP) or 3α-hydroxy-5β-pregnan-20-one,

https://en.m.wikipedia.org/wiki/Pregnanolone

 

PAM of GABAaR

 

4. 3α,5β-P sulfate, pregnanolone sulfate (see notes below on sulfated steroids)

 

 

https://www.ncbi.nlm.nih.gov/pubmed/9593594

 

NAM or negative modulator of the GABAaR

 

5. 3β,5α-P, epiallopregnanolone or isopregnanolone

 

Quote

Neuroactive steroids (widely known as neurosteroids), including progesterone and several of its metabolites, have been shown to mediate some of their physiological effects though a modulatory site on GABAA receptors.1 Epiallopregnanolone is a metabolite of progesterone and a 3β-isomer of allopregnanolone , which has been shown to enhance GABA neurotransmission.2,3 Epiallopregnanolone is inactive as a GABAA receptor modulator and is used as a control substance to examine GABA neurotransmission.4

End quote

 

Note epiallopregnanolone itself is inactive as a GABAaR PAM, but is a GABAA  subunit selective negative allosteric modulator of the GABAaR , and it does this by antagonizing allopregnanolone, which is a potent PAM of the GABAaR. It does not modulate the GABAaR itself….

 

https://en.m.wikipedia.org/wiki/Isopregnanolone

 

Quote

Isopregnanolone, also known as isoallopregnanolone and epiallopregnanolone, as well as sepranolone (INN), and as 3β-hydroxy-5α-pregnan-20-one or 3β,5α-tetrahydroprogesterone (3β,5α-THP), is an endogenous neurosteroid and a natural 3β-epimer of allopregnanolone.[1][2] It has been reported to act as a subunit-selective negative allosteric modulator of the GABAA receptor,[2] and antagonizes in animals and humans some but not all of the GABAA receptor-mediated effects of allopregnanolone, such as anesthesia,[3]sedation,[4] and reduced saccadic eye movements,[4] but not learning impairment.[2] Isopregnanolone has no hormonal effects and appears to have no effect on the GABAA receptor by itself; it selectively antagonizes allopregnanolone and does not affect the effects of other types of GABAA receptor positive allosteric modulators such as benzodiazepines or barbiturates.[1][5]

End quote

 

6. 3β,5α-P-sulfate or sulfated epiallopregnanolone

 

PAM of NMDA receptor

 

7. 3β,5β-P, epipregnanolone

 

http://www.hmdb.ca/metabolites/HMDB01471

Quote

Epipregnanolone is a pregnane found in the urine of pregnant women and sows. It has anesthetic, hypnotic, and sedative properties. It is a substrate of the enzyme 3beta-hydroxy-5beta-steroid dehydrogenase (EC 1.1.1.277).

End quote

 

PAM of GABAaR

 

8. 3β,5β-P sulfate, epipregnanolone sulfate

 

Negative modulator or NAM of NMDA receptors

AND

NAM of GABAaR

 

 

 

 

 

 

c.Testosterone

 

1. 3α,5α-A, androsterone

Androsterone, or 5α-androstan-3α-ol-17-one

https://en.m.wikipedia.org/wiki/Androsterone

 

Quote

The unnatural enantiomer of androsterone is more potent as a positive allosteric modulator of GABAA receptors and as an anticonvulsant than the natural form.[9] Androsterone's 3β-isomer is epiandrosterone, and its 5β-epimer is etiocholanolone. The 3β,5β-isomer is epietiocholanolone.(dm123: see below)

End quote

 

PAM of GABAaR

 

2. androsterone sulfate

 

NAM of GABAaR

 

3. Epiandrosterone

Epiandrosterone, or isoandrosterone,[1][2] also known as 3β-androsterone, 3β-hydroxy-5α-androstan-17-one, or 5α-androstan-3β-ol-17-one

 

Unsulfated Epiandrosterone is not a modulator

https://en.m.wikipedia.org/wiki/Epiandrosterone

 

4. Sulfated Epiandrosterone is a NAM (see notes below on sulfated steroids)

https://pubchem.ncbi.nlm.nih.gov/compound/9929317#section=Top

 

NAM of GABAaR

 

Note: dehyroepiandrosterone sulfate or DHEA-S is not the same neurosteroid.  DHEA-S is much higher in the figure, whereas epiandrosterone is metabolized from adrosterone, which is 3 α , 5 α -Α in the bottom of the figure.  DHEA-S is a PAM of the NMDAR and a NAM of the GABAaR.]

https://www.ncbi.nlm.nih.gov/pubmed/9593594

https://en.m.wikipedia.org/wiki/Dehydroepiandrosterone_sulfate

 

 

5. 3α,5β-A, etiocholanolone

https://en.m.wikipedia.org/wiki/Etiocholanolone

Etiocholanolone, also known as 5β-androsterone, as well as 3α-hydroxy-5β-androstan-17-one or etiocholan-3α-ol-17-one

https://pubchem.ncbi.nlm.nih.gov/compound/etiocholanolone#section=Top

 

PAM of GABAaR

 

6. Epietiocholanolone, also known as 5β-androstan-3β-ol-17-one or as etiocholan-3β-ol-17-one

 

Not a modulator

 

7. 3α-Androstanediol (often abbreviated as 3α-diol), also known as 5α-androstane-3α,17β-diol

https://en.wikipedia.org/wiki/3%CE%B1-Androstanediol

 

Quote

3α-Androstanediol (often abbreviated as 3α-diol), also known as 5α-androstane-3α,17β-diol, is an endogenous inhibitory androstane neurosteroid and weak androgen, and a major metabolite of dihydrotestosterone (DHT).[1][2][3] As a neurosteroid, it acts as a potent positive allosteric modulator of the GABAA receptor,[4] and has been found to have rewarding,[5][6] anxiolytic,[7] pro-sexual,[8] and anticonvulsant effects.

An orally active synthetic analogue of 3α-androstanediol, 17α-ethynyl-5α-androstane-3α,17β-diol (HE-3235, Apoptone), was formerly under investigation for the treatment of prostate cancer and breast cancer.[14]

End quote

 

also in your citation….

https://www.ncbi.nlm.nih.gov/pubmed/20551294

 

And others

https://www.ncbi.nlm.nih.gov/pubmed/15094514

https://www.ncbi.nlm.nih.gov/pubmed/15489042

 

 

PAM of GABAaR

 

 

More detail for the adventurous !  Talk about tongue twisters…

 

Quote

Transformation of these precursors, respectively, first by 5α-reductase and then by 3α-hydroxysteroid dehydrogenase (HSD) produces 3α,5α-THDOC, 3α,5α-P, and 5α-androstan- 3α-ol-17-one (3α,5α-A; androsterone). Each of these steroids, in addition to the 5β-reduced pregnane steroid 3α-hydroxy- 5β-pregnan-20-one (3α,5β-P, pregnanolone), positively modu- lates responses to GABA at GABAA receptors (Puia et al., 1990; Park-Chung et al., 1999). Specifically, this means that the effi- cacy of GABA is increased by concentrations of steroid that do not, by themselves, activate the receptor.

 

In contrast, muscimol and gaboxadol [4,5,6,7-tetrahydroisoxazolo (5,4-c)pyridin-3(-ol); THIP] are direct agonists of GABAA receptors because they open the Cl− channel in the absence of GABA.

Transformation by 5β-reductase and then by 3β-HSD results in neuroactive steroids that have distinct phar- macological activity resembling neuroactive steroids to which a sulfate group has been added (Wang et al., 2002). Sulfation by sulfotransferase enzymes is a low-energy strategy by which the effects of neuroactive steroids on neurotransmission may be adjusted (Gibbs et al., 2006).

 

Sulfated or 3β-reduced steroids neg- atively modulate GABAA receptors (e.g., pregnanolone sulfate, epipregnanolone sulfate, androsterone sulfate, epiandrosterone sulfate). Other activity includes negative modulation (e.g., allo- pregnanolone sulfate, epipregnanolone sulfate) or positive mod- ulation of NMDA receptor responses (e.g., epiallopregnanolone sulfate). Thus, sulfation may rapidly and transiently enhance exci- tatory neurotransmission, as suggested by Wu et al. (1991). The effects of sulfated steroids on glutamate transmission are hypothe- sized to regulate sensory processing and memory (Valenzuela et al., 2007). Overall, steroidogenesis allows for modulation of excitatory and inhibitory neurotransmission related to endocrine activity that may be an important regulator of sensitivity to environmental stimuli and behavior.

End quote

 

And this….Neurosteroids and Neurotransmitter release modulation

 

Quote

In addition to modulating receptor responses, neurosteroids have been shown to regulate neurotransmitter release. For exam- ple, pregnenolone sulfate increased glutamate release in neonatal cerebellar synapses (Zamudio-Bulcock and Valenzuela, 2011) and cultured hippocampal neurons (Meyer et al., 2002). Likewise, an increased probability of GABA release after application of preg- nanolone was observed in studies using spinal motor neurons in toad embryos (Reith and Sillar, 1997). Haage et al. (2002) reported increased GABA release in isolated neurons from the medial pre- optic area of rats after application of allopregnanolone. Thus, neurosteroids can modulate excitatory and inhibitory synaptic transmission by modulating receptor activity and neurotransmit- ter release. However, the efficacious actions of neuroactive steroids at GABAA receptors are particularly powerful (Park-Chung et al., 1999).

End quote

[[li...]]

Thanks for that very nice part of work.

 

'When faced with “adrenal fatigue”, one can enter into a very perilous and treacherous path, guided by naturopaths,  chiropractors (functional practitioners), LAcs ,and even an MDs. “Adrenal fatigue” is a marketing term.  It truly does exist, but it is in essence HPA dysfunction, and it has nothing to do with Addisonian-autoimmune-adrenal destruction of the cortex or dysfunction of the adrenal gland itself..  In most cases, the hypothalamus starts to severely dysregulate after an extended period of extreme stress and lack of sleep.  The exact causative agent is often very very elusive.  I can tell you that it’s a very real phenomenon. ' Oh, don't I know that ! That's where my troubles started.

 

'Note corticosterone ( hydrocortisone )is included. ' I think we've been over this, but my memory fails me.

Hydrocortisone is supposed to be the same as cortisol, right ? I just compared the chemical formulas (wiki), and these two: https://en.wikipedia.org/wiki/Corticosterone https://en.wikipedia.org/wiki/Hydrocortisone are different.

 

 

 

[[fr...]]

  No wonder I'm in such bad shape after all the steroid injections I have had over the years for different conditions.  Also have been using a hydrocortisone cream for hemorrhoids.  I just can't win.  I am so terrified now of these meds the drs. have me on for years.  I feel no hope. 

[[cs...]]

Thanks for that very nice part of work.

 

'When faced with “adrenal fatigue”, one can enter into a very perilous and treacherous path, guided by naturopaths,  chiropractors (functional practitioners), LAcs ,and even an MDs. “Adrenal fatigue” is a marketing term.  It truly does exist, but it is in essence HPA dysfunction, and it has nothing to do with Addisonian-autoimmune-adrenal destruction of the cortex or dysfunction of the adrenal gland itself..  In most cases, the hypothalamus starts to severely dysregulate after an extended period of extreme stress and lack of sleep.  The exact causative agent is often very very elusive.  I can tell you that it’s a very real phenomenon. ' Oh, don't I know that ! That's where my troubles started.

 

'Note corticosterone ( hydrocortisone )is included. ' I think we've been over this, but my memory fails me.

Hydrocortisone is supposed to be the same as cortisol, right ? I just compared the chemical formulas (wiki), and these two: https://en.wikipedia.org/wiki/Corticosterone https://en.wikipedia.org/wiki/Hydrocortisone are different.

 

 

Hi liberty, I've added the source  link to that quote, and will remove the hydrocortisone, but hydrocortisone differs in a  OH from corticosterone.  See diagram below.    However I did a quick search on corticosterone as a proneurosteroid and even it needs more investigation as well.  I can't find an obvious link.  That quote above from wiki is not footnoted so I will have to see if there is a connection on my own.......

I'm not sure if that metabolic pathway leads to Neurosteroids and we had a brief PM on that.  I will have to search from scratch.

 

Here is the source link I added.  I also added some info on DHEA-S and some more reference links.

https://en.m.wikipedia.org/wiki/Neurosteroid

 

 

 

-----

 

 

Corticosterone

 

https://en.m.wikipedia.org/wiki/Corticosterone

 

 

 

 

Cortisone and cortisol

Cortisone

 

 

https://en.m.wikipedia.org/wiki/Cortisone

 

Cortisol or hydrocortisone

 

https://en.m.wikipedia.org/wiki/Cortisol

 

 

Corticosteroids

 

https://en.m.wikipedia.org/wiki/Corticosteroid

 

 

Some common naturally occurring steroid hormones are cortisol (C21H30O5), corticosterone (C21H30O4), cortisone (C21H28O5) and aldosterone (C21H28O5). (Note that aldosterone and cortisone share the same chemical formula but the structures are different.) The main corticosteroids produced by the adrenal cortex are cortisol and aldosterone.[2]

 

 

 

 

 

Here is the diagram.  Please look to the right to find corticosterone and cortisol. Note the OH bond.

https://en.m.wikipedia.org/wiki/Cortisol#/media/File%3ASteroidogenesis.svg

 

 

 

 

[[cs...]]

Thanks for that very nice part of work.

 

'When faced with “adrenal fatigue”, one can enter into a very perilous and treacherous path, guided by naturopaths,  chiropractors (functional practitioners), LAcs ,and even an MDs. “Adrenal fatigue” is a marketing term.  It truly does exist, but it is in essence HPA dysfunction, and it has nothing to do with Addisonian-autoimmune-adrenal destruction of the cortex or dysfunction of the adrenal gland itself..  In most cases, the hypothalamus starts to severely dysregulate after an extended period of extreme stress and lack of sleep.  The exact causative agent is often very very elusive.  I can tell you that it’s a very real phenomenon. ' Oh, don't I know that ! That's where my troubles started.

 

'Note corticosterone ( hydrocortisone )is included. ' I think we've been over this, but my memory fails me.

Hydrocortisone is supposed to be the same as cortisol, right ? I just compared the chemical formulas (wiki), and these two: https://en.wikipedia.org/wiki/Corticosterone https://en.wikipedia.org/wiki/Hydrocortisone are different.

Yes, same here.  My troubles started with the hypothalamus.

[[cs...]]

Thanks for that very nice part of work.

 

'When faced with “adrenal fatigue”, one can enter into a very perilous and treacherous path, guided by naturopaths,  chiropractors (functional practitioners), LAcs ,and even an MDs. “Adrenal fatigue” is a marketing term.  It truly does exist, but it is in essence HPA dysfunction, and it has nothing to do with Addisonian-autoimmune-adrenal destruction of the cortex or dysfunction of the adrenal gland itself..  In most cases, the hypothalamus starts to severely dysregulate after an extended period of extreme stress and lack of sleep.  The exact causative agent is often very very elusive.  I can tell you that it’s a very real phenomenon. ' Oh, don't I know that ! That's where my troubles started.

 

'Note corticosterone ( hydrocortisone )is included. ' I think we've been over this, but my memory fails me.

Hydrocortisone is supposed to be the same as cortisol, right ? I just compared the chemical formulas (wiki), and these two: https://en.wikipedia.org/wiki/Corticosterone https://en.wikipedia.org/wiki/Hydrocortisone are different.

 

 

Hi liberty, I've added the source  link to that quote, and will remove the hydrocortisone, but hydrocortisone differs in a double OH from corticosterone.  See diagram below.    However I did a quick search on corticosterone as a proneurosteroid and even it needs more investigation as well.  I can't find an obvious link.  That quote above from wiki is not footnoted so I will have to see if there is a connection on my own.......

I'm not sure if that metabolic pathway leads to Neurosteroids and we had a brief PM on that.  I will have to search from scratch.

 

Here is the source link I added.  I also added some info on DHEA-S and some more reference links.

https://en.m.wikipedia.org/wiki/Neurosteroid

 

 

 

-----

 

 

Corticosterone

 

https://en.m.wikipedia.org/wiki/Corticosterone

 

 

 

 

Cortisone and cortisol

Cortisone

 

 

https://en.m.wikipedia.org/wiki/Cortisone

 

Cortisol or hydrocortisone

 

https://en.m.wikipedia.org/wiki/Cortisol

 

 

Corticosteroids

 

https://en.m.wikipedia.org/wiki/Corticosteroid

 

 

Some common naturally occurring steroid hormones are cortisol (C21H30O5), corticosterone (C21H30O4), cortisone (C21H28O5) and aldosterone (C21H28O5). (Note that aldosterone and cortisone share the same chemical formula but the structures are different.) The main corticosteroids produced by the adrenal cortex are cortisol and aldosterone.[2]

 

 

 

 

 

Here is the diagram.  Please look to the right to find corticosterone and cortisol. Note the OH bond.

https://en.m.wikipedia.org/wiki/Cortisol#/media/File%3ASteroidogenesis.svg

 

Liberty please see this link

 

 

The PDF embedded in it is excellent.  I printed it out.

Do you know where Pers found the info on cortisol as a PAM?  I can't find the association so far.  Even with corticosterone as a proneurohormone, it's not obvious.    Will try again tomorrow.

 

https://www.researchgate.net/post/what_is_the_differnce_between_corticosterone_cortisol_cortisone_and_is_cortisol_present_in_rat

 

 

https://www.researchgate.net/file.PostFileLoader.html?assetKey=AS%3A352889634607105%401461146853022&id=571754e5cbd5c2a8ac6ff581

 

 

[[cs...]]

  No wonder I'm in such bad shape after all the steroid injections I have had over the years for different conditions.  Also have been using a hydrocortisone cream for hemorrhoids.  I just can't win.  I am so terrified now of these meds the drs. have me on for years.  I feel no hope.

 

Hi freeme I would not be too concerned with the cream.    Still trying to find out more on corticosterone and cortisol and if they modulate Neurosteroids.  The wiki link is not referenced. 

[[fr...]]

  Thanks for always trying to make me feel not so terrified.  I really appreciate it. 

[[cs...]]

  Thanks for always trying to make me feel not so terrified.  I really appreciate it.

 

Yes. Please no fear.  Almost everything is reversible.  We know what to stay away from at this point:

 

DHEA

Pregnenolone

Estrogens (estradiol and estriol are mentioned in the first neurosteroid post, but I've come across a lot of additional references in this area)

Testosterone

Progesterone

 

Unless you need it for HRT, it's best to stay clear of the above during a taper.

[[...]]

  Thanks for always trying to make me feel not so terrified.  I really appreciate it.

 

Yes. Please no fear.  Almost everything is reversible.  We know what to stay away from at this point:

 

DHEA

Pregnenolone

Estrogens (estradiol and estriol are mentioned in the first neurosteroid post, but I've come across a lot of additional references in this area)

Testosterone

Progesterone

 

Unless you need it for HRT, it's best to stay clear of the above during a taper.

 

Thank you for this DM , I'm gald you posted this summary of things to avoid . I've been taking  a small dose of pregnenelone for a while now , fro my adrenals ! Mostly 2.5 mgs . I think I'll just stop it now , it can't be a good idea ! I'm hoping as its a small amount I won't get a kickback from it ......

 

I also don't metabolize estrogen well , a genetic polymorphism ..... Wonder if that contributes to a difficult withdrawal and if anything can be done . I avoid xenoestrogens as much as possible .

 

I'm wondering if you could summarize in simple terms how we can best avoid tolerance ?

I am noticing now I have switched to part Klonopin I'm already getting increased anxiety .... It's only been three weeks . I couldn't stay on all Valium , I was getting really sick on it , not that K seems much better ... Agh ....

 

MiYu

 

Thank you for all the great research .

[[...]]

Also ,was ther some mention of niacinamide and NADH in there somewhere ? I couldn't read all of it but wondered if you had some thoughts about these supplements ?

Thank you ! MiYu

[[Su...]]

  Thanks for always trying to make me feel not so terrified.  I really appreciate it.

 

Yes. Please no fear.  Almost everything is reversible.  We know what to stay away from at this point:

 

DHEA

Pregnenolone

Estrogens (estradiol and estriol are mentioned in the first neurosteroid post, but I've come across a lot of additional references in this area)

Testosterone

Progesterone

 

Unless you need it for HRT, it's best to stay clear of the above during a taper.

Interesting about the estradiol.... I think the tiny dab that I use helps me sleep.  Progesterone was a nightmare long before I ever started a taper, didn't sleep a wink for days!

Thanks for all of this

SS

[[cs...]]

Also ,was ther some mention of niacinamide and NADH in there somewhere ? I couldn't read all of it but wondered if you had some thoughts about these supplements ?

Thank you ! MiYu

Hi MiYu, yes I did the research on this a while back and I just forwarded the link to a fellow BB.  It's listed as a PAM but the research wasn't there. 

If you can't find the thread let me know and I will find it.  It's ok in moderation.  I'm taking 80 mg in my b complex.  Best not to go way overboard and start very slow.

[[cs...]]

  Thanks for always trying to make me feel not so terrified.  I really appreciate it.

 

Yes. Please no fear.  Almost everything is reversible.  We know what to stay away from at this point:

 

DHEA

Pregnenolone

Estrogens (estradiol and estriol are mentioned in the first neurosteroid post, but I've come across a lot of additional references in this area)

Testosterone

Progesterone

 

Unless you need it for HRT, it's best to stay clear of the above during a taper.

 

Thank you for this DM , I'm gald you posted this summary of things to avoid . I've been taking  a small dose of pregnenelone for a while now , fro my adrenals ! Mostly 2.5 mgs . I think I'll just stop it now , it can't be a good idea ! I'm hoping as its a small amount I won't get a kickback from it ......

 

I also don't metabolize estrogen well , a genetic polymorphism ..... Wonder if that contributes to a difficult withdrawal and if anything can be done . I avoid xenoestrogens as much as possible .

 

I'm wondering if you could summarize in simple terms how we can best avoid tolerance ?

I am noticing now I have switched to part Klonopin I'm already getting increased anxiety .... It's only been three weeks . I couldn't stay on all Valium , I was getting really sick on it , not that K seems much better ... Agh ....

 

MiYu

 

Thank you for all the great research .

Hi MiYu, try to maintain steady state of the benzodiazaphine.  That's the most important thing.  If you have to split the K dose it might help.  Are you taking it all at once?  I know it's hard.

[[cs...]]

Hi liberty and all,  I've edited this original post below to offer a bit more clarity.  The research can be conflicting in some areas but both corticosteroids and corticosterone appear to affect inhibitory currents through the GR and MRs.  needs much more research.  I haven't found clinical studies yet indicating they bind directly to the GABAaR as a modulator, but this is a start, especially how some people including myself felt a lot worse while on corticosteroids.

 

Regarding the corticosteroids vs corticosterones, the medical papers use the terms quite loosely and interchangeably even though chemically they are a bit different.  Also, in the previous post with the PDF from researchgate, it's known that both corticosteroids and corticosterone are both glucocorticoids.  Cortisol is the primary human glucocorticoid, and in many animals corticosterone is the primary glucocorticoid, both relative to the stress response.    What's interesting is that aldosterone has an effect on inhibitory ciurrents as well. via the MR.

 

Further research in this area is pending and required specifically in the area of direct modulation of the GABAAR itself.

-------

 

Major EDIT 10/3/17

 

Corticosteroids and corticosterones and neuronal inhibitory currents

 

 

Reference

Maggio, N., and Segal, M. (2009). Differential corticosteroid modulation of inhibitory synaptic currents in the dorsal and ventral hippocampus. J. Neurosci. 29, 2857–2866.

http://www.jneurosci.org/content/jneuro/29/9/2857.full.pdf

 

The term corticosteroid and corticosterone are used interchangeably.  I think that’s where some of the confusion came. This will require more research, but it does look like “steroids” do affect inhibitory currents, but via glucocorticoid(GR) and minerocorticoid(MR) receptors.  How relevant this is to us requires more research….

https://en.m.wikipedia.org/wiki/Dexamethasone

Dexamethasone is a corticosteroid. This increased the magnitude of inhibitory currents in the brain.

https://en.m.wikipedia.org/wiki/Aldosterone

 

Aldosterone is a mineralcorticoid. This reduced inhibitory currents in certain parts of the brain

 

Quote

Corticosterone has been known to mediate the effects of stress on cognitive functions associated with the hippocampus. Acting at mineralocorticosteroid receptors (MRs) and glucocorticosteroid receptors (GRs), corticosterone exerts several effects in the hippocam- pus and elsewhere. Assuming that there are major functional differences between the dorsal hippocampus (DH) and ventral hippocam- pus (VH), and that these may be regulated by local interneurons, we analyzed the action of corticosterone on inhibitory synaptic currents in patch-clamped pyramidal neurons, recorded in acute slices of DH and VH. Corticosterone, through activation of MRs, reduced the frequency of spontaneous IPSCs in VH but not in DH neurons, and markedly suppressed paired-pulse facilitation of evoked inhibitory synaptic currents. These effects were mimicked by aldosterone, an MR agonist, and were blocked by an MR antagonist. In contrast, corticosterone caused an increase in the magnitude of IPSCs in both the DH and VH via its activation of GRs. This effect was mimicked by a GR agonist, dexamethasone, which produced a slow-onset, large potentiation reaching a peak within 45– 60 min after onset of perfusion, and was blocked by a GR antagonist. The amplitude of mIPSCs was markedly increased by the GR agonist, indicating a synaptic locus of effect. These results indicate that corticosterone has a dual action, which may underlie the differential functional effects of stress hormones in the DH and VH.

End quote

 

 

Here are some more references,  and this will require further research , as the data is not consistent , but nonetheless we know they do effect inhibitory current and it’s not via conversion to Neurosteroids, which we know act as direct PAMs from the previous post…..

 

Quote

Similarly, a high dose of exogenous corticosterone has been shown to decrease mIPSC frequency (Verkuyl et al., 2005) and adrenalectomy increases miniature inhibitory postsynaptic currents (mIPSC) frequency (Verkuyl and Joels, 2003) and the number of GABAergic synapses on CRH neurons (Miklos and Kovacs, 2002).

3

Further, demonstrating presynaptic changes in GABAergic inhibition following stress, the expression of receptors for stress-derived steroid hormones (MRs and GRs) have been identified on interneurons(dm123: note increasing the burst firing of an interneuron will release more GABA from its axon terminals, and inhibit the principal neuron more, i.e. Increase mIPSCs in the principal neuron) in the peri-PVN region and stress hormones have been shown to increase the burst firing of these neurons (Shin et al., 2011). These findings are in contrast with the decreased frequency of both mIPSCs and sIPSCs (dm123: in principal neurons) following stress (Verkuyl et al., 2004) and may represent a compensatory (dm123: body is seeking homeostasis)change to restore inhibition in this region following stress.

End quote

 

 

Reference

Verkuyl, J. M., Karst, H., and Joels, M. (2005). GABAergic transmission in the rat paraventricular nucleus of the hypothalamus is suppressed by corticosterone and stress. Eur. J. Neurosci. 21, 113–121.

 

Quote

Parvocellular neurons in the hypothalamic paraventricular nucleus receive hormonal inputs mediated by corticosterone as well as neuronal inputs, prominent among which is a GABAergic inhibitory projection. In the present study we examined the functional properties of this GABAergic innervation when corticosteroid levels fluctuate. Frequency, amplitude and kinetic properties of miniature inhibitory postsynaptic potentials (mIPSCs), mediated by γ amino butyric acid (GABA) were studied with whole cell recording in parvocellular neuronsInjection of a high dose of corticosterone in vivo suppressed the frequency but did not change the amplitude and kinetic properties of mIPSCs recorded 1–5 h later in vitro. Similar effects were observed after restraint stress. The corticosteroid actions do not require involvement of extrahypothalamic brain regions, because in vitro administration of 100 nm corticosterone (20 min) directly to a hypothalamic slice also suppressed the frequency of mIPSCs recorded several hours later. Corticosterone administration to hypothalamic slices from restraint rats did not result in stronger reduction of mIPSC frequency than either treatment alone, pointing to a common underlying mechanism. Paired pulse response inhibition was reduced by corticosterone, suggesting that the hormone decreases the release probability of GABA-containing vesicles. Unlike neurosteroids, corticosterone induced no rapid effects on mIPSC properties. These results indicate that increases in glucocorticoid level due to stress can slowly but persistently inhibit the GABAergic tone on parvocellular hypothalamic neurons via a hitherto unknown local mechanism independent of limbic projections.

End quote

 

Ref

Shin, S. Y., Han, T. H., Lee, S. Y., Han, S. K., Park, J. B., Erdelyi, F., Szabo, G., and Ryu, P. D. (2011). Direct corticosteroid modulation of GABAergic neurons in the anterior hypothalamic area of GAD65-eGFP mice. Korean J. Physiol. Pharmacol. 15, 163–169.

 

 

Quote

 

 

Corticosterone is known to modulate GABAergic synaptic transmission in the hypothalamic paraventricular nucleus. However, the underlying receptor mechanisms are largely unknown. In the anterior hypothalamic area (AHA), the sympathoinhibitory center that project GABAergic neurons onto the PVN (dm123: i.e., interneurons), we examined the expression of glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) of GABAergic neurons using intact GAD65-eGFP transgenic mice, and the effects of corticosterone on the burst firing using adrenalectomized transgenic mice. GR or MR immunoreactivity was detected from the subpopulations of GABAergic neurons in the AHA. The AHA GABAergic neurons expressed mRNA of GR (42%), MR (38%) or both (8%). In addition, in brain slices incubated with corticosterone together with RU486 (MR-dominant group), the proportion of neurons showing a burst firing pattern was significantly higher than those in the slices incubated with vehicle, corticosterone, or corticosterone with spironolactone (GR-dominant group; 64 vs. 11∼14%, p＜0.01 by ՗2-test). Taken together, the results show that the corticosteroid receptors are expressed on the GABAergic neurons in the AHA, and can mediate the corticosteroid-induced plasticity in the firing pattern of these neurons. This study newly provides the experimental evidence for the direct glucocorticoid modulation of GABAergic neurons in the AHA in the vicinity of the PVN.

 

End quote

 

[[...]]

  Thanks for always trying to make me feel not so terrified.  I really appreciate it.

 

Yes. Please no fear.  Almost everything is reversible.  We know what to stay away from at this point:

 

DHEA

Pregnenolone

Estrogens (estradiol and estriol are mentioned in the first neurosteroid post, but I've come across a lot of additional references in this area)

Testosterone

Progesterone

 

Unless you need it for HRT, it's best to stay clear of the above during a taper.

 

Thank you for this DM , I'm gald you posted this summary of things to avoid . I've been taking  a small dose of pregnenelone for a while now , fro my adrenals ! Mostly 2.5 mgs . I think I'll just stop it now , it can't be a good idea ! I'm hoping as its a small amount I won't get a kickback from it ......

 

I also don't metabolize estrogen well , a genetic polymorphism ..... Wonder if that contributes to a difficult withdrawal and if anything can be done . I avoid xenoestrogens as much as possible .

 

I'm wondering if you could summarize in simple terms how we can best avoid tolerance ?

I am noticing now I have switched to part Klonopin I'm already getting increased anxiety .... It's only been three weeks . I couldn't stay on all Valium , I was getting really sick on it , not that K seems much better ... Agh ....

 

MiYu

 

Thank you for all the great research .

Hi MiYu, try to maintain steady state of the benzodiazaphine.  That's the most important thing.  If you have to split the K dose it might help.  Are you taking it all at once?  I know it's hard.

 

Thank you DM .... Good to know ......I'm actually dosing the K - 4 X day . I see, to metabolize everything so fast . That was one of the problems with Valium for me m even with dosing 3 X day , a tiny bit would completely knock me out in 5 mins and take me two hours to recover from . The K is better , it takes more like an hour to 1-1/2 hrs to come on so I know it's metabolizing more slowly .

 

So now I take a little Valium at night and early am along with a half dose of K , and this seems like a better balance . In the day I just take K .

I'm still bed bound though and my nervous system is very destabilized now from the switch of meds .

 

I need to do a long hold in the hopes of getting stable . The meds themselves feel so bad though also !

I know you understand .

 

Thanks again DM ,

MiYu

Ps , I accidentally took 1000 mgs of niacinamide a week ago , I meant to take 1/4 of that but got my pills mixed up . I think it also effected me a lot .

 

[[...]]

Interesting,y , when Drs increased my steroids as they thought they 'weren't working ' I ended up practically comatose . Instead of being stimulating they almost paralyzed me .

 

I was taking 60 plus mgs of hydrocortisone a day .... And I'm a small woman .

 

It was awful!

I finally took myself off the as I felt they were literally killing me .....

Soon after I had a salivaL cortsol test and my levels were normal ! I still went through terrible WDs .

 

Maybe this is why I'm having such a difficult time withdrawing from benzos ......kindled from the steroids ?

 

MiYu

[[cs...]]

  Thanks for always trying to make me feel not so terrified.  I really appreciate it.

 

Yes. Please no fear.  Almost everything is reversible.  We know what to stay away from at this point:

 

DHEA

Pregnenolone

Estrogens (estradiol and estriol are mentioned in the first neurosteroid post, but I've come across a lot of additional references in this area)

Testosterone

Progesterone

 

Unless you need it for HRT, it's best to stay clear of the above during a taper.

 

Thank you for this DM , I'm gald you posted this summary of things to avoid . I've been taking  a small dose of pregnenelone for a while now , fro my adrenals ! Mostly 2.5 mgs . I think I'll just stop it now , it can't be a good idea ! I'm hoping as its a small amount I won't get a kickback from it ......

 

I also don't metabolize estrogen well , a genetic polymorphism ..... Wonder if that contributes to a difficult withdrawal and if anything can be done . I avoid xenoestrogens as much as possible .

 

I'm wondering if you could summarize in simple terms how we can best avoid tolerance ?

I am noticing now I have switched to part Klonopin I'm already getting increased anxiety .... It's only been three weeks . I couldn't stay on all Valium , I was getting really sick on it , not that K seems much better ... Agh ....

 

MiYu

 

Thank you for all the great research .

Hi MiYu, try to maintain steady state of the benzodiazaphine.  That's the most important thing.  If you have to split the K dose it might help.  Are you taking it all at once?  I know it's hard.

 

Thank you DM .... Good to know ......I'm actually dosing the K - 4 X day . I see, to metabolize everything so fast . That was one of the problems with Valium for me m even with dosing 3 X day , a tiny bit would completely knock me out in 5 mins and take me two hours to recover from . The K is better , it takes more like an hour to 1-1/2 hrs to come on so I know it's metabolizing more slowly .

 

So now I take a little Valium at night and early am along with a half dose of K , and this seems like a better balance . In the day I just take K .

I'm still bed bound though and my nervous system is very destabilized now from the switch of meds .

 

I need to do a long hold in the hopes of getting stable . The meds themselves feel so bad though also !

I know you understand .

 

Thanks again DM ,

MiYu

Ps , I accidentally took 1000 mgs of niacinamide a week ago , I meant to take 1/4 of that but got my pills mixed up . I think it also effected me a lot .

 

Hi MiYu, I'm glad you recognize 1000 mg is too high.  I don't know if you can take it with the other b complexes, as some find the other b's to be a bit stimulating. 

 

Regarding tolerance, that's good, keep,the dose steady, avoid these PAMs ,and the Neurosteroids I posted.  The jury is still out on corticosteroids, but I'm going to update the post above with a few notes to clarify things in that area.

If you are bedbound, try to get yourself to just stand 5 minutes at a time per my earlier post in this thread.  Do this several times a day if you can.  It will help build up stress resiliency , as a form of exercise.  If you are able to increase the standing times each week that would be ideal.

 

Avoid alcohol as well.

[[cs...]]

Interesting,y , when Drs increased my steroids as they thought they 'weren't working ' I ended up practically comatose . Instead of being stimulating they almost paralyzed me .

 

I was taking 60 plus mgs of hydrocortisone a day .... And I'm a small woman .

 

It was awful!

I finally took myself off the as I felt they were literally killing me .....

Soon after I had a salivaL cortsol test and my levels were normal ! I still went through terrible WDs .

 

Maybe this is why I'm having such a difficult time withdrawing from benzos ......kindled from the steroids ?

 

MiYu

 

Hi MiYu, I'm glad you supplied me with that info.  I'm going to update the info above with some of my own notes.  Corticosteroids and corticosterone both appear to affect the inhibitory ciurrents.  Some of the research as you will see when I edit the post is a bit conflicting.  Stress response plays a huge part in all this as it does effect CRH release from the hypothalamus and thus cortisol release.  This area still needs a lot more research, but so far it's affecting GABAa interneurons and principal neurons through the glucocorticoid and mineralcorticoid receptors.  So even though we haven't found the research that corticosteroids and corticosterone affects or binds to the GABAaR directly as a PAM, etc... we do know they influence the inhibitory currents in the post synaptic neuron and GABA interneurons.

 

60 mg is a very large dose.  I was on 30 mg for quite a while and it did contribute to the Inhibitory dysfunction.    I will update he above info today....so,that it's a bit clearer.

[[fr...]]

  DM,  Does this relate to cortisone injections into joints etc or just oral steroids?  Dr. wants me to have more injections but I am resisting as I feel so awful now.  He claims the steroid stays in the joint and is only slowly absorbed so it doesn't affect us as badly.  How true is this in your opinion.  Thanks for all your work again. 

[[li...]]

dm123,

 

That these 'steroids' affect the brain through the glucocorticoid and mineralocorticoid receptors seems very sensible. As Perseverance stated, low amounts affect MRs, high amonts GRs (or something like that)

 

I know  (?) that the theory says that in humans the only active glucocorticoid is cortisol, but I've doubted that myself.

 

What I recall from exercise, and running is a good example, is that there are long lasting effects from one session. Also the 'acute' (post acute?) effect after the exercise can last a long time. It feels like a high amount of an active glucocorticoid has has been released, one that also has a long half life. And I'm writing this as I remember, the reported half lives for cortisol seem to differ. Aside from any other issues, I would describe the effect as a dampening effect, typically improving mental lucidity and dampening metabolic rate ('body temperature') This may mostly be a clonazepam thing.

[[cs...]]

  DM,  Does this relate to cortisone injections into joints etc or just oral steroids?  Dr. wants me to have more injections but I am resisting as I feel so awful now.  He claims the steroid stays in the joint and is only slowly absorbed so it doesn't affect us as badly.  How true is this in your opinion.  Thanks for all your work again.

Hi freeme, I'm not a doctor, but I have experience with both oral and injected cortisol.  I too had a a few injections into the lower back(which incidentally is 100% normal, they should have never injected me there)

Your doctor knows this, but I'm not sure he will tell you this.  They limit cortisol injections to typically 2 max per 6 months, or around there.  They do this for a reason.  The transient serum peaks after injection can get very high depending how much they inject and where.  They limit number of injections truly because they don't want your pituitary to shut down.  Once that happens it takes a while to recover and it's not pleasant    I had my first adrenal issues shortly after my first injection.  I was on benzos, very low dose at that time as well, which contributed to the shutdown.

 

Can you tell me if you are sleeping ok?  It's critical for your HPA to be resilient when you get the shot.

 

In a nutshell, I'm more concerned about you HPA than your inhibitory currents, even though it looks like that might be affected as well.

 

I assume they are going to use methyl prednisone for the shot, which is a very potent corticosteroids.

 

As I said I'm not a doctor of medicine(nor do I want to be), so its best to insure that your doctor knows you are not ignorant of these things.  Please talk to him about these items above. In that way, he might be more cautious with the dosing of the injection. Especially if you are in taper, as your HPA axis is already under considerable stress

 

You can google HPA suppression due to steroid injections and you will find anecdotal and clinical studies in this area.  Unfortunately as many others have mentioned, the docs don't fully disclose things all the time....  we are all familiar with this in the context of our first Benzo Rx.