Ashoka

Member
Joined
Aug 20, 2015
Messages
209
Major chemical vendors like Sigma Aldrich sell it, but it is very expensive and even then the amounts sold usually do not exceed 50mg. Most animal studies used the equivalent of 5mg-20mg daily, so it becomes prohibitively expensive. That one of the reasons I did not release ALLO as a product but its direct precursors 5a-DHP, which is (a bit) more affordable.

I think even at an expense, a lot of people with PFS and other conditions might be willing to pay more to try allopregnanolone. Or perhaps I’m speaking for myself! Its definiciency seems to be the site of a great deal of the problems, and things like pregnenolone or progesterone can be hard to work with. I appreciate that you released 5a-DHP though. I’m very sad that this pharmaceutical means the end of a straight up supplement. It seems unbelievably stupid.
 

alywest

Member
Joined
Apr 19, 2017
Messages
1,028
See study below outlining why steroidogenesis may not be occurring with people with PTSD, PFS, postnatal depression, PMS, major depression:


A refined approach to more specifically “bio-define” PTSD can be to establish a biomarker axis or in other words, to assess the relation of various biomarkers, which fluctuate in concert and correlate uniquely with PTSD behavioral modifications. Insofar, a biomarker axis may provide a higher accuracy in the diagnosis of the disorder with benefits for prediction in PTSD treatment response and relapse (Locci et al., 2018; Pinna and Izumi, 2018). As a matter of fact, the “gold standard” treatment for PTSD and depression, the selective serotonin reuptake inhibitors (SSRIs), improve only half of the treatment-seeking patients and they are associated with severe side-effects (Golden et al., 2002; Rush et al., 2006; Kemp et al., 2008; reviewed in Bernardy and Friedman, 2017). This also suggests these psychiatric disorders are complex, multifaceted diseases arising from multiple and diverse neurobiological backgrounds and therefore, symptoms may not always recapitulate to a serotonergic deficit and administering an SSRI may not always improve symptoms. Unveiling reliable biomarkers is also a necessity for patient stratification in treatment selection as well as for drug development through clinical trials. The development of state-of-the-art technologies and methodological rigor are essential to allow for the discovery of more reliable biomarkers in psychiatry. Employing the gas chromatography-mass spectrometry (GC-MS) to achieve this goal is highly innovative and provides reliable information based on a powerful technology with high sensitivity and unsurpassed structure selectivity (Uzunov et al., 1996; Pinna et al., 2000). Hence, by applying the GC-MS measurements of neuroactive steroids in serum, plasma, CSF and post-mortem brain, in the past decade, we have shed light in the fundamental role of neuroactive steroids in patients with neuropsychiatric disorders (Rasmusson et al., 2006, 2017; Agis-Balboa et al., 2014; Pineles et al., 2018; reviewed in Locci and Pinna, 2017a).


The biosynthesis of allopregnanolone, a positive allosteric modulator of GABA's action at GABAAreceptors has been found deficient in a number of neuropsychopathologies, including epilepsy (e.g., PHDH19), major depression, PTSD, perceived social isolation, post-partum depression, premenstrual syndrome, and anorexia nervosa or obesity complicated by anxiety and depression symptoms in women (Romeo et al., 1998; Uzunova et al., 1998; Rasmusson et al., 2006, 2018; Nemeroff, 2008; Lovick, 2013; Trivisano et al., 2017; Dichtel et al., 2018; Pineles et al., 2018). Therapeutic measures aimed at reinstating normal allopregnanolone levels in deficient-patients correlates with improved symptoms (Kanes et al., 2017). The question arises as to whether allopregnanolone biosynthesis per se is a reliable biomarker to predict, diagnose and instruct treatment selection of patients or whether its relation with neurotransmitter systems (GABAA and NMDA receptors), stimulation of neurotropic factors (e.g., BDNF), and/or crosstalk with the endocannabinoid system (e.g., PPAR-α) may provide a valuable biomarker axis with a higher disorder-selectivity. This analysis includes both neurosteroids that are positive allosteric modulators of GABAA receptors (Pinna et al., 2000; Belelli and Lambert, 2005), such as allopregnanolone and pregnanolone and their sulfated forms that are inhibitors of NMDA-mediated tonic neurotransmission, which results in neuroprotection (Vyklicky et al., 2016).


The novel discovery that the endocannabinoid system regulates the biosynthesis of neurosteroids, including allopregnanolone has recently opened the field for assessing valuable PTSD biomarkers at the interface of these neuronal systems. In recent years, cannabinoid-based agents have become an integral part of drug discovery for PTSD treatment (Ruehle et al., 2012; Neumeister et al., 2014). The impact of the endocannabinoid system is under-scored by the density of receptors in glutamatergic neurons of emotion-relevant areas, including the the amygdaloid complex, the hippocampus and the frontal cortex (Katona, 2009). Synthetic cannabinoid receptor antagonists or knockouts enhance fear acquisition and impair fear extinction, a core feature of PTSD (Reich et al., 2008; Papini et al., 2015). In addition to the well assessed role of the endocannabinoid, anandamide (AEA) or 2-arachidonoyl-glycerol (2-AG) both in neuropsychiatric disorders and animal models of stress (Chhatwal et al., 2005; Umathe et al., 2011; Dubreucq et al., 2012), compelling evidence indicates stimulation of the intracellular endocannabinoid target, peroxisome-proliferator activated receptor (PPAR)-α by its endogenous neuromodulator, N-palmitoylethanolamine (PEA) engages the biosynthesis of neurosteroids to modulate emotional behavior (Locci and Pinna, 2017b; Locci et al., 2018) (please see Figure Figure11 for a graphic representation).


In addition to these cell-surface cannabinoid receptors (O'Sullivan, 2007), there is growing evidence that PPAR-α's activation represents a novel mechanism by which cannabinoids modulate behavior. Stimulation of PPAR-α by PEA or synthetic PPAR-α agonists was recently shown to elevate corticolimbic allopregnanolone levels in hippocampus, amygdala, frontal cortex and in olfactory bulb, which correlated with improvement of PTSD-like behavior in socially isolated mice (Locci and Pinna, 2017a). PEA facilitates contextual fear extinction and fear extinction retention and induces anti-aggressive, anxiolytic, and antidepressant-like effects in socially isolated mice (Locci and Pinna, 2017b; Locci et al., 2017). PPAR-α synthetic agonists normalized allopregnanolone levels and improved behavior, whereas antagonism at PPAR-α, inhibition of allopregnanolone biosynthetic enzymes, or PPAR-α KO mice prevented both PEA-induced behavior and its neurosteroidogenic effects (Locci and Pinna, 2017b). While the role of PPAR-α in neuropsychiatric disorders is just emerging, studies in the field suggest serum PEA and oleoylethanolamide (OEA) concentrations increase after acute social stressor (Dlugos, 2012) and decrease following recovery (Hill et al., 2009a). Stress evokes fast induction of fatty acid amide hydrolase (FAAH), which reduces PEA and AEA levels (Patel et al., 2005; Hill et al., 2009b). In PTSD patients, symptoms are inversely correlated with reduced hair levels of PEA, OEA and stearoylethanolamide (SEA) in both males and females (Wilker et al., 2016). PEA adjunctive therapy to citalopram improves symptoms in depressed patients (Ghazizadeh-Hashemi, 2018). Furthermore, intense workouts increase PEA and OEA levels and improve depression and PTSD (Heyman, 2012). In rodents, exposure to predator stressors reduces cardiac PEA and OEA levels (Holman et al., 2014), but, antidepressant-like effects are induced by increasing PEA and OEA (Adamczyk et al., 2008; Umathe et al., 2011; Melis et al., 2013). Collectively, the crosstalk between the endocannabinoid system and neurosteroid biosynthesis during stress may unveil biomarker axis uniquely altered in specific stress-induced mood disorders.


Psychiatric disorders, such as PTSD, are not currently amenable to objective neurobiological determinations as is routine practice in the diagnosis and treatment of other medical conditions. This is most likely due to the general complexity and multifactorial origins of these disorders and the difficulty to establish a consistent bio-signature. While no biomarkers for PTSD have to date been firmly assessed with diagnostic validity, a consistent progress in the field has been done. Biomarker candidates for PTSD have been proposed but often they share overlaps with other psychiatric disorders with similar symptoms and that are currently treated with same drugs. Indeed, the first-choice pharmacological treatments for PTSD, the SSRIs, act through multiple molecular mechanisms other than by inhibiting serotonin reuptake. These mechanisms include the stimulation of neurosteroid and endocannabinoid biosynthesis and neurotrophic factors, such as BDNF, which are found deficient in PTSD. Increasing allopregnanolone levels is also associated with increased BDNF expression (Nin et al., 2011a). Collectively, these findings have contributed to improve our understanding of the psychobiological abnormalities associated with PTSD and promote the development of novel targeted treatment options. For instance, the correlation between the impairment of neurosteroid biosynthesis and behavioral modifications in neuropsychiatric disorders has been the focus of several studies (van Broekhoven and Verkes, 2003; reviewed in Pinna, 2013; Agis-Balboa et al., 2014; Locci and Pinna, 2017a). A reduction in the content of the GABAergic modulator allopregnanolone and its equipotent isomer pregnanolone was reported in cerebrospinal fluid (CSF) and serum of major depression and PTSD patients (Romeo et al., 1998; Uzunova et al., 1998; Rasmusson et al., 2006, 2016; Pineles et al., 2018). A negative correlation between CSF allopregnanolone levels and PTSD symptoms was more recently confirmed in male patients (Rasmusson et al., 2018). Other clinical studies support the significance of allopregnanolone biosynthesis as a biomarker of mood disorders (Uzunova et al., 1998; Agis-Balboa et al., 2014; reviewed in Zorumski et al., 2013; Schüle et al., 2014; Locci and Pinna, 2017a) with finding showing decreased allopregnanolone levels in postpartum depression (Nemeroff, 2008), under treatment with finasteride, an allopregnanolone biosynthetic enzyme blocker (Altomare and Capella, 2002; Caruso, 2015; Welk et al., 2017), and with anorexia nervosa or obesity complicated by anxiety and depression (Dichtel et al., 2018). Intriguingly, SSRI treatments normalize plasma, CSF, and brain allopregnanolone content in association with improvement of symptoms in responders only (Romeo et al., 1998; Uzunova et al., 1998; Agis-Balboa et al., 2014). These findings are in support of the role of allopregnanolone in the mechanisms of SSRIs' anxiolytic effects (Pinna, 2015). The downregulation of neurosteroid levels found in PTSD and depressed patients can be modeled in rodents exposed to protracted stress, including the socially-isolated mouse. Allopregnanolone is produced in brain corticolimbic neurons (Figure (Figure1)1) and a reduction of its levels by prolonged social isolation (Agís-Balboa et al., 2006, 2007) or exposure to single prolonged stressors, results in development of anxiety-like behavior, aggression and enhanced contextual fear conditioning responses associated with impairment of fear extinction and elevated spontaneous fear responses at recall (Pinna et al., 2003; Pibiri et al., 2008; Pinna and Rasmusson, 2014; Qiu et al., 2015). These preclinical studies further support allopregnanolone as a putative biomarkerfor stress-induced emotional modification, such as exaggerated fear responses and impaired fear extinction, a hallmark in PTSD (Pibiri et al., 2008; Pinna et al., 2008; Pinna and Rasmusson, 2012). This evidence also suggests that new therapeutic approaches should counteract the downregulation of neurosteroid biosynthesis to improve symptoms in PTSD patients. In recent phase 3 clinical trials, intravenous allopregnanolone (brexanolone or SAGE-547) or an oral analog (SAGE-217) showed a rapid and long-lasting remission of post-partum depression and major depressive disorder symptoms, conditions highly comorbid with PTSD (Kanes et al., 2017; Sage Announces Pivotal Phase 3 Trial Status for SAGE-217 in Major Depressive Disorder and Postpartum Depression based on FDA Breakthrough Therapy Meeting | Sage Therapeutics, Inc.). If successfully developed, SAGE-217 will be the first durable, rapid-acting, oral, short-course treatment for mood disorders with potential application for PTSD treatment. Stress tremendously affects the expression of GABAA receptor subunits (Pinna et al., 2006; reviewed in Locci and Pinna, 2017a). After social isolation, the α4, α5, and δ subunit expression was increased, and the α1, α2, and γ2 were significantly decreased in corticolimbic areas. These changes result in decreased benzodiazepine recognition sites and lower pharmacological response to benzodiazepines (Pinna et al., 2006). Remarkably, protracted stress favors a GABAA receptor composition with high sensitivity for allopregnanolone and its analogs (Locci et al., 2017; reviewed in Locci and Pinna, 2017a). Clinical findings support lower benzodiazepine recognition site binding in brain of PTSD patients in association with benzodiazepine-insensitivity (Geuze et al., 2008). Altogether, these findings suggest that isolation stress results in: (i) changes in GABAA receptor subunit composition; (ii) downregulated neurosteroidogenesis; and (iii) lack of response to benzodiazepines, which may provide a unique biomarker axis for PTSD (Figure (Figure2).2). Allopregnanolone, analogs or stimulation of allopregnanolone biosynthesis may be a valuable therapeutic strategy for stress-induced psychiatric disorders, characterized by benzodiazepine-inefficacy and poor response to SSRIs. The pharmacological profile of SSRIs on stimulation of neurotropic factors, including the brain-derived neurotrophic factor (BDNF), via stimulation of allopregnanolone biosynthesis is an additional important mechanism to consider when establishing biomarkers for PTSD. BDNF expression decrease in PTSD patients is associated with symptom severity. In the socially isolated mouse, fluoxetine improves behavior by elevating the corticolimbic levels of allopregnanolone and BDNF expression, independently from the action of these drugs on serotonin reuptake inhibition. This and other evidence suggest that neurosteroid biosynthesis and BDNF expression may be interrelated (Nin et al., 2011a; Frye et al., 2014), and this may provide further support for biomarker selection.


While many aspects that relate to the endocannabinoid and neurosteroid cross-talk remain presently obscure, our current findings highlight the potential for: (i) assessing novel biomarkers to predict, diagnose, and treat PTSD at the interface of the PPAR-α-allopregnanolone axis; and (ii) repurposing FDA-approved PPAR-α agonists for the treatment of PTSD after positive clinical trials. Very few drugs are direct agonists of PPAR-α, and none have been tested for their potential effects in fear responses. However, one class of drugs, the fibrates are fibric acid derivatives that are prescribed to lower plasma lipids and triglyceride levels and are synthetic PPAR-α agonists that may be exploited in rodent models of PTSD to improve behavioral deficits.

Go to:

Conclusions

Progress in assessing biomarkers to predict PTSD and its treatment response will guide the future of novel PTSD medications that may be designed to improve neurotransmission (GABA, NMDA), and neuroendocrinologic (allopregnanolone biosynthesis) and anti-inflammatory (PPAR-α) responses. Research supports precision medicine for PTSD designed to stimulate neurosteroidogenesis after assessing in subpopulations of PTSD patients a downregulation of allopregnanolone biosynthesis. This can be achieved by acting at neurosteroidogenic targets or by mimicking allopregnanolone's function (e.g., analogs). Several neuronal targets to enhance steroidogenesis have recently been discovered and these include the endocannabinoid target PPAR-α. The crosstalk between the endocannabinoid system and the biosynthesis of neurosteroids, involving their targeted receptors or the biosynthetic enzymes promises to provide unique bio-signatures for stress-induced disorders.

Collectively, advances in the field suggest biomarker-based diagnosis and treatments for PTSD that encompass the neurosteroid and endocannabinoid systems may not be a far reach and these may provide a pivotal complement to the current practice of assessing the disorder based on self-reported symptoms and psychiatrist assessments.


Biomarkers for PTSD at the Interface of the Endocannabinoid and Neurosteroid Axis
 

Ashoka

Member
Joined
Aug 20, 2015
Messages
209
See study below outlining why steroidogenesis may not be occurring with people with PTSD, PFS, postnatal depression, PMS, major depression:


A refined approach to more specifically “bio-define” PTSD can be to establish a biomarker axis or in other words, to assess the relation of various biomarkers, which fluctuate in concert and correlate uniquely with PTSD behavioral modifications. Insofar, a biomarker axis may provide a higher accuracy in the diagnosis of the disorder with benefits for prediction in PTSD treatment response and relapse (Locci et al., 2018; Pinna and Izumi, 2018). As a matter of fact, the “gold standard” treatment for PTSD and depression, the selective serotonin reuptake inhibitors (SSRIs), improve only half of the treatment-seeking patients and they are associated with severe side-effects (Golden et al., 2002; Rush et al., 2006; Kemp et al., 2008; reviewed in Bernardy and Friedman, 2017). This also suggests these psychiatric disorders are complex, multifaceted diseases arising from multiple and diverse neurobiological backgrounds and therefore, symptoms may not always recapitulate to a serotonergic deficit and administering an SSRI may not always improve symptoms. Unveiling reliable biomarkers is also a necessity for patient stratification in treatment selection as well as for drug development through clinical trials. The development of state-of-the-art technologies and methodological rigor are essential to allow for the discovery of more reliable biomarkers in psychiatry. Employing the gas chromatography-mass spectrometry (GC-MS) to achieve this goal is highly innovative and provides reliable information based on a powerful technology with high sensitivity and unsurpassed structure selectivity (Uzunov et al., 1996; Pinna et al., 2000). Hence, by applying the GC-MS measurements of neuroactive steroids in serum, plasma, CSF and post-mortem brain, in the past decade, we have shed light in the fundamental role of neuroactive steroids in patients with neuropsychiatric disorders (Rasmusson et al., 2006, 2017; Agis-Balboa et al., 2014; Pineles et al., 2018; reviewed in Locci and Pinna, 2017a).


The biosynthesis of allopregnanolone, a positive allosteric modulator of GABA's action at GABAAreceptors has been found deficient in a number of neuropsychopathologies, including epilepsy (e.g., PHDH19), major depression, PTSD, perceived social isolation, post-partum depression, premenstrual syndrome, and anorexia nervosa or obesity complicated by anxiety and depression symptoms in women (Romeo et al., 1998; Uzunova et al., 1998; Rasmusson et al., 2006, 2018; Nemeroff, 2008; Lovick, 2013; Trivisano et al., 2017; Dichtel et al., 2018; Pineles et al., 2018). Therapeutic measures aimed at reinstating normal allopregnanolone levels in deficient-patients correlates with improved symptoms (Kanes et al., 2017). The question arises as to whether allopregnanolone biosynthesis per se is a reliable biomarker to predict, diagnose and instruct treatment selection of patients or whether its relation with neurotransmitter systems (GABAA and NMDA receptors), stimulation of neurotropic factors (e.g., BDNF), and/or crosstalk with the endocannabinoid system (e.g., PPAR-α) may provide a valuable biomarker axis with a higher disorder-selectivity. This analysis includes both neurosteroids that are positive allosteric modulators of GABAA receptors (Pinna et al., 2000; Belelli and Lambert, 2005), such as allopregnanolone and pregnanolone and their sulfated forms that are inhibitors of NMDA-mediated tonic neurotransmission, which results in neuroprotection (Vyklicky et al., 2016).


The novel discovery that the endocannabinoid system regulates the biosynthesis of neurosteroids, including allopregnanolone has recently opened the field for assessing valuable PTSD biomarkers at the interface of these neuronal systems. In recent years, cannabinoid-based agents have become an integral part of drug discovery for PTSD treatment (Ruehle et al., 2012; Neumeister et al., 2014). The impact of the endocannabinoid system is under-scored by the density of receptors in glutamatergic neurons of emotion-relevant areas, including the the amygdaloid complex, the hippocampus and the frontal cortex (Katona, 2009). Synthetic cannabinoid receptor antagonists or knockouts enhance fear acquisition and impair fear extinction, a core feature of PTSD (Reich et al., 2008; Papini et al., 2015). In addition to the well assessed role of the endocannabinoid, anandamide (AEA) or 2-arachidonoyl-glycerol (2-AG) both in neuropsychiatric disorders and animal models of stress (Chhatwal et al., 2005; Umathe et al., 2011; Dubreucq et al., 2012), compelling evidence indicates stimulation of the intracellular endocannabinoid target, peroxisome-proliferator activated receptor (PPAR)-α by its endogenous neuromodulator, N-palmitoylethanolamine (PEA) engages the biosynthesis of neurosteroids to modulate emotional behavior (Locci and Pinna, 2017b; Locci et al., 2018) (please see Figure Figure11 for a graphic representation).


In addition to these cell-surface cannabinoid receptors (O'Sullivan, 2007), there is growing evidence that PPAR-α's activation represents a novel mechanism by which cannabinoids modulate behavior. Stimulation of PPAR-α by PEA or synthetic PPAR-α agonists was recently shown to elevate corticolimbic allopregnanolone levels in hippocampus, amygdala, frontal cortex and in olfactory bulb, which correlated with improvement of PTSD-like behavior in socially isolated mice (Locci and Pinna, 2017a). PEA facilitates contextual fear extinction and fear extinction retention and induces anti-aggressive, anxiolytic, and antidepressant-like effects in socially isolated mice (Locci and Pinna, 2017b; Locci et al., 2017). PPAR-α synthetic agonists normalized allopregnanolone levels and improved behavior, whereas antagonism at PPAR-α, inhibition of allopregnanolone biosynthetic enzymes, or PPAR-α KO mice prevented both PEA-induced behavior and its neurosteroidogenic effects (Locci and Pinna, 2017b). While the role of PPAR-α in neuropsychiatric disorders is just emerging, studies in the field suggest serum PEA and oleoylethanolamide (OEA) concentrations increase after acute social stressor (Dlugos, 2012) and decrease following recovery (Hill et al., 2009a). Stress evokes fast induction of fatty acid amide hydrolase (FAAH), which reduces PEA and AEA levels (Patel et al., 2005; Hill et al., 2009b). In PTSD patients, symptoms are inversely correlated with reduced hair levels of PEA, OEA and stearoylethanolamide (SEA) in both males and females (Wilker et al., 2016). PEA adjunctive therapy to citalopram improves symptoms in depressed patients (Ghazizadeh-Hashemi, 2018). Furthermore, intense workouts increase PEA and OEA levels and improve depression and PTSD (Heyman, 2012). In rodents, exposure to predator stressors reduces cardiac PEA and OEA levels (Holman et al., 2014), but, antidepressant-like effects are induced by increasing PEA and OEA (Adamczyk et al., 2008; Umathe et al., 2011; Melis et al., 2013). Collectively, the crosstalk between the endocannabinoid system and neurosteroid biosynthesis during stress may unveil biomarker axis uniquely altered in specific stress-induced mood disorders.


Psychiatric disorders, such as PTSD, are not currently amenable to objective neurobiological determinations as is routine practice in the diagnosis and treatment of other medical conditions. This is most likely due to the general complexity and multifactorial origins of these disorders and the difficulty to establish a consistent bio-signature. While no biomarkers for PTSD have to date been firmly assessed with diagnostic validity, a consistent progress in the field has been done. Biomarker candidates for PTSD have been proposed but often they share overlaps with other psychiatric disorders with similar symptoms and that are currently treated with same drugs. Indeed, the first-choice pharmacological treatments for PTSD, the SSRIs, act through multiple molecular mechanisms other than by inhibiting serotonin reuptake. These mechanisms include the stimulation of neurosteroid and endocannabinoid biosynthesis and neurotrophic factors, such as BDNF, which are found deficient in PTSD. Increasing allopregnanolone levels is also associated with increased BDNF expression (Nin et al., 2011a). Collectively, these findings have contributed to improve our understanding of the psychobiological abnormalities associated with PTSD and promote the development of novel targeted treatment options. For instance, the correlation between the impairment of neurosteroid biosynthesis and behavioral modifications in neuropsychiatric disorders has been the focus of several studies (van Broekhoven and Verkes, 2003; reviewed in Pinna, 2013; Agis-Balboa et al., 2014; Locci and Pinna, 2017a). A reduction in the content of the GABAergic modulator allopregnanolone and its equipotent isomer pregnanolone was reported in cerebrospinal fluid (CSF) and serum of major depression and PTSD patients (Romeo et al., 1998; Uzunova et al., 1998; Rasmusson et al., 2006, 2016; Pineles et al., 2018). A negative correlation between CSF allopregnanolone levels and PTSD symptoms was more recently confirmed in male patients (Rasmusson et al., 2018). Other clinical studies support the significance of allopregnanolone biosynthesis as a biomarker of mood disorders (Uzunova et al., 1998; Agis-Balboa et al., 2014; reviewed in Zorumski et al., 2013; Schüle et al., 2014; Locci and Pinna, 2017a) with finding showing decreased allopregnanolone levels in postpartum depression (Nemeroff, 2008), under treatment with finasteride, an allopregnanolone biosynthetic enzyme blocker (Altomare and Capella, 2002; Caruso, 2015; Welk et al., 2017), and with anorexia nervosa or obesity complicated by anxiety and depression (Dichtel et al., 2018). Intriguingly, SSRI treatments normalize plasma, CSF, and brain allopregnanolone content in association with improvement of symptoms in responders only (Romeo et al., 1998; Uzunova et al., 1998; Agis-Balboa et al., 2014). These findings are in support of the role of allopregnanolone in the mechanisms of SSRIs' anxiolytic effects (Pinna, 2015). The downregulation of neurosteroid levels found in PTSD and depressed patients can be modeled in rodents exposed to protracted stress, including the socially-isolated mouse. Allopregnanolone is produced in brain corticolimbic neurons (Figure (Figure1)1) and a reduction of its levels by prolonged social isolation (Agís-Balboa et al., 2006, 2007) or exposure to single prolonged stressors, results in development of anxiety-like behavior, aggression and enhanced contextual fear conditioning responses associated with impairment of fear extinction and elevated spontaneous fear responses at recall (Pinna et al., 2003; Pibiri et al., 2008; Pinna and Rasmusson, 2014; Qiu et al., 2015). These preclinical studies further support allopregnanolone as a putative biomarkerfor stress-induced emotional modification, such as exaggerated fear responses and impaired fear extinction, a hallmark in PTSD (Pibiri et al., 2008; Pinna et al., 2008; Pinna and Rasmusson, 2012). This evidence also suggests that new therapeutic approaches should counteract the downregulation of neurosteroid biosynthesis to improve symptoms in PTSD patients. In recent phase 3 clinical trials, intravenous allopregnanolone (brexanolone or SAGE-547) or an oral analog (SAGE-217) showed a rapid and long-lasting remission of post-partum depression and major depressive disorder symptoms, conditions highly comorbid with PTSD (Kanes et al., 2017; Sage Announces Pivotal Phase 3 Trial Status for SAGE-217 in Major Depressive Disorder and Postpartum Depression based on FDA Breakthrough Therapy Meeting | Sage Therapeutics, Inc.). If successfully developed, SAGE-217 will be the first durable, rapid-acting, oral, short-course treatment for mood disorders with potential application for PTSD treatment. Stress tremendously affects the expression of GABAA receptor subunits (Pinna et al., 2006; reviewed in Locci and Pinna, 2017a). After social isolation, the α4, α5, and δ subunit expression was increased, and the α1, α2, and γ2 were significantly decreased in corticolimbic areas. These changes result in decreased benzodiazepine recognition sites and lower pharmacological response to benzodiazepines (Pinna et al., 2006). Remarkably, protracted stress favors a GABAA receptor composition with high sensitivity for allopregnanolone and its analogs (Locci et al., 2017; reviewed in Locci and Pinna, 2017a). Clinical findings support lower benzodiazepine recognition site binding in brain of PTSD patients in association with benzodiazepine-insensitivity (Geuze et al., 2008). Altogether, these findings suggest that isolation stress results in: (i) changes in GABAA receptor subunit composition; (ii) downregulated neurosteroidogenesis; and (iii) lack of response to benzodiazepines, which may provide a unique biomarker axis for PTSD (Figure (Figure2).2). Allopregnanolone, analogs or stimulation of allopregnanolone biosynthesis may be a valuable therapeutic strategy for stress-induced psychiatric disorders, characterized by benzodiazepine-inefficacy and poor response to SSRIs. The pharmacological profile of SSRIs on stimulation of neurotropic factors, including the brain-derived neurotrophic factor (BDNF), via stimulation of allopregnanolone biosynthesis is an additional important mechanism to consider when establishing biomarkers for PTSD. BDNF expression decrease in PTSD patients is associated with symptom severity. In the socially isolated mouse, fluoxetine improves behavior by elevating the corticolimbic levels of allopregnanolone and BDNF expression, independently from the action of these drugs on serotonin reuptake inhibition. This and other evidence suggest that neurosteroid biosynthesis and BDNF expression may be interrelated (Nin et al., 2011a; Frye et al., 2014), and this may provide further support for biomarker selection.


While many aspects that relate to the endocannabinoid and neurosteroid cross-talk remain presently obscure, our current findings highlight the potential for: (i) assessing novel biomarkers to predict, diagnose, and treat PTSD at the interface of the PPAR-α-allopregnanolone axis; and (ii) repurposing FDA-approved PPAR-α agonists for the treatment of PTSD after positive clinical trials. Very few drugs are direct agonists of PPAR-α, and none have been tested for their potential effects in fear responses. However, one class of drugs, the fibrates are fibric acid derivatives that are prescribed to lower plasma lipids and triglyceride levels and are synthetic PPAR-α agonists that may be exploited in rodent models of PTSD to improve behavioral deficits.

Go to:

Conclusions

Progress in assessing biomarkers to predict PTSD and its treatment response will guide the future of novel PTSD medications that may be designed to improve neurotransmission (GABA, NMDA), and neuroendocrinologic (allopregnanolone biosynthesis) and anti-inflammatory (PPAR-α) responses. Research supports precision medicine for PTSD designed to stimulate neurosteroidogenesis after assessing in subpopulations of PTSD patients a downregulation of allopregnanolone biosynthesis. This can be achieved by acting at neurosteroidogenic targets or by mimicking allopregnanolone's function (e.g., analogs). Several neuronal targets to enhance steroidogenesis have recently been discovered and these include the endocannabinoid target PPAR-α. The crosstalk between the endocannabinoid system and the biosynthesis of neurosteroids, involving their targeted receptors or the biosynthetic enzymes promises to provide unique bio-signatures for stress-induced disorders.

Collectively, advances in the field suggest biomarker-based diagnosis and treatments for PTSD that encompass the neurosteroid and endocannabinoid systems may not be a far reach and these may provide a pivotal complement to the current practice of assessing the disorder based on self-reported symptoms and psychiatrist assessments.


Biomarkers for PTSD at the Interface of the Endocannabinoid and Neurosteroid Axis

That’s interesting finasteride got a mention there along with PTSD and major depression. Nice find and thanks for pointing that out.
 

Terma

Member
Joined
May 8, 2017
Messages
1,063
See study below outlining why steroidogenesis may not be occurring with people with PTSD, PFS, postnatal depression, PMS, major depression:


A refined approach to more specifically “bio-define” PTSD can be to establish a biomarker axis or in other words, to assess the relation of various biomarkers, which fluctuate in concert and correlate uniquely with PTSD behavioral modifications. Insofar, a biomarker axis may provide a higher accuracy in the diagnosis of the disorder with benefits for prediction in PTSD treatment response and relapse (Locci et al., 2018; Pinna and Izumi, 2018). As a matter of fact, the “gold standard” treatment for PTSD and depression, the selective serotonin reuptake inhibitors (SSRIs), improve only half of the treatment-seeking patients and they are associated with severe side-effects (Golden et al., 2002; Rush et al., 2006; Kemp et al., 2008; reviewed in Bernardy and Friedman, 2017). This also suggests these psychiatric disorders are complex, multifaceted diseases arising from multiple and diverse neurobiological backgrounds and therefore, symptoms may not always recapitulate to a serotonergic deficit and administering an SSRI may not always improve symptoms. Unveiling reliable biomarkers is also a necessity for patient stratification in treatment selection as well as for drug development through clinical trials. The development of state-of-the-art technologies and methodological rigor are essential to allow for the discovery of more reliable biomarkers in psychiatry. Employing the gas chromatography-mass spectrometry (GC-MS) to achieve this goal is highly innovative and provides reliable information based on a powerful technology with high sensitivity and unsurpassed structure selectivity (Uzunov et al., 1996; Pinna et al., 2000). Hence, by applying the GC-MS measurements of neuroactive steroids in serum, plasma, CSF and post-mortem brain, in the past decade, we have shed light in the fundamental role of neuroactive steroids in patients with neuropsychiatric disorders (Rasmusson et al., 2006, 2017; Agis-Balboa et al., 2014; Pineles et al., 2018; reviewed in Locci and Pinna, 2017a).


The biosynthesis of allopregnanolone, a positive allosteric modulator of GABA's action at GABAAreceptors has been found deficient in a number of neuropsychopathologies, including epilepsy (e.g., PHDH19), major depression, PTSD, perceived social isolation, post-partum depression, premenstrual syndrome, and anorexia nervosa or obesity complicated by anxiety and depression symptoms in women (Romeo et al., 1998; Uzunova et al., 1998; Rasmusson et al., 2006, 2018; Nemeroff, 2008; Lovick, 2013; Trivisano et al., 2017; Dichtel et al., 2018; Pineles et al., 2018). Therapeutic measures aimed at reinstating normal allopregnanolone levels in deficient-patients correlates with improved symptoms (Kanes et al., 2017). The question arises as to whether allopregnanolone biosynthesis per se is a reliable biomarker to predict, diagnose and instruct treatment selection of patients or whether its relation with neurotransmitter systems (GABAA and NMDA receptors), stimulation of neurotropic factors (e.g., BDNF), and/or crosstalk with the endocannabinoid system (e.g., PPAR-α) may provide a valuable biomarker axis with a higher disorder-selectivity. This analysis includes both neurosteroids that are positive allosteric modulators of GABAA receptors (Pinna et al., 2000; Belelli and Lambert, 2005), such as allopregnanolone and pregnanolone and their sulfated forms that are inhibitors of NMDA-mediated tonic neurotransmission, which results in neuroprotection (Vyklicky et al., 2016).


The novel discovery that the endocannabinoid system regulates the biosynthesis of neurosteroids, including allopregnanolone has recently opened the field for assessing valuable PTSD biomarkers at the interface of these neuronal systems. In recent years, cannabinoid-based agents have become an integral part of drug discovery for PTSD treatment (Ruehle et al., 2012; Neumeister et al., 2014). The impact of the endocannabinoid system is under-scored by the density of receptors in glutamatergic neurons of emotion-relevant areas, including the the amygdaloid complex, the hippocampus and the frontal cortex (Katona, 2009). Synthetic cannabinoid receptor antagonists or knockouts enhance fear acquisition and impair fear extinction, a core feature of PTSD (Reich et al., 2008; Papini et al., 2015). In addition to the well assessed role of the endocannabinoid, anandamide (AEA) or 2-arachidonoyl-glycerol (2-AG) both in neuropsychiatric disorders and animal models of stress (Chhatwal et al., 2005; Umathe et al., 2011; Dubreucq et al., 2012), compelling evidence indicates stimulation of the intracellular endocannabinoid target, peroxisome-proliferator activated receptor (PPAR)-α by its endogenous neuromodulator, N-palmitoylethanolamine (PEA) engages the biosynthesis of neurosteroids to modulate emotional behavior (Locci and Pinna, 2017b; Locci et al., 2018) (please see Figure Figure11 for a graphic representation).


In addition to these cell-surface cannabinoid receptors (O'Sullivan, 2007), there is growing evidence that PPAR-α's activation represents a novel mechanism by which cannabinoids modulate behavior. Stimulation of PPAR-α by PEA or synthetic PPAR-α agonists was recently shown to elevate corticolimbic allopregnanolone levels in hippocampus, amygdala, frontal cortex and in olfactory bulb, which correlated with improvement of PTSD-like behavior in socially isolated mice (Locci and Pinna, 2017a). PEA facilitates contextual fear extinction and fear extinction retention and induces anti-aggressive, anxiolytic, and antidepressant-like effects in socially isolated mice (Locci and Pinna, 2017b; Locci et al., 2017). PPAR-α synthetic agonists normalized allopregnanolone levels and improved behavior, whereas antagonism at PPAR-α, inhibition of allopregnanolone biosynthetic enzymes, or PPAR-α KO mice prevented both PEA-induced behavior and its neurosteroidogenic effects (Locci and Pinna, 2017b). While the role of PPAR-α in neuropsychiatric disorders is just emerging, studies in the field suggest serum PEA and oleoylethanolamide (OEA) concentrations increase after acute social stressor (Dlugos, 2012) and decrease following recovery (Hill et al., 2009a). Stress evokes fast induction of fatty acid amide hydrolase (FAAH), which reduces PEA and AEA levels (Patel et al., 2005; Hill et al., 2009b). In PTSD patients, symptoms are inversely correlated with reduced hair levels of PEA, OEA and stearoylethanolamide (SEA) in both males and females (Wilker et al., 2016). PEA adjunctive therapy to citalopram improves symptoms in depressed patients (Ghazizadeh-Hashemi, 2018). Furthermore, intense workouts increase PEA and OEA levels and improve depression and PTSD (Heyman, 2012). In rodents, exposure to predator stressors reduces cardiac PEA and OEA levels (Holman et al., 2014), but, antidepressant-like effects are induced by increasing PEA and OEA (Adamczyk et al., 2008; Umathe et al., 2011; Melis et al., 2013). Collectively, the crosstalk between the endocannabinoid system and neurosteroid biosynthesis during stress may unveil biomarker axis uniquely altered in specific stress-induced mood disorders.


Psychiatric disorders, such as PTSD, are not currently amenable to objective neurobiological determinations as is routine practice in the diagnosis and treatment of other medical conditions. This is most likely due to the general complexity and multifactorial origins of these disorders and the difficulty to establish a consistent bio-signature. While no biomarkers for PTSD have to date been firmly assessed with diagnostic validity, a consistent progress in the field has been done. Biomarker candidates for PTSD have been proposed but often they share overlaps with other psychiatric disorders with similar symptoms and that are currently treated with same drugs. Indeed, the first-choice pharmacological treatments for PTSD, the SSRIs, act through multiple molecular mechanisms other than by inhibiting serotonin reuptake. These mechanisms include the stimulation of neurosteroid and endocannabinoid biosynthesis and neurotrophic factors, such as BDNF, which are found deficient in PTSD. Increasing allopregnanolone levels is also associated with increased BDNF expression (Nin et al., 2011a). Collectively, these findings have contributed to improve our understanding of the psychobiological abnormalities associated with PTSD and promote the development of novel targeted treatment options. For instance, the correlation between the impairment of neurosteroid biosynthesis and behavioral modifications in neuropsychiatric disorders has been the focus of several studies (van Broekhoven and Verkes, 2003; reviewed in Pinna, 2013; Agis-Balboa et al., 2014; Locci and Pinna, 2017a). A reduction in the content of the GABAergic modulator allopregnanolone and its equipotent isomer pregnanolone was reported in cerebrospinal fluid (CSF) and serum of major depression and PTSD patients (Romeo et al., 1998; Uzunova et al., 1998; Rasmusson et al., 2006, 2016; Pineles et al., 2018). A negative correlation between CSF allopregnanolone levels and PTSD symptoms was more recently confirmed in male patients (Rasmusson et al., 2018). Other clinical studies support the significance of allopregnanolone biosynthesis as a biomarker of mood disorders (Uzunova et al., 1998; Agis-Balboa et al., 2014; reviewed in Zorumski et al., 2013; Schüle et al., 2014; Locci and Pinna, 2017a) with finding showing decreased allopregnanolone levels in postpartum depression (Nemeroff, 2008), under treatment with finasteride, an allopregnanolone biosynthetic enzyme blocker (Altomare and Capella, 2002; Caruso, 2015; Welk et al., 2017), and with anorexia nervosa or obesity complicated by anxiety and depression (Dichtel et al., 2018). Intriguingly, SSRI treatments normalize plasma, CSF, and brain allopregnanolone content in association with improvement of symptoms in responders only (Romeo et al., 1998; Uzunova et al., 1998; Agis-Balboa et al., 2014). These findings are in support of the role of allopregnanolone in the mechanisms of SSRIs' anxiolytic effects (Pinna, 2015). The downregulation of neurosteroid levels found in PTSD and depressed patients can be modeled in rodents exposed to protracted stress, including the socially-isolated mouse. Allopregnanolone is produced in brain corticolimbic neurons (Figure (Figure1)1) and a reduction of its levels by prolonged social isolation (Agís-Balboa et al., 2006, 2007) or exposure to single prolonged stressors, results in development of anxiety-like behavior, aggression and enhanced contextual fear conditioning responses associated with impairment of fear extinction and elevated spontaneous fear responses at recall (Pinna et al., 2003; Pibiri et al., 2008; Pinna and Rasmusson, 2014; Qiu et al., 2015). These preclinical studies further support allopregnanolone as a putative biomarkerfor stress-induced emotional modification, such as exaggerated fear responses and impaired fear extinction, a hallmark in PTSD (Pibiri et al., 2008; Pinna et al., 2008; Pinna and Rasmusson, 2012). This evidence also suggests that new therapeutic approaches should counteract the downregulation of neurosteroid biosynthesis to improve symptoms in PTSD patients. In recent phase 3 clinical trials, intravenous allopregnanolone (brexanolone or SAGE-547) or an oral analog (SAGE-217) showed a rapid and long-lasting remission of post-partum depression and major depressive disorder symptoms, conditions highly comorbid with PTSD (Kanes et al., 2017; Sage Announces Pivotal Phase 3 Trial Status for SAGE-217 in Major Depressive Disorder and Postpartum Depression based on FDA Breakthrough Therapy Meeting | Sage Therapeutics, Inc.). If successfully developed, SAGE-217 will be the first durable, rapid-acting, oral, short-course treatment for mood disorders with potential application for PTSD treatment. Stress tremendously affects the expression of GABAA receptor subunits (Pinna et al., 2006; reviewed in Locci and Pinna, 2017a). After social isolation, the α4, α5, and δ subunit expression was increased, and the α1, α2, and γ2 were significantly decreased in corticolimbic areas. These changes result in decreased benzodiazepine recognition sites and lower pharmacological response to benzodiazepines (Pinna et al., 2006). Remarkably, protracted stress favors a GABAA receptor composition with high sensitivity for allopregnanolone and its analogs (Locci et al., 2017; reviewed in Locci and Pinna, 2017a). Clinical findings support lower benzodiazepine recognition site binding in brain of PTSD patients in association with benzodiazepine-insensitivity (Geuze et al., 2008). Altogether, these findings suggest that isolation stress results in: (i) changes in GABAA receptor subunit composition; (ii) downregulated neurosteroidogenesis; and (iii) lack of response to benzodiazepines, which may provide a unique biomarker axis for PTSD (Figure (Figure2).2). Allopregnanolone, analogs or stimulation of allopregnanolone biosynthesis may be a valuable therapeutic strategy for stress-induced psychiatric disorders, characterized by benzodiazepine-inefficacy and poor response to SSRIs. The pharmacological profile of SSRIs on stimulation of neurotropic factors, including the brain-derived neurotrophic factor (BDNF), via stimulation of allopregnanolone biosynthesis is an additional important mechanism to consider when establishing biomarkers for PTSD. BDNF expression decrease in PTSD patients is associated with symptom severity. In the socially isolated mouse, fluoxetine improves behavior by elevating the corticolimbic levels of allopregnanolone and BDNF expression, independently from the action of these drugs on serotonin reuptake inhibition. This and other evidence suggest that neurosteroid biosynthesis and BDNF expression may be interrelated (Nin et al., 2011a; Frye et al., 2014), and this may provide further support for biomarker selection.


While many aspects that relate to the endocannabinoid and neurosteroid cross-talk remain presently obscure, our current findings highlight the potential for: (i) assessing novel biomarkers to predict, diagnose, and treat PTSD at the interface of the PPAR-α-allopregnanolone axis; and (ii) repurposing FDA-approved PPAR-α agonists for the treatment of PTSD after positive clinical trials. Very few drugs are direct agonists of PPAR-α, and none have been tested for their potential effects in fear responses. However, one class of drugs, the fibrates are fibric acid derivatives that are prescribed to lower plasma lipids and triglyceride levels and are synthetic PPAR-α agonists that may be exploited in rodent models of PTSD to improve behavioral deficits.

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Conclusions

Progress in assessing biomarkers to predict PTSD and its treatment response will guide the future of novel PTSD medications that may be designed to improve neurotransmission (GABA, NMDA), and neuroendocrinologic (allopregnanolone biosynthesis) and anti-inflammatory (PPAR-α) responses. Research supports precision medicine for PTSD designed to stimulate neurosteroidogenesis after assessing in subpopulations of PTSD patients a downregulation of allopregnanolone biosynthesis. This can be achieved by acting at neurosteroidogenic targets or by mimicking allopregnanolone's function (e.g., analogs). Several neuronal targets to enhance steroidogenesis have recently been discovered and these include the endocannabinoid target PPAR-α. The crosstalk between the endocannabinoid system and the biosynthesis of neurosteroids, involving their targeted receptors or the biosynthetic enzymes promises to provide unique bio-signatures for stress-induced disorders.

Collectively, advances in the field suggest biomarker-based diagnosis and treatments for PTSD that encompass the neurosteroid and endocannabinoid systems may not be a far reach and these may provide a pivotal complement to the current practice of assessing the disorder based on self-reported symptoms and psychiatrist assessments.


Biomarkers for PTSD at the Interface of the Endocannabinoid and Neurosteroid Axis

Yeah this is thrilling, that's a new one (2018), thanks, was not aware of everything they mentioned. The PEA was already documented and even tried it on myself: Thoughts On 5ar And Post Finasteride Syndrome
The PEA is slightly sedating but I think either it doesn't make it huge enough quantities from gut to brain or we're not using it correctly [and perhaps there's simply no way to emulate a 15mg 5a-DHP dose using endogenous synthesis].

Also plan on trialing some CBD and stuff once it's legalized in my country on October 17th (yeah they did something right for once, who knew they had it in them?? Hilarious this gets legalized and then 5a-DHP might become inaccessible). Any alternate route to increased endogenous Allo synthesis will be welcome.

If cannabinoids increase Allo significantly endogenously, that may be another route through which they increase hunger: https://www.researchgate.net/public..._in_feeding_regulation_overeating_and_obesity

Research is certainly converging.
 

nwo2012

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Wouldnt shock me if this is the usual forward thinking of our leading inbreds. How to get progesterone and eventually all the steroid hormones as presscription only synthetic garbage cant have less people playing the cancer/disease lottery, can we?!?
 

alywest

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Yeah this is thrilling, that's a new one (2018), thanks, was not aware of everything they mentioned. The PEA was already documented and even tried it on myself: Thoughts On 5ar And Post Finasteride Syndrome
The PEA is slightly sedating but I think either it doesn't make it huge enough quantities from gut to brain or we're not using it correctly [and perhaps there's simply no way to emulate a 15mg 5a-DHP dose using endogenous synthesis].

Also plan on trialing some CBD and stuff once it's legalized in my country on October 17th (yeah they did something right for once, who knew they had it in them?? Hilarious this gets legalized and then 5a-DHP might become inaccessible). Any alternate route to increased endogenous Allo synthesis will be welcome.

If cannabinoids increase Allo significantly endogenously, that may be another route through which they increase hunger: https://www.researchgate.net/public..._in_feeding_regulation_overeating_and_obesity

Research is certainly converging.

So it's my understanding that women with PTSD, and perhaps those who struggle with PFS, are having difficulty converting the 5a-DHP and progesterone to Allopregnanolone-and keeping it that way. It sounds like it's a defective use of the 3a-HSD enzyme. I noticed when I have taken progesterone in the past it didn't make a huge difference for me. Now I am trying a very low dose of zoloft (I know, kill me! About 6 mg based on my bodyweight of 150 lb.-it would be about 2mg of fluoxetine) and now if I take progesterone I can really feel the calmness that people have talked about. For instance, taking it orally makes me really sleepy whereas in the past I could take 400mg orally and barely notice a difference. The addition of PEA has also been helping a lot with the physical pains that I struggle with. The last piece of the puzzle as explained in the study I introduced above, would be the fibrates, which I am not sure how to mimic that without taking an actual fibrate.
I also take niacinamide, thiamine, methylfolate, myo-inositol, and cytomel and levothyroxine, as well as the progesterone. I have at times gotten the same feeling I had when I had taken MDMA in the distant past, which I found to be somewhat addicting because I do suffer with PTSD from childhood and it was the first time I felt good in such a long time. Also, I became "addicted" to marijuana which many people would argue, but I would say I was an addict as it was hampering my ability to function for a long time. I think the calmness it gave me for a long time was more important to me than being a really successful person in career or life in general. I'm glad that CBDs are being offered as an option to those who don't want to live their lives being high all the time, as I now do believe that MMJ is detrimental to most people. While it may solve short term problems, it becomes a crutch and ultimately a destructive one at that.
 

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So it's my understanding that women with PTSD, and perhaps those who struggle with PFS, are having difficulty converting the 5a-DHP and progesterone to Allopregnanolone-and keeping it that way. It sounds like it's a defective use of the 3a-HSD enzyme. I noticed when I have taken progesterone in the past it didn't make a huge difference for me. Now I am trying a very low dose of zoloft (I know, kill me! About 6 mg based on my bodyweight of 150 lb.-it would be about 2mg of fluoxetine) and now if I take progesterone I can really feel the calmness that people have talked about. For instance, taking it orally makes me really sleepy whereas in the past I could take 400mg orally and barely notice a difference. The addition of PEA has also been helping a lot with the physical pains that I struggle with. The last piece of the puzzle as explained in the study I introduced above, would be the fibrates, which I am not sure how to mimic that without taking an actual fibrate.
I also take niacinamide, thiamine, methylfolate, myo-inositol, and cytomel and levothyroxine, as well as the progesterone. I have at times gotten the same feeling I had when I had taken MDMA in the distant past, which I found to be somewhat addicting because I do suffer with PTSD from childhood and it was the first time I felt good in such a long time. Also, I became "addicted" to marijuana which many people would argue, but I would say I was an addict as it was hampering my ability to function for a long time. I think the calmness it gave me for a long time was more important to me than being a really successful person in career or life in general. I'm glad that CBDs are being offered as an option to those who don't want to live their lives being high all the time, as I now do believe that MMJ is detrimental to most people. While it may solve short term problems, it becomes a crutch and ultimately a destructive one at that.
Good post and interesting experiences. I wanted to try MDMA (due to testimonials that regular users have made that Phenibut in high doses has a similar feeling) but found out much of the street product is not even real MDMA. Which of course is directly created by it being illegal. I'm hoping legalization in Canada will help solve that issue for THC and CBD (yes, CBD was illegal here!) [sometimes tainted unless you have a good local grower, which I don't] [Note that even THC increases Pregnenolone through a feedback mechanism, but seems to lowers Allo over the long run though that observation may be distorted by clinical diagnosis - yet even further confounded because many cannabis users are simply self-medicating for diagnosed or undiagnosed disorders]

I've come to believe Allopregnanolone is a major (if not the major) canary in the coalmine for health problems, because either 5-AR1 or 3a-HSD function can be ruined so easily, and because Allo is a heavy influence on circadian rhythm.

Unfortunately all these solutions including CBD are too broad-spectrum are practically end up perpetuating wrong ideas about it. Only PEA seemed promising for a short time. Maybe another cannabinoid will do it... but because they seem to work through stress mechanisms, they don't appear ideal (PPARalpha tends to associate with stressors such as fasting, in liver at least; in brain I'm not as sure).

Recently someone posted this hypothesis about ME/CFS and the physician response was to try to lower Progesterone levels by increasing androgens, estrogen and cortisol. Of course, cortisol ends up low, but that's misleading. Testosterone is useful but even that is misleading so I'm dumbfounded by the response (also Berberine which has been promoted even on this forum is a cellular stressor - at very best you hope it improves your gut).
 
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Terma

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5a-DHP was great because it bypasses the broad effects of all those substances and even Progesterone supplementation (unless the enzyme works backward?).

The only issue I found with it besides tolerance is it could have "anti-inflammatory" effects that often translate to immune suppression, which might be counterproductive long-term in some diseases.
 

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Major chemical vendors like Sigma Aldrich sell it, but it is very expensive and even then the amounts sold usually do not exceed 50mg. Most animal studies used the equivalent of 5mg-20mg daily, so it becomes prohibitively expensive. That one of the reasons I did not release ALLO as a product but its direct precursors 5a-DHP, which is (a bit) more affordable.

What human dosage of 5a-DHP are researchers experimenting with these days?

Thanks!
 
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What human dosage of 5a-DHP are researchers experimenting with these days?

Thanks!

Usually the HED based on the animal studies, namely 5mg-8mg daily.
 
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and at what time before bed to promote better sleep for a chronic insomniac due o PFS?

Its effects seem to be felt within 30min, so it should be timed accordingly.
 

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What human dosage and administration route of of 5a-DHP are researchers experimenting with at this time?
 
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What human dosage and administration route of of 5a-DHP are researchers experimenting with at this time?

You already asked this question earlier and I answered it. Look at the previous responses.
 

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Oh that is strange. I posted it but didn't see it, so i repeated the post. Sorry about that and thank you very, very much.

I have a test subject with degenerative myelopathy. I think it might help him regain nerve function. Care to speculate?

GABA and myelination | Report Summary | NEUROSTEROIDS & AGEI | FP5 | CORDIS | European Commission

I can't discuss specific conditions but as I posted in the main thread on 5a-DHP, the protective effects of progesterone in the central and peripheral nervous system is thought to be mediated primarily by 5-AR derived metabolites of progesterone such as 5a-DHP and allopregnanolone.
5α-DHP - Liquid 5α-Dihydroprogesterone For Lab/R&D
 

broozer

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Its effects seem to be felt within 30min, so it should be timed accordingly.
thanks haidut. i tried 5mg and 10. both doses were not enough to put me to sleep.i dont wanna go beyond due the breast cancer risk. so can i conclude the coming allopregnenolone drug wont help my sleep either?
are there proven ways to increase the amount of GABA in the system? my receptors have desensitized after months on zopiclone/benzos.
 

alywest

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thanks haidut. i tried 5mg and 10. both doses were not enough to put me to sleep.i dont wanna go beyond due the breast cancer risk. so can i conclude the coming allopregnenolone drug wont help my sleep either?
are there proven ways to increase the amount of GABA in the system? my receptors have desensitized after months on zopiclone/benzos.

So in my experience, if you can't convert the 5aDHP to allopregnanolone, then it won't really have much effect for you. The same with progesterone supplementation. If it doesn't convert to allopregnanolone, which is the active form, it's not going to really have much effect. And I was having the same issue with progesterone. 5a-DHP is nice because it's further down the pathway, but it's possible you're still not able to make the conversion due to a lack of 3a-HSD. The new drug would eliminate all those issues because it would already be converted for you. And trust me-allopregnanolone, if you have enough of it in your system, will make you sleepy. It is really frustrating when you're taking these supplements to not get any effects. You could be lacking the 3a-HSD enzyme for several reasons, but it seems to be a problem for people with PTSD, severe PMS (PMDD), and even possibly post finasteride syndrome which is discussed a lot on this forum because of how miserable it is for the men who suffer with it. So Haidut has pointed out on another thread that mirtazapine helps with the conversion to allopregnanolone.
 

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alywest

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thanks alywest. i heard the same about mirtazapin. but its a small edge between enough to put to sleep and an unbearable sedation throughout the next day.
i found this on fluoxetine.

Fluoxetine and norfluoxetine stereospecifically and selectively increase brain neurosteroid content at doses that are inactive on 5-HT reuptake. - PubMed - NCBI

ii wonder if one can take ultra low dose fluoxetine (1/50), raise allo but dont get the nasty sides of SSRI action?
Yes, and that is what I am doing with zoloft currently, until I can get some mirtazapine. I take about 6 mg (the doctor prescribed 25mg which is pretty much the lowest dose because they assume it's for serotonin reuptake inhibition/"anti-depressant"! lol) Anyways, it's been fine. In fact, the research shows that the purpose of low dose ssri is to avoid the sleepiness of progesterone supplementation.
 

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