Terma

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With the cannabos, I think the biggest risk from the protocol is distorting the gut flora, because the gut transit lowering effects last several days and several of the substances affect stomach pH. The worst concern would be ending up with SIBO, though so far most of my issues were related to lower in the gut and appear due to caprylic acid (one brand was not quite as good either... might as well stick to the popular stuff).

Here is a "mini" version of this protocol for weekdays (1-2 days/week, 3 max):

Low-dose phenibut (< 1g) + topical DHEA+pregnenolone (oil) + calcium/magnesium

Phenibut as a VGCC inhibitor always appeared to be able to lower the same types of stress signals in my brain as do the cannabos (my best guess being somewhere along the lines of TRP/5-HT3, or overactive histamine neurons in certain areas; also possible it lacks neurotransmission that normally behaves like VGCC inhibition, or rather both).

This is nowhere near what I've been describing - and it's definitely not high-dose phenibut (high concern/targeted-empathy state at ~3-5g) - but it produces very natural days and helped sleep. This seems to give the socialization and stress lowering benefits of phenibut for less backlash, and helps deal with withdrawal from cannabos since I'm more sensitive to that than most people.

I think cannabos and phenibut can probably be exploited to temporarily improve calcium usage for healing, and everything requires magnesium, and magnesium goes better with calcium. Having options is nice. (histidine+beta-alanine works with a lot of things as well...)
 
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Terma

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This post relates to the thread: Increasing Oxytocin And Gut Motility With Ozonated Magnesium

Cholinergic stimulation, through muscarinic receptors, of oxytocin and progesterone secretion from bovine granulosa cells undergoing spontaneous lu... - PubMed - NCBI
Bovine granulosa cells were cultured in a defined serum-free system to examine their responsiveness to acetylcholine (ACh). Continuous exposure to concentrations of ACh between 10(-8)-10(-4) M resulted in dose-dependent increases (up to 6.7-fold) in the secretion of oxytocin and progesterone, with an ED50 of 6.6 microM. Ascorbic acid (0.5 mM), a known stimulator of granulosa secretion, synergized with ACh, resulting in an increase in the amounts of hormone secreted and a 7-fold increase in cellular sensitivity to ACh (ED50 = approximately 0.9 microM). Treatment of cells with ACh for 24 h at various times during a typical 5-day culture resulted in a stimulation that persisted for up to 4 days after removal of ACh. Carbachol (10(-8)-10(-4) M), a receptor antagonist with both antimuscarinic and antinicotinic actions, had no distinct effect on hormone secretion by the cells, but the effects of 10(-5) M ACh could be completely abolished by equimolar or hypomolar concentrations of the specific muscarinic receptor antagonists atropine and scopolamine. Nicotine bitratrate (10(-8)-10(4) M), a dose-dependent nicotinic receptor agonist/antagonist, had no effect on the cells. It is concluded that bovine granulosa cells, exhibiting a luteinized phenotype in culture, are responsive to cholinergic agonists in a specific and saturable manner. The response of the cells is probably mediated through muscarinic receptors and has both medium and long term (persistent) components. These results indicate that cholinergic neurotransmitters may play a direct role in the regulation of ovarian function in the ruminant.
These studies demonstrate for the first time that bovine granulosa cells are capable of responding to cholinergic stimulation. They do so by increasing their secretion of both oxytocin and progesterone in a manner independent of any change in cell number. The response to ACh was dose dependent, saturable, and, on the basis of the response to the antagonists to atropine and scopolamine and the lack of response to nicotine, likely to be mediated exclusively through muscarinic receptors.

This curiously parallels my experience: modulation of muscarinic receptors seems likely involved, if you go by the sedation, sleepiness, thirst (Pilocarpine-induced salivation and thirst in conscious rats. - PubMed - NCBI), and other effects. Last night and today, I had some highly empathetic experiences, and these were notably after eating 2 rolls of tamago sushi and probably 1g or so of ascorbic acid (combined with some potassium bicarbonate, and other things). Muscarinic receptors appear to set conditions for oxytocin release.

The duration of those effects (4 days) reflects roughly the length of time I can sustain a higher level of empathy than normal - through seemingly biochemical signals - after an experience such as this - alongside continued DHEA + pregnenolone supplementation, as well as some others intermittently. Of course, being so sedating as well as upregulating CB1 receptors, progesterone is also stimulated by muscarinic receptor agonists. However, afterward progesterone - as well as pregnenolone - feeds back and antagonizes muscarinic receptors:
The effects of the neurosteroids: pregnenolone, progesterone and dehydroepiandrosterone on muscarinic receptor-induced responses in Xenopus oocytes... - PubMed - NCBI
The neurosteroids pregnenolone, progesterone, and dehydroepiandrosterone (DHEA) occur naturally in the nervous system. They act on neural tissues, participate in neuronal signaling, and are reported to alter neuronal excitability via nongenomic mechanisms. Muscarinic receptors have important roles in neuronal functions in the brain and autonomic nervous system. In this study, we investigated the effects of pregnenolone, progesterone, and DHEA on M(1) and M(3) muscarinic receptors using the Xenopus oocyte expression system. Pregnenolone and progesterone inhibited the acetylcholine (ACh)-mediated responses of M(1) and M(3) receptors expressed in Xenopus oocytes, whereas DHEA did not. The half-maximal inhibitory concentrations (IC(50)) for pregnenolone inhibition of M(1) receptor- and M(3) receptor-mediated currents were 11.4 and 6.0 microM respectively; the IC(50) values for progesterone inhibition of M(1) receptor- and M(3) receptor-mediated currents were 2.5 and 3.0 microM respectively. The selective protein kinase C (PKC) inhibitor GF109203X had little effect on the pregnenolone or progesterone inhibition of the ACh-induced currents in Xenopus oocytes expressing M(1) or M(3) receptors. The inhibitory effects of pregnenolone and progesterone were overcome at higher concentrations of ACh. Pregnenolone and progesterone inhibited the [(3)H]quinuclidinyl benzilate (QNB) binding to M(1) and M(3) receptor expressed in Xenopus oocytes, and Scatchard plot analysis of [(3)H]QNB binding revealed that pregnenolone and progesterone altered the K(d) value and the B(max), indicating noncompetitive inhibition. In conclusion, pregnenolone and progesterone inhibited M(1) and M(3) receptor functions noncompetitively by the mechanism independent of PKC and by interfering with ACh binding to the receptors.

Finally,
Activation of Muscarinic Acetylcholine Receptors Enhances the Release of Endogenous Cannabinoids in the Hippocampus
Endogenous cannabinoids (endocannabinoids) are endogenous compounds that resemble the active ingredient of marijuana and activate the cannabinoid receptor in the brain. They mediate retrograde signaling from principal cells to both inhibitory [“depolarization-induced suppression of inhibition” (DSI)] and excitatory (“depolarization-induced suppression of excitation”) afferent fibers. Transient endocannabinoid release is triggered by voltage-dependent Ca2+ influx and is upregulated by group I metabotropic glutamate receptor activation. Here we show that muscarinic acetylcholine receptor (mAChR) activation also enhances transient endocannabinoid release (DSI) and induces persistent release. Inhibitory synapses in the rat hippocampal CA1 region of acute slices were studied using whole-cell patch-clamp techniques. We found that low concentrations (0.2–0.5 μm) of carbachol (CCh) enhanced DSI without affecting basal evoked IPSCs (eIPSCs) by activating mAChRs on postsynaptic cells. Higher concentrations of CCh (≥1 μm) enhanced DSI and also persistently depressed basal eIPSCs, mainly by releasing endocannabinoids. Persistent CCh-induced endocannabinoid release did not require an increase in [Ca2+]i but was dependent on G-proteins. Although they were independent at the receptor level, muscarinic and glutamatergic mechanisms of endocannabinoid release shared intracellular machinery. Replication of the effects of CCh by blocking acetylcholinesterase with eserine suggests that mAChR-mediated endocannabinoid release is physiologically relevant. This study reveals a new role of the muscarinic cholinergic system in mammalian brain.
It seems to me the muscarinic/parasympathetic cholinergic system appears important in promoting the conditions for empathy and trust. GABA activation - notably GABAA (Amanita muscaria - PsychonautWiki) - is likely involved as well, I think, one way or the other. Nicotinic receptors also seem involved, but they are toward the stimulant side of things.

This combination appears to recur:
Euphoria - Wikipedia
Chewing areca nut (seeds from the Areca catechu palm) with slaked lime (calcium hydroxide) – a common practice in South- and Southeast Asia – produces stimulant effects and euphoria.[42][43][44] The major psychoactive ingredients – arecoline (a muscarinic receptor partial agonist)[43][45] and arecaidine (a GABA reuptake inhibitor)[46][47] – are responsible for the euphoric effect.[48][49]

I think vitamin C may be more important than I gave it credit for, but it is limited by absorption anyway. Perhaps the change in gut motility from the protocol also affects the absorption of vitamin C? It would in fact be expected counteract its diarrhea-promoting effects in higher doses. Perhaps the protocol results in an increase in the absorption of vitamin C? I don't know, just a thought... I can't quite piece all this together yet, but GABAA, muscarinic receptor stimulation, and oxytocin would all appear to be involved. However, pregnenolone and progesterone would antagonize - or rather balance out the effects of - certain muscarinic receptors, though they may also promote the formation of the downstream hormones, not the least if NADPH and other resources are increased - allopregnenolone notably, but also others. Perhaps the effects of the pregnenolone molecule itself promote the more "rational" and in-touch-with-the-universe side? Hard to say exactly. GABAA should also have a role in that

It is clear this is a heavily parasympathetic protocol if you go by most of the substances and the design I was going for. At least that seems to set the stage for all the effects. Subjectively, I associate this with feelings of peace, or the conditions necessary for deep rest. Of course, sleep is the time we must put the most trust in others since that's when we are at our most vulnerable. Sharing water in scarcity is a second important driver.

However, pregenenolone and progesterone themselves do seem to oppose some muscarinic receptor signaling. Of course, muscarinic receptors can also stop acetylcholine release (Muscarinic and GABAA receptors modulate acetylcholine release in feline basal forebrain. - PubMed - NCBI). It all seems to feedback, so there is some sort of balance. I suppose it would be in line to say that pregnenolone's increase in consciousness reflect a wake-promoting effect, which might counteract the dreaminess and sedation induced by the other substances. At least this is what the original study said: the increase in pregnenolone synthesis due to cannabinoids was a compensatory response to the effects of the cannabinoids. This reflects what I was trying to say much earlier in the thread: you get interesting effects from the "loss" of consciousness as well - perhaps one of them is a diversion of resources toward processes which explore and support emotionality? I'm reaching, but this is fun to think about.

One caveat: this post does not go into detail about the several muscarinic receptor types, which might be important. I am not sure if muscarinic receptors dominate in all these effects or not, but I expect them to be involved.

I'm basically daydreaming.

dreaming-adrienne-bresnahan.jpg
 
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Terma

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It seems that DHEAS and estrone sulfate have the potential to increase hippocampal activity, seemingly via muscarinic M2 receptor activation, which being an inhibitor signal, releases the "brake" (GABA) on the hippocampal neurons, allowing greater hippocampal activity (in effect a disinhibition):
Sci-Hub | Dehydroepiandrosterone sulfate and estrone sulfate reduce GABA-recurrent inhibition in the hippocampus via muscarinic acetylcholine receptors. Hippocampus, 16(12), 1080–1090 | 10.1002/hipo.20232
Several recent studies have established a role for estrogens in ameliorating specific neurodegenerative disorders, mainly those associated with the cholinergic neurons of the basal forebrain and their targets in the cortex and hippocampus. We have previously demonstrated that endogenous and exogenous application of the neurosteroid dehydroepiandrosterone sulfate (DHEAS) markedly reduces GABA-mediated recurrent inhibition and synchronizes hippocampal unit activity to theta rhythm (Steffensen (1995) Hippocampus 5:320-328). In this study, we evaluated the role of muscarinic receptors in mediating the effects of DHEAS and estrone sulfate (ES), the principal circulating estrogen in humans, on short-latency-evoked potential responses, paired-pulse inhibition (PPI), paired-pulse facilitation, and GABA interneuron activity in the dentate gyrus and CA1 subfields of the rat hippocampus. In situ microelectrophoretic application of the muscarinic M2 subtype cholinergic receptor agonist cis-dioxolane, DHEAS, and ES markedly reduced PPI in the dentate and CA1 that was blocked by the M2 receptor antagonist gallamine. Similar to DHEAS, microelectrophoretic administration of ES increased population spike amplitudes, without increasing excitatory transmission, but this effect was not blocked by gallamine. Microelectrophoretic application of cis-dioxolane and ES markedly increased the firing rate of dentate hilar interneurons and CA1 oriens/alveus interneurons and enhanced their synchrony to hippocampal theta rhythm. These findings suggest that select GABA-modulating neurosteroids and neuroactive estrogen sulfates alter septohippocampal cholinergic modulation of hippocampal GABAergic interneurons mediating recurrent, but not feedforward, inhibition of hippocampal principal cell activity.
Basal forebrain ACh neurons that project to the hippocampus via the septohippocampal pathway are potential substrates for estrogen effects in the hippocampus, as cholinergic neurons in the medial septum bind estrogen and express estrogen receptors (Merchenthaler and Shugrue, 1999), estrogen increases basal forebrain choline acetyltransferase activity (Luine, 1985), high-affinity choline uptake (Gibbs, 2000), ACh release (Gibbs et al., 1997), and some estrogen effects on hippocampal excitatory synaptic function are blocked by M2 muscarinic receptor antagonists (Daniel and Dohanich, 2001). However, as mentioned earlier, a second possibility is that estrogen acts directly on cholinergic septohippocampal projection neurons to increase ACh release (Gibbs et al., 1997), and thereby influences a subset of hippocampal GABAergic synapses that is sensitive to ACh modulation.

This is neatly in line with DHEAS's known ability to stimulate tyrosine hydroxylase (implementing persistence and relentlessness):
Dehydroepiandrosterone Sulfate and Allopregnanolone Directly Stimulate Catecholamine Production via Induction of Tyrosine Hydroxylase and Secretion by Affecting Actin Polymerization

As other people posted (might as well) it has a plethora of other effects:
Neurobiological and Neuropsychiatric Effects of Dehydroepiandrosterone (DHEA) and DHEA Sulfate (DHEAS)

In other words DHEAS and probably estrone sulfate and estrogens balance out the parasympathetic, inhibitory and (depending on location) GABAA effects. They probably help increase cognitive ability and drive during the experience, which offset some of the effects stereotypically associated with cannabinoids. I'd expect allopregnenolone to be significant in this as well.
 

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I'll leave this 2019 carnosine (beta-alanine + histidine) review here:
The Potential of Carnosine in Brain-Related Disorders: A Comprehensive Review of Current Evidence

Aggregates a bunch of references old and new worth reading. Of course it has a few circumstantially questionable effects (Cu/Zn handling; obviously it acts as a histidine/histamine reserve - but that I count on; note also carnosine itself appears to have the ability to agonize histamine receptors directly and thus vasoconstriction: "Recently, O’Dowd and Miller reported that, like histamine, carnosine directly activates smooth muscle H1, receptors to evoke vasoconstriction, with greater efficacy than noradrenaline" - Sci-Hub | Carnosine protects against NMDA-induced neurotoxicity in differentiated rat PC12 cells through carnosine-histidine-histamine pathway and H1/H3 receptors. Biochemical Pharmacology, 73(5), 709–717 | 10.1016/j.bcp.2006.11.007)... but its range of beneficial effects together with all the beta-alanine research and the potential for its derivatives (homocarnosine, anserine; GABA relatives) there's no question about this one having a strong modulatory effect on brain power and emotional processing. I don't think I'll ever go a week without it ever again, as it is not far from phenibut in terms of the amount of ***t it gets me through. Side effects from overdoing have been gastrointestinal and maybe headache (I eventually get this from vasoconstriction or too many nitric oxide inhibitors - possibility) though these are confounded.
 

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This is a correction to a comment I made in another thread, which is full of generalizations:
Enhancement Of Serotonin Uptake By Cortisol
Yes indeed (Sci-Hub | Correlation between cortisol level and serotonin uptake in patients with chronic stress and depression. Cognitive, Affective, & Behavioral Neuroscience, 1(4), 388–393 | 10.3758/cabn.1.4.388), I think cortisol acutely increasing SERT is logical because that helps explain its role in anxiety disorders: in organisms where 5-HT2c or other 5-HT receptors that can induce anxiety are highly expressed, cortisol feels good by lowering serotonin. That is, until the feedback GR downregulate or become simply dysfunctional (their assembly/shuttling) at which point you begin to disintegrate. Likely, having sensitive 5-HT2c (and possibly others) together with feedback GR insensitivity is part of what makes people very sensitive to stress. Something similar might be true for 5-HT3 but I'm not as sure. Of course when GR feedback is dysregulated, this turns on the dynorphin system and you feel terrible followed by something like PTSD where essentially you can't stop thinking about your failures because the resulting KOR system insensitivity (due to to the higher levels of dynorphin) prevents failure memory reconsolidation.
Because of several conflicting articles about KOR, I can't really make the claim that KOR might be expected to desensitize at chronically high levels of dynorphin. It could be graded by dynorphin concentrations somehow, but the doses didn't seem to support that. It happens, but I can't tell in what circumstances or levels. It's further complicated by brain anatomy.

More realistically, I think maybe it works this way: when dynorphin is chronically high (anxiety, fear, low motivation, perhaps disgust response - that last one a suggestion from personal experience), spikes of dynorphin may be less effectual as the pool of dynorphin is already large, thus the spike diluted. This may be true even if dynorphin release or KOR receptors were upregulated. This means one or two things: 1) During the recall of a fear memory, as it cannot be extinguished during chronically high dynorphin, the true moments of fear and failure are not properly represented, or distinguished, since high dynorphin and KOR activation occur during the whole recall, perhaps even "marking" it or even strengthening the fear memory, at the extreme, and 2) The constant dynorphin activity and KOR activation may make it difficult for the mind to acknowledge one's true emotions and failures while recalling fear memories, and in other words, seeing the "good" from the bad, or learning the good from the bad, instead of everything just bad and constantly replaying fears and negative emotions. It is like unfiltered depressive white noise. Like several other stress hormones, the dynorphin molecules are relatively short-lived and become problematic only once chronically upregulated (through its interactions with CRH/ACTH). It's the spikes that matter. They identify the failures and fears in memories (Dynorphins Regulate Fear Memory: from Mice to Men), and allow you to see the good in the experience. Then somehow with GABAA, probably endorphins, maybe oxytocin, and other things, the fears can be extinguished, by forming new extinction memories or maybe even depotentiation - there is more than one extinction mechanism (Different mechanisms of fear extinction dependent on length of time since fear acquisition). They filter the noise, and probably other details.

I would go so far as to say it's through this I would expect for comedy to work: forms of comedy are based on contrast of expectations of outcomes. So a peaceful (GABAA, low adrenaline) experience with bouts of fear and pain (KOR, maybe without adrenaline) - seemingly no matter how strong, and perhaps necessitating a minimum strength - followed by reward (endorphins, oxytocin, etc.?) - would set the stage for the creation of effective extinction/resolution memories?

That was my guess with propranolol: its GABA(A) effects counter the effects of acute and chronic dynorphin activation and help distinguish - or "filter" - the fear memories. It should generally counter adrenaline, CRH and dynorphin (triggered by CRH, but also amplifying the stress response the other way around: ), one way or the other. But dynorphin is known to antagonize effects and release of catecholamines (Opioid peptides decrease noradrenaline release and blood pressure in the rabbit at peripheral receptors, Dynorphin Knockout Reduces Fat Mass and Increases Weight Loss during Fasting in Mice), and given its apparent role in behavior, it would be expected that less dynorphin would be needed under lower adrenergic system activation. Further, adrenaline appears to regulate the function of KOR receptors:
Locus Coeruleus Kappa-Opioid Receptors Modulate Reinstatement of Cocaine Place Preference Through a Noradrenergic Mechanism
The principal findings of this report are that KORs within the LC NA nuclei are involved in kappa opioid-mediated reinstatement of cocaine CPP behavior. This report highlights the behavioral consequences of interactions between KORs and NA systems. In this study, we used KOR-induced reinstatement of a cocaine CPP as a behavioral paradigm to isolate the select role of KOR–NA interactions. We identified that KOR expression in the LC is partially required for KOR-induced reinstatement to cocaine CPP and that the magnitude of the KOR-induced reinstatement response is regulated by post-synaptic β-adrenergic activation. However, this NA-mediated reinstatement efficacy is exclusive to KOR-induced reinstatement and has no effect on the magnitude of reinstatement observed following a cocaine-primed reinstatement. The resulting evidence indicates a role for interactions between the NA system and KORs in the modulation of downstream KOR circuits. This circuitry has recently been well established to control KOR- and stress-induced reinstatement of cocaine seeking and cocaine place preference (Figure 5d; Bruchas et al, 2011; Graziane et al, 2013). The results presented here support the hypothesis that KOR function and β-adrenergic receptor modulation act together to negatively modulate KOR-mediated reinstatement behavior at known downstream circuits (ie, dopaminergic, serotonergic) reported to be critical for KOR function in behavioral affect (Figure 5d).
So β-adrenergic stimulation controls the magnitude of KOR signaling. More specifically, it appears that β1-adrenergic receptors antagonize the effects of KOR:
Our results also demonstrate a role for β1-adrenergic, but not β2-adrenergic, receptors in KOR-mediated cocaine reinstatement. β1-adrenergic receptors are widely expressed in the mammalian brain, including in the basolateral amygdala, BNST, hippocampus, cortex, and striatum (Correll et al, 2005; Flavin and Winder, 2013; Rosenkranz and Grace, 2002); additional studies to further isolate the critical sites and cell types that mediate the β1-adrenergic receptor's influence on KOR reinstatement behavior will be required. Although the current findings in this study seem contrary to some recent reports showing that β-adrenergic receptor antagonism prevents stress-induced cocaine reinstatement in CPP models (Vranjkovic et al, 2012), it is important to note that our model selectively examined the reinstatement of cocaine preference to a KOR agonist. It is therefore likely that circuits expressing KORs and β1-adrenergic receptors act in opposing ways, and antagonizing β1-adrenergic receptors coupled with KOR stimulation promotes further excitatory drive of circuits that control the reinstatement response (Figure 5c).
This could potentially be sufficient to explain the most crucial effects of propranolol in PTSD: it removes the dampening of adrenaline on the KOR signal, so that the "failure" signal can register, and probably further lower adrenaline through lowering of catecholamines in general and other effects.

It is logical for a "failure" signal to be a resolution signal. KOR activation serves a purpose in terminating stress loops that would otherwise cost an organism precious energy. But it has to be activated at the right times at the right intensity to properly represent error, failure and the cost of failure. And it must not be blocked by adrenaline. Consider how dynorphin increases food intake (Neuropeptide regulation of feeding in dogs. - PubMed - NCBI, https://www.ncbi.nlm.nih.gov/pubmed/29056156); failed hunts cost predators energy they must be then motivated to replenish. Failure to quell KOR signaling then leads to addiction.

However, dynorphin is known to have some non-KOR effects as well (Dynorphin - Wikipedia).

Also a decent summary of the effects of dynorphin/KOR from that article:
It is well accepted that the dynorphin/kappa opioid system has a key role in the mediation and vulnerability to stress, anxiety, dysphoria, and depression-like behaviors. Dynorphins are released during stress exposure and the dynorphin/KOR system has been shown to be critical for stress-induced depression-like and anxiety-like behaviors as well as reinstatement to drug seeking (Beardsley et al, 2005; Carey et al, 2007; Carlezon et al, 2006; Chartoff et al, 2012; Ebner et al, 2010; Land et al, 2008; Mague et al, 2003; McLaughlin et al, 2003). It has been shown that following stress, the subsequent release of dynorphin activates KORs within dopaminergic and serotonergic nuclei to produce reinstatement, aversion, and negative affective-like behavioral states (Bruchas et al, 2011; Graziane et al, 2013; Land et al, 2009; Tejeda et al, 2013; Van't Veer et al, 2013). In addition to decreasing striatal dopamine levels and inhibiting the firing of dopamine neurons, several reports demonstrate that KOR agonists inhibit dopamine release and alter behavioral affect via action within the nucleus accumbens and/or VTA dopaminergic system (Ebner et al, 2010; Graziane et al, 2013; Shippenberg et al, 2007). Recently, we also demonstrated that activation of KORs within dorsal raphe serotoninergic circuits reduces serotonergic tone to influence cocaine place preference and reinstatement (Land et al, 2009; Bruchas et al, 2011; Schindler et al, 2012; Lemos et al, 2012). Together these reports suggest that KOR function in both serotonergic and dopaminergic circuits have a necessary role in the processing of KOR-mediated behaviors. These reports, however, also highlight the unique complexity of KOR function within various monoamine nuclei. In the current study, we found an additional role for KORs in reinstatement behavior that requires KOR expression and interaction with NA systems.

Previous reports have shown that the corticotropin-releasing factor (CRF) system is involved in drug-seeking and drug-withdrawal behaviors (Bale and Vale, 2004; Koob and Le Moal, 2008; Shaham et al, 2000a) and that both stress and CRF engage LC NA cell firing (Aston-Jones et al, 1999; Devilbiss et al, 2012; Valentino et al, 1993, 2001). Recent evidence has also shown that dynorphin/KOR signaling occurs downstream of CRF release to induce a negative affective state (Bruchas et al, 2010; Knoll et al, 2011; Land et al, 2008; Walker and Koob, 2008). The strong presence of both CRF and dynorphin within the LC NA system also suggests that these systems engage one another to affect kappa-opioid-dependent behavioral responses; however, this remains undefined. Here we report, for the first time, that kappa-opioid-induced behaviors are indeed regulated by KOR function within the LC and by KOR-dependent interactions with NA signaling, and future studies will be implemented to investigate potential CRF interactions. It will also be useful to explore the role of NA–KOR interactions on additional KOR-mediated behaviors, including aversion, intracranial self-stimulation threshold, anxiety, and fear (Bruchas et al, 2011; Ebner et al, 2010; Knoll et al, 2011; Van't Veer et al, 2013). Given the complexity of LC NA and dynorphinergic projection sites, we focused the current study on establishing a foundational connection between dynorphin/KOR systems and NA tone in the modulation of KOR-induced reinstatement of cocaine CPP. In this study, we used viral expression, which may not completely mimic endogenous expression levels or cell type specificity of KOR in LC circuits; thus future studies with higher cellular resolution are needed to completely dissect the complexity of these dynorphin/KOR stress neuropeptide neural circuits, their cell types and the signaling pathways that mediate the effects described.

The presence of KORs within the LC NA system has been established in several reports. Recent evidence suggests that KORs are expressed both presynaptically on GABA and glutamate inputs into the LC, as well as potentially expressed on pericoerulear GABA interneurons adjacent to the LC (Kreibich et al, 2008). Furthermore, KOR agonist injection into the LC attenuates phasic LC discharge events evoked by stimuli that engage LC afferents, suggesting that KORs presynaptically inhibit afferent inputs into the LC system. KOR is also thought to be expressed directly on NA neurons to inhibit NE release, as evidenced by anatomical and physiological studies (Van Bockstaele et al, 2010; Limberger et al, 1986). However, it is important to note that few, if any, studies have examined the cell type and function of KOR signaling within the LC, and future studies in vitro and in vivo with cell type conditional KOR KO (Tejeda et al, 2013; Van't Veer et al, 2013), cell type-selective restoration, and local circuit identification will be needed to advance our understanding of dynorphin/KOR's role within cell types in the LC.

Note that dynorphin also triggers the stress response itself - as you might expect from something released with memories - with probably some complications from anatomy:

Dynorphin stimulates corticotropin release from mouse anterior pituitary AtT-20 cells through nonopioid mechanisms. - PubMed - NCBI
Dynorphin, stress, and depression
KOR systems also regulate the expression of other stress hormones, although these interactions are complicated. For example, decreases are observed in serum corticosterone and in CRF levels in the CeA and paraventricular nucleus of the hypothalamus of PDyn −/− mice, and this effect can be reproduced in wild-type mice treated with KOR antagonist (Wittmann et al., 2009). However, there is also evidence from other strains of PDyn −/− mice that the absence of KOR signaling may have no effect (McLaughlin et al., 2006a) or may prolong the stress response (Bilkei-Gorzo et al., 2008), highlighting the complexity of interactions that likely depend upon basal stress levels.

But as the article before that already said, dynorphin may antagonize GABA neurons directly, I forgot about that:
Central Amygdala Neuroplasticity in Alcohol Dependence - ScienceDirect
Dynorphin is an opioid peptide that acts primarily at kappa opioid receptors (KORs) and is generally associated with negative emotional states. Dynorphin and KORs are both abundantly expressed in the CeA (Mansour et al., 1987, Marchant et al., 2007). Recent data from our lab and others show that the dynorphin/KOR system modulates GABAergic transmission in the CeA of alcohol-naïve rodents Gilpin, 2014, Kang-Park et al., 2013). Dynorphin decreases GABAA-mediated synaptic transmission and attenuates acute alcohol-induced increases in GABAergic transmission in the CeA by reducing presynaptic GABA release (see Figure 11.1A). Furthermore, antagonism of KORs augments GABAergic transmission in the CeA, suggesting a tonic inhibitory effect of endogenous dynorphin on inhibitory transmission in the CeA. These results agree with recent findings that dynorphin and KOR agonists decrease GABAergic transmission in the BNST by reducing presynaptic GABA release, effects that are blocked by a KOR antagonist (Li et al., 2012).

Also highly reminiscent of allopregnanolone.

It can also lower glutamate signaling (Kappa opioid receptor inhibition of glutamatergic transmission in the nucleus accumbens shell. - PubMed - NCBI), a feature shared with cannabinoids, it seems.

All this is without taking into account brain anatomy, which I can only guess would multiply the number of possible disorders (Alcohol-induced plasticity in the dynorphin/kappa-opioid receptor system).

If you take too much THC, like I do, it stimulates dynorphin, in experiments - and it feels that way, too, if left unopposed. So either the things in the protocol I describe are strong enough to counter and filter the noise from constant dynorphin release and help restore GABA signaling, endorphins, oxytocin, etc.; and/or the huge increase in dynorphin by THC is a strong-enough "spike" of dynorphin to surmount a chronically high state. I think it is both together: the inhibitory, cannabinoid and GABAA effects, probably with involvement of histamine and other things, antagonize the chronic dynorphin/KOR noise and the effects of adrenaline and glutamate, and perhaps the negative effects of histamine; THC maybe goes even further by allowing a spike of dynorphin/KOR signaling to get through during memory recall, to filter and represent the fear memories. Just guessing.

How does this fit into consciousness? I'm not completely sure, but I think a raw increase in power of self-analysis helps to filter the experiences and memories, in other words to identify your real problems and the problems with your decisions. It should help shape extinction memories. Since peace of mind is not an easy thing to find, I can say that, noise filtering aside, it's largely about confidence in one's choices in the present, or knowing you're doing the right thing. Well, that increases. Meanwhile, the increase in emotionality can be seen as an increase in the amplitude and strategic triggering of the signals that govern our emotions and the way we feel, i.e. endorphins vs dynorphin/KOR, and there would appear to be important modulation at post-synaptic receptors.

It also recently re-crossed my mind that consciousness together with emotionality seem to produce a greater ability to influence and even control my own mental processes, reactions, feelings of reward - but even in physical stimulation (analgesia, physical pleasure signals) - like trivially triggering what feel like endorphin surges and analgesic effects. It is like the amount of unity among your brain cells. This is a stretch, but it's always felt to me that choice is tied into consciousness - but beyond the philosophical, it is like having more control over or greater ability to influence your neural processes, or being "in command", which is another way to see it (it must have relations to dopamine). Over that you can superimpose empathetic neural activity, and that might shift or hand over the "influence" over your processes to "external" sources, whatever they may be. It's like letting the GPS drive your vehicle, on a roadmap for a better future ;3. There are some more advanced neurobiological concepts at play, these are general analogies.
 
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Terma

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I forgot to point out this part:
However, dynorphin is known to have some non-KOR effects as well (Dynorphin - Wikipedia).
It seems best exemplified by another of the studies above:
Dynorphin stimulates corticotropin release from mouse anterior pituitary AtT-20 cells through nonopioid mechanisms. - PubMed - NCBI
Dynorphin (Dyn) peptides were previously shown to increase plasma corticotropin (ACTH) in the ovine fetus, but the site of its action remains unclear. In the present study, Dyn A(1-17) was found to stimulate ACTH release from mouse anterior pituitary tumor AtT-20 cells in a dose-dependent manner. Naloxone did not block the effect of Dyn A(1-17) and the selective kappa-opioid receptor agonist U50488H did not stimulate ACTH release. Dyn A(2-17), a degradative peptide fragment that does not bind to opioid receptors, also stimulated ACTH release from AtT-20 cells. Although the nonopioid effects of Dyn have previously been attributed to N-methyl-D-aspartate (NMDA) receptors, the ACTH-releasing effects of Dyn A(1-17) in AtT-20 cells were not affected by co-administration of NMDA receptor antagonist LY235959. The ACTH response to Dyn A(1-17) could not be blocked by alpha-helical CRH (CRH antagonist) and was additive with a maximal stimulatory dose of CRH, suggesting different mechanisms of action. These results show that the release of ACTH by Dyn A(1-17) in AtT-20 cells is not mediated by kappa-opioid receptors or by the NMDA receptor.

Non-KOR effects of dynorphin help distinguish between the roles of dynorphin vs KOR activation. It suggests KOR activation could be characterized as a failure/resolution signal or at least a major part of or requirement for it, while dynorphin itself is more part of the ongoing stress response, or as they write in the Mice and Men article, it "encodes" the aversive (emotional, consequential) component of stress, or measures the level of it. It also paints images of dynorphin's neurotoxicity in higher doses (see other thread). This is hard to distinguish otherwise because KOR does mediate much of the aversive processing. But it some cases it suggests direct KOR agonism may be safer or more appropriate than dynorphin release, or that potential dynorphin releasers (like cannabinoid) really should be accompanied by protective substances.

(Sorry if I missed anyone's posts or didn't interact much, I still have much ***t to get through. 2 months in, these experiences have changed and carried over into my life, successfully. But fixing seemingly permanent health insults remains a long road. At least to some extent you can tide over freedom with peace of mind... or as close as I can get to it)
 
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Terma

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Finally, here was another lead related to KOR activation:
Sciatic Nerve Ligation-Induced Proliferation of Spinal Cord Astrocytes Is Mediated by κ Opioid Activation of p38 Mitogen-Activated Protein Kinase
Partial sciatic nerve ligation (pSNL) markedly increased glial fibrillary acidic protein immunoreactivity (GFAP-IR) 1 week after lesion in the L4–L5 spinal dorsal horn of wild-type, but not in dynorphin knock-out, mice lacking κ opioid receptors (KOR−/−) or in wild-type mice pretreated with the KOR antagonist nor-binaltorphimine (norBNI). A direct effect of KOR on glial cell proliferation was suggested by the findings that primary cultures of type II GFAP-immunoreactive astrocytes isolated from mouse spinal cord express KOR. Sustained treatment with the κ agonist U50,488 (trans-3,4-dichloro-N-methyl-N-[2-(1-pyrolytinil)-cyclohexyl]-benzeneacetamide methane sulfonate) significantly increased the proliferation rate of GFAP-immunoreactive astrocytes isolated from wild-type mice, and this effect was blocked by norBNI pretreatment. Proliferation of cultured type II astrocytes may have been stimulated by mitogen-activated protein kinase (MAPK) activation by KOR because (1) U50,488 treatment increased phospho-p38 MAPK-immunoreactivity 247 ± 44% over untreated cells, (2) the increase in phospho-p38 induced by U50,488 was blocked by norBNI and not evident in KOR−/− cultures, and (3) GFAP-immunoreactive astrocyte proliferation induced by U50,488 was blocked by the p38 MAPK inhibitor SB 203580 [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole]. Similar mechanisms of astrocyte activation may also be responsible in vivo because intrathecal injection of SB 203580 blocked the increased GFAP-IR in lumbar spinal cord induced by pSNL. Although the relationship between κ-stimulated astrocyte proliferation and neuropathic pain mechanisms was not directly established in these studies, the results support the hypothesis that KOR activation induces spinal astrocyte proliferation, which may contribute to cellular reorganization after sciatic nerve damage.
KAPPA OPIOIDS PROMOTE THE PROLIFERATION OF ASTROCYTES VIA Gβγ AND β-ARRESTIN 2 DEPENDENT MAPK-MEDIATED PATHWAYS

If you consider the multiple ways in which astrocytes may be involved in mental disorders (already explored elsewhere), then increasing their proliferation could be therapeutic, and help justify high-dose cannabinoids. Besides signal like BDNF and maybe muscarinic receptors, this could be involved in the healing response and longer-lasting effects. I've already wondered if perhaps my astrocyte populations might have gotten compromised. This article for example suggests several realistic generalized mechanisms in which they might be driven to apoptosis - besides immunity and such - including through FFA and ceramide overload:
Sci-Hub | Is there an astrocyte–neuron ketone body shuttle? Trends in Endocrinology & Metabolism, 12(4), 169–173 | 10.1016/S1043-2760(00)00370-2

Several other things could trigger astrocyte proliferation, but this alone lends to the idea of a healing/recovery protocol, and suggests researching a protocol specifically targeted to restoring astrocyte populations and function.
 

Terma

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I wondered about this for a while. THC's been reported to have pro- and anti-estrogenic effects, pro-progesteronic effects, anti-androgen effects and I can cherry-pick from in vitro studies as well as anyone when I feel like it:
Δ9-Tetrahydrocannabinol Disrupts Estrogen-Signaling through Up-Regulation of Estrogen Receptor β (ERβ)
Δ9-Tetrahydrocannabinol (Δ9-THC) has been reported as possessing antiestrogenic activity, although the mechanisms underlying these effects are poorly delineated. In this study, we used the estrogen receptor α (ERα)-positive human breast cancer cell line, MCF-7, as an experimental model and showed that Δ9-THC exposures markedly suppresses 17β-estradiol (E2)- induced MCF-7 cell proliferation. We demonstrate that these effects result from Δ9-THC’s ability to inhibit E2-liganded ERα activation. Mechanistically, the data obtained from biochemical analyses revealed that (i) Δ9-THC up-regulates ERβ, a repressor of ERα, inhibiting the expression of E2/ERα-regulated genes that promote cell growth and that (ii) Δ9-THC induction of ERβ modulates E2/ERα signaling in the absence of direct interaction with the E2 ligand binding site. Therefore, the data presented support the concept that Δ9-THC’s antiestrogenic activities are mediated by the ERβ disruption of E2/ERα signaling.

Meanwhile THC was thought to impede androgen signaling:
Sci-Hub | MARIHUANA INHIBITS DIHYDROTESTOSJERONE BINDING TO THE ANDROGEN RECEPTOR. Endocrinology, 107(3), 848–850 | 10.1210/endo-107-3-848

But if your existing stores of DHT when THC is dosed become ineffective, perhaps it would encourage more of its metabolites? THC surely promotes hormone conversions, at least - but much more so in combination with the rest of the protocol I described:

3α-Androstanediol - Wikipedia
Sci-Hub | Dissociating Behavioral, Autonomic, and Neuroendocrine Effects of Androgen Steroids in Animal Models. Psychiatric Disorders, 397–431 | 10.1007/978-1-61779-458-2_26
Relative to its isomer 3β-androstanediol, which is a potent estrogen, 3α-androstanediol has substantially lower, though still significant affinity for the estrogen receptors, with a several-fold preference for ERβ over ERα.
Although the affinity is pretty weak, I figure a hormone with preferential ERβ activity might be key, or something to desire. There might be another somewhere.

Besides ERβ the point is, THC and DHT would make for an interesting combination, probably more appropriate than testosterone, as DHT might counterbalance THC more effectively. Meanwhile you might wonder about: DHEA Is Preferentially Converted Into DHT In Humans

Awhile ago I had a really good time on this protocol after supplementing with creatine the week before. It seemed to have amplified all bodily sensations. Well among other things: Three weeks of creatine monohydrate supplementation affects dihydrotestosterone to testosterone ratio in college-aged rugby players. - PubMed - NCBI . It probably helps I don't have low testosterone normally.

Although I suspect this generates some estrogen it's far from clear it's the main hormone acting on these pathways, and there are multiple roads to oxytocin, including ERβ, histamine (histidine), acetylcholine, mineral balance (Na+/H2O, Ca2+) and of course 5-HT1a at the cost of cortisol.

Although these were cancer cells (never the best model) the interesting property of DHT/androgens is they seem to increase mTorC2 signaling thus Akt which increases glucose utilization, which would be particularly important if it worked in the brain (Androgen Receptor Enhances p27 Degradation in Prostate Cancer Cells through Rapid and Selective TORC2 Activation). It would make sense since DHT (and low- but not high-dose testosterone) improves insulin sensitivity (Androgen Therapy Improves Insulin Sensitivity and Decreases Leptin Level in Healthy Adult Men With Low Plasma Total Testosterone, Testosterone, Dihydrotestosterone, Sex Hormone–Binding Globulin, and Incident Diabetes Among Older Men: The Cardiovascular Health Study). It might be a little redundant since other things I mentioned probably do that as well, but nonetheless mTorC2 can be an important clue as to the function of a substance.

Part of the reason I suspect whey powder + carbs works so well here is simply because whey is highly insulinogenic. Meanwhile DHEA is pro-IGF1. Of it that drives tryptophan into the brain but again it has multiple roads to go down and THC opposes the worst 5-HT receptors and several aspects of this can counter 5-HT release or increase uptake.

It's a lot of conjecture but besides acetylcholine there is not a lot to explain effects that persist for several days and can get rid of a neurological disorder, so hormones and changes to transcriptional signaling jump out. But imagine the therapeutic potential if THC + DHT could work (THC + pregnenolone + DHEA + DHT + ketones, why limit yourself?). Since DHT is known to oppose cortisol (more reliably than DHEA iirc?), assuming it works on the right pathways then it could be the perfect complement to prevent adverse effects from THC, provided your condition is not from excess AR signaling in the first place. I don't plan to use this protocol that much in the next year for non-brain-related health reasons but there is so much potential here it's hard to let it die.
 
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