Onemorestep
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Posts posted by Onemorestep
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On 6/24/2018 at 8:14 AM, olivier24445 said:
sure.
About Flunarizine, it seems that it's very risky (Parkinson...) so, bad idea...
It’s not Parkinson’s. It’s parkinsomism.
Introduction
Cinnarizine (CNZ) and flunarizine (FNZ) belong to the calcium channel blockers class of medication.
Main text
The aim of this literature review is to evaluate the clinical epidemiological profile, pathological mechanisms, and management of CNZ/FNZ-associated movement disorder (MD). Relevant reports in six databases were identified and assessed by two reviewers without language restriction. One hundred and seventeen reports containing 1920 individuals who developed a CNZ/FNZ-associated MD were identified. The MD encountered were 1251 parkinsonism, 23 dyskinesias, 11 akathisia, 16 dystonia, and 5 myoclonus, and in the group not clearly defined, 592 extrapyramidal symptoms, 19 tremors, 2 bradykinesia, and 1 myokymia. The predominant sex was female with a percentage of 72.69% (466/641). The mean age was 74.49 (SD, 7.88) years. The mean CNZ dose was 148.19 mg (SD, 42.51) and for the FNZ dose, 11.22 mg (5.39). The mean MD onset and recovery were 1.83 years (SD, 1.35) and 3.71 months (SD, 1.26). In the subgroup of subjects that had improvement of the symptoms, the complete recovery was achieved within 6 months of the drug withdrawal in almost all subjects (99%). The most common management was drug withdrawal. A complete recovery was observed in 93.77% of the patients (437/466).
https://ejnpn.springeropen.com/articles/10.1186/s41983-020-00197-w
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I encourage 2 months of clonazepam 1 mg twice daily followed by a taper over 30 days using a mg scale to do daily dose reductions.
There is a study that showed that patients on this protocol faired better at the 8th month mark than their peers who did not do this.
- If i had to guess, there is an accumulative effect in the few months after onset that can be dampened.
I did this therapy and the second time i got hppd it worked well
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On 6/22/2022 at 6:45 PM, Crunchy said:
Did it help visuals?
No. But it’s been about 8 years since I got hppd and visuals are mostly gone. Psych symptoms remained
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I have tried it. It felt great. Weirdly, had opposite effects compared to baclofen for 5 hours and then switched to muscle relation and antidepressant effect.
I have paws from prior baclofen use so I can not use.
I also believe withdrawals will be present but no where near to the degree that benzos would cause.
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On 5/27/2022 at 12:21 AM, Crunchy said:
Whatever anyone does don't take fluoroquinolones!!! I'm pretty crippled still 3 years later.
I read about a doctor using c60 fullerene to sure his flox. I take it daily.
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“The anticonvulsant drug lamotrigine has been shown to produce strong antidepressant effects in the treatment of bipolar disorder patients. Our previous studies have demonstrated that brain derived neurotrophic factor (BDNF) signaling plays an important role in regulating its behavioral actions in several rodent models of depression. The current study extends earlier work on BDNF and explores the role of another important neurotrophin vascular endothelial growth factor (VEGF) in regulating the antidepressant actions of lamotrigine. The results showed that chronic administration of 30 mg/kg lamotrigine (14 days) normalized the down-regulated frontal and hippocampal VEGF protein expression as well as the behavioral deficits induced by chronic unpredictable stress. In addition, pharmacological inhibition of VEGF signaling by infusion of SU5416, a selective Flk-1 receptor inhibitor, blocks the antidepressant effects of lamotrigine in all behavioral paradigms. Taken together, this study provides further evidence that VEGF is also an essential regulator for the antidepressant effects of lamotrigine.”
vegf is complex. There are several subgroups of vegf and they do different things.
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Lipopolysaccharides and tlr4 are implicated in disease states caused by pathogenic infection. Activation of tlr4 by lipopolysaccharides, endotoxins released by many pathogens such as lipid a, and other endotoxins such as those release by fungal infections, causes an increase in vegf and lymphangiogenesis (to promote clearance of these endotoxins via increased lymphatic function)- but also an increase in inflammatory cytokines. Tlr4 has been implicated in many disease states and neurological disorders.
Tlr4 antagonization is a method of symptom reduction in disease states, be a pathogenic or otherwise, that act upon tlr4 positively.
however, some lipopolysaccharides act as antagonists at tlr4 receptors. This, I would assume, benefits the pathogen as tlr4 activation is the body’s response to pathogenic infection in its attempts to clear it.
this is interesting when looking at hppd in respects to inflammation and possibly hppd when suspected pathogenic infection is present.
This article is intended to increase the knowledge base of levetiracetam and help elucidate why some people respond to it and some do not.
tldr: levetiracetam antagonizes tlr4 and thus decreases lymphatic response to pathogenic infection and also decreases pathogenic or neurological states that increase inflammatory cytokines via the tlr4 receptor.
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I use this. Reduces visuals and snow. powerful, longevity drug, easy to source on Amazon. Must be in glass bottle. Wrap in duct tape and store in room temperature dark place. C60 converts into other carbon molecules when exposed to ANY light and heat. It becomes toxic.
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Polyhydroxylated C(60), fullerenols, as glutamate receptor antagonists and neuroprotective agents:
Derivatives of C(60) have been shown to be effective free radical scavengers. Hence, many of the biological functions of fullerene are believed to be due to their antioxidant properties. Here we present evidence to show that fullerenols, that are caged fullerene oxides, exert their neuroprotective functions by blocking glutamate receptors and lowering the intracellular calcium, [Ca(2+)](i). In neuronal cultures, fullerenols reduce glutamate-induced neurotoxicity by about 80% at 50microM. No significant effect was observed on H(2)O(2)/Fe(2+)-induced neurotoxicity under the same conditions. Fullerenols were found to inhibit glutamate receptor binding in a dose-dependent manner inhibiting 50% of glutamate binding at 50 microM. Furthermore, AMPA receptors were found to be more sensitive to fullerenols than NMDA and KA receptors. On the other hand, GABA(A) receptors and taurine receptors were not significantly affected by fullerenols at the same concentrations used, suggesting that fullerenols inhibit primarily the glutamate receptors. In addition, fullerenols were also found to lower glutamate (Glu) receptor-induced elevation of [Ca(2+)](i), suggesting that the underlying mechanism of neuronal protective function of fullerenols is likely due to its ability to block the glutamate receptors and to reduce the level of [Ca(2+)](i).
** mentions derivatives so cannot conclude that c60 does it too. These derivatives enact different mechanisms but only c60 is available.
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Flunarizine:
Flunarizine is a first-generation H1-antihistamine. H1-antihistamines interfere with the agonist action of histamine at the H1 receptor and are administered to attenuate inflammatory process in order to treat conditions such as allergic rhinitis, allergic conjunctivitis, and urticaria. Reducing the activity of the NF-κB immune response transcription factor through the phospholipase C and the phosphatidylinositol (PIP2) signalling pathways also decreases antigen presentation and the expression of pro-inflammatory cytokines, cell adhesion molecules, and chemotactic factors. Furthermore, lowering calcium ion concentration leads to increased mast cell stability which reduces further histamine release. First-generation antihistamines readily cross the blood-brain barrier and cause sedation and other adverse central nervous system (CNS) effects (e.g. nervousness and insomnia). Second-generation antihistamines are more selective for H1-receptors of the peripheral nervous system (PNS) and do not cross the blood-brain barrier. Consequently, these newer drugs elicit fewer adverse drug reactions.
https://smpdb.ca/view/SMP0061047
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shared mechanism between pramipexole and Flunarizine:
flunarizine:
“Cinnarizine and flunarizine, but not verapamil, diltiazem, isradipine, Bay K 8644 or nitrendipine, caused a fast and dramatic Na(+)-independent Ca2+ loss.”
https://pubmed.ncbi.nlm.nih.gov/7540145/
prami:
Post-stroke treatment with pramipexole reduced levels of mitochondrial ROS and Ca2+ after ischemia. Pramipexole elevated the mitochondrial membrane potential and mitochondrial oxidative phosphorylation.
https://pubmed.ncbi.nlm.nih.gov/31235613/—-
negative: https://www.science.org/doi/10.1126/sciadv.abk2376
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Flunarizine is a selective calcium entry blocker with calmodulin binding properties and histamine H1 blocking activity. It is effective in the prophylaxis of migraine, occlusive peripheral vascular disease, vertigo of central and peripheral origin, and as an adjuvant in the therapy of epilepsy.
**see vinpocetine
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20 hours ago, Fawkinchit said:
Neuronal damage as far as modern medicine goes is entirely reversable. They would technically heal/repair on their own accord with do time, as far as we understand the nervous system. No deep brain stimulation required.
Additionally, I’m not sure stimulating an altered neuronal organization would result in LESS symptoms. Off the cuff, seems that would probably just make everything more intense. Throwing stimulation into a brain organized the way ours may be… sounds bad.
everything I’m looking at (besides the effects of mono and co-morbid infections) is based around the restructuring of brain systems towards increases excitatory neurotransmission. How to temper that excitation, and then, if present— based upon your ideas about glia/astrocytes and subsequent research— how to repair damage by that neuronal excitation.
still, this won’t return the brain to a pre-rewired state. That is something I can’t even imagine how to do.
I have a particular interest in creating dialogue surrounding what hppd combined with other disease/disordered states causes. It’s not something we talk about often here. I was diagnosed with mcas this year, and taking away any ideas about potential causation, it’s still not a question of if people with hppd have mcas. It’s how many. Too researchers put population frequency at 18%. It’s so disruptive to the normal functioning of the body, I wonder how the healing period of those with hppd and mcas is impacted.
I am particularly interested in diseases that decrease the brains ability to inhibit itself. Bartonella strains have an amazing ability to alter the brains ability to inhibit itself. It is also the kind of infection the body could fight off, lay dormant, and opportunistically come out under the correct immune circumstances. The immune alterations caused by psychedelics are of importance in this hypothesis. The inability to inhibit, combined with increases excitatory tone— well you get it. I became interested in it after learning I have an acute infection that resurfaced this summer. I have been, more than other patients my doctors have treated, particularly susceptible to the neurological symptoms of bartonella. By a long shot. I can’t help but wonder how hppd effects the outcomes, neurologically, of bartonella infection. But at a glance, they seem highly synergistic from an excitatory standpoint. Whether I have true mcas, or just severe mast cell activation from the infection, will become apartment later down the road. But despite the cause of the mcas, the effect on neural microglia is to increase glutamate release from them via stimulation by histamine released by the mast cells.
bartonella is scarily prevalent in all sorts of animals— most notably cats in which the prevalence in house cats may be as high as 30%. Lyme disease is considered to be a silent epidemic, but through asking experts all agree that bartonella is more prevalent but more often suppressed by the immune system in most hosts.
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On 5/3/2022 at 7:35 AM, kynerer said:
Hello. Can you explain your theory in simple terms?
It’s really just some extrapolations for medication options based off of some current psychedelic research and the mechanism of actions of drugs that are anecdotally reported to help with hppd such as lamictal. It also involves some immune components, as I imagine that the sheer stress and accompanied sleep disruption alone can probably cause immune dysfunction. I also believe that a subset of people with hppd do have immune alterations— and there is even at least one current pig study showing alterations in neuro immune genes— and so some benefit might be had by tweaking the cytokine release by the brain.
but I also think that a subset of people with hppd may have pathogenic infection— be it in the body or brain— and they may react negatively to too much immune suppression. One cannot know until they try the drugs.
I believe I have had Epstein Barr virus in my brain since a child— and I have experienced Alice in wonderland syndrome independent of drug use. Interestingly, my hppd from psilocybin and the much worse hppd from 25i-nbome were strictly the growing and shrinking of objects. Should the hallucinogens have altered my neuro immune genes that were responsible for keeping my neuro EBV in check, it would explain the permanent Alice in wonderland like symptoms. I do not have starbursts or fractals or anything else. I acquired visual snow and afterimages after a run with oxiracetam— which is a powerful immune altering drug if you know what terms to search for. The only other drug I’ve tried with at least one part of racetam moa is Vinpocetine and this also causes an increase in these Alice in wonderland like visuals.
but for those not like me, these drugs may provide benefit. And many provide me benefit too. Particularly those impacting ampa receptors, I have found.
additionally, I have seen great benefit in suppressing microglial activation. Drugs such as Selegiline will send me into a lsd like panic— especially combined with any cannabinoid— and I attribute this to it being an mao-b inhibitor. Mao-b is how microglia end up releasing gaba. They can also release glutamate— and id this happens chronically and unfettered it will cause a range of emotional and cognitive symptoms as well as, if strong enough, damage to themselves and nearby neurons.
for those who do not have suspected damage, suppression should provide great benefit in reducing negative symptoms and returning positive ones. For those with neuronal injury, drugs such as vinpocetine or dihexa may be of benefit. This is theoretical, however.
any and all of these drugs should be personally researched and adequate and tempered dosing should be practiced until you understand how they effect you. Hppd is a tricky beast.
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Vinpocetine, a Classic PDE1 Inhibitor
The alkaloid vinpocetine (vinpocetine – ethyl apovincaminate) is a classic inhibitor of PDE1 activity (Vereczkey, 1985; Nicholson, 1990). Vinpocetine treatment has been shown to facilitate LTP (Molnar and Gaal, 1992; Molnar et al., 1994), enhance the structural dynamics of dendritical spines (Lendvai et al., 2003), improve memory retrieval (DeNoble, 1987), and enhance performance on cognitive tests in humans (Hindmarch et al., 1991). In a model of fetal alcohol spectrum disorders, vinpocetine was able to restore neuronal plasticity in visual cortex (Medina et al., 2006) as well as the functional organization of this area (Krahe et al., 2009). Furthermore, vinpocetine treatment was also shown to revert the effects of early alcohol exposure in learning performance in the water maze (Filgueiras et al., 2010). In rats treated with intracerebroventricular streptozocin, a paradigm that mimics some Alzheimer-like cognitive problems, a vinpocetine treatment was able to restore performance in the water maze and the passive avoidance test (Deshmukh et al., 2009).In addition of its potential as a plasticity enhancer, it was recently demonstrated that vinpocetine has a strong anti-inflammatory effect (Jeon et al., 2010). Vinpocetine inhibits IKK, preventing IkB degradation and the consequent translocation of NF-κB to the nucleus. Surprisingly, this mechanism is independent of vinpocetine action on PDE1. This new action of vinpocetine, combined with its potential to enhance neuronal plasticity suggest that this drug may have beneficial effects in conditions such as Alzheimer’s and Parkinson’s where inflammation and poor neuronal plasticity are present (Medina, 2010).
https://www.frontiersin.org/articles/10.3389/fnins.2011.00021/full
vinpocetinr and ketamine induced synaptic ultrastructure alterations :Background: Schizophrenia is a mental disorder characterized by hyperlocomotion, cognitive symptoms, and social withdrawal. Brain-derived neurotrophic factor (BDNF) and postsynaptic density (PSD)-95 are related to schizophrenia-like deficits via regulating the synaptic ultrastructure, and play a role in drug therapy. Vinpocetine is a nootropic phosphodiesterase-1 (PDE-1) inhibitor that can reverse ketamine-induced schizophrenia-like deficits by increasing BDNF expression.However, the effects of vinpocetine on alleviating schizophrenia-like deficits via reversing the synaptic ultrastructure by regulating BDNF-related PSD-95 have not been sufficiently studied.
Methods: In this study, the schizophrenic model was built using ketamine (30 mg/kg) for 14 consecutive days. The effect of vinpocetine on reversing schizophrenia-like behaviors was examined via behavioral testing followed by treatment with certain doses of vinpocetine (20 mg/kg, i.p.). The BDNF and PSD-95 levels in the posterior cingulate cortex (PCC) were measured using biochemical assessments. In addition, the synaptic ultrastructure was observed using transmission electron microscopy (TEM).
Results: Ketamine induced drastic schizophrenia-like behaviors, lower protein levels of BDNF and PSD-95, and a change in the synaptic ultrastructure in the PCC. After treatment, the vinpocetine revealed a marked amendment in schizophrenia-like behaviors induced by ketamine, including higher locomotor behavior, lower cognitive behavior, and social withdrawal defects. Vinpocetine could increase the PSD-95 protein level by up-regulating the expression of BDNF. In addition, the synaptic ultrastructure was changed after vinpocetine administration, including a reduction in the thickness and curvature of the synaptic interface, as well as an increase in synaptic cleft width in the PCC.
Conclusion: Vinpocetine can reverse the synaptic ultrastructure by regulating BDNF-related PSD-95 to alleviate schizophrenia-like deficits induced by ketamine in rats
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Sildenafil: I personally need to look up the difference between the subunits on the ampa receptor— but without doing that overall this seems a good drug. The side effects of daily use may be… annoying to some men.
PCS rats show neuroinflammation in cerebellum, with microglia and astrocytes activation, increased IL-1b and TNF-a and reduced YM-1 and IL-4. Membrane expression of the GABA transporter GAT1 is reduced, while GAT3 is increased. Extracellular GABA and motor in-coordination are increased. Sildenafil treatment eliminates neuroinflammation, microglia and astrocytes activation; changes in membrane expression of GABA transporters; and restores motor coordination.
https://onlinelibrary.wiley.com/doi/10.1111/cns.12688
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Membrane expression of subunits α1 of GABA A receptor and GluR2 of AMPA receptor are increased in PCS rats, while subunits GluR1 of AMPA receptors and NR1 and NR2a of NMDA receptors are reduced. PCS rats show reduced spatial learning in the radial and Morris water mazes. Sildenafil treatment normalizes IL-1β and TNF-α levels, p38 phosphorylation, and membrane expression of GABA A , AMPA, and NMDA receptors and restores spatial learning.
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royal Jelly: neuro protection, ampa/nmda balance, reduction of glutamate excitotoxcicity, neurite outgrowth, immune alteration.
https://pubmed.ncbi.nlm.nih.gov/34651043/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5440900/
https://www.jstage.jst.go.jp/article/biomedres/28/3/28_3_139/_article
https://applbiolchem.springeropen.com/articles/10.1007/s13765-018-0349-5
Its kind a toss up. Ymmv but overall I think probably positive and best pulsed. If you have an infection, such as lyme or other tick born diseases it will enhance mine function and killing power against those pathogens (extremely common; not a question of if people with hppd have these it’s a question of how many and how these infections influence the hppd state (considering anecdally those with Lyme/bartonella can have bad reactions to cannabis and hallucinogens similar to us I would say it doesn’t help)).
https://www.frontiersin.org/articles/10.3389/fnagi.2018.00050/full
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https://m.scirp.org/papers/58919
“In the hippocampal slice preparation Coffea facilitated signal transfer presumably by enhancing glutamate AMPA receptor transmission. ”
avoid: caffeine
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https://pubmed.ncbi.nlm.nih.gov/25225100/
We found that GHB and baclofen elicited dose-dependent (ED50: 1.6 mM and 1.3 µM, respectively) transient increases in intracellular Ca(2+) in VTA and VB astrocytes of young mice and rats, which were accounted for by activation of their GABA(B)Rs and mediated by Ca(2+) release from intracellular store release. In contrast, prolonged GHB and baclofen exposure caused a reduction in spontaneous astrocyte activity and glutamate release from VTA astrocytes. These findings have key (patho)physiological implications for our understanding of the addictive and proepileptic actions of GHB.
—This is not recommended. It’s for personal understanding.—
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Dihexa: reduction of glutamate via reduced microglial activation (not amentioned but this is how that works.) but also very complex in how it works too— and the effects of when the drug leaves the brain is another story as it changes the brain. Especially in regards to dendrites.
”Furthermore, Dihexa decreased the activation of astrocytes and microglia, markedly reduced levels of the pro-inflammatory cytokines IL-1β and TNF-α and increased the levels of the anti-inflammatory cytokine IL-10. ”
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8615599/
To further support this conclusion, mEPSCs, the frequency of which corresponds to the number of functional synapses, were recorded from mRFP-β-actin–transfected hippocampal neurons (Fig. 8). The mean frequency of AMPA-mediated mEPSCs recorded from vehicle-treated neurons was 3.06 ± 0.23 Hz from 33 cells, while Nle1-AngIV induced a 1.7-fold increase [5.27 ± 0.43 Hz from 25 cells (mean ± S.E.M.); P < 0.001 versus control group] and dihexa produced a 1.6-fold increase (4.82 ± 0.34 Hz from 29 cells; P < 0.001 versus control group), confirming the expected expansion of functional synapses. No differences in amplitude, rise, or decay times were observed (data not shown), which suggests that the individual properties of the synapse were not altered.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3533412/
vglut1:
Again, dihexa and Nle1-AngIV treatment significantly augmented dendritic spinogenesis (Fig. 7, B, D, and F) in each of the three studies [mean spine numbers for the combined studies for Nle1-AngIV = 39.4, for dihexa = 44.2 and for vehicle-treated neurons = 23.1 (mean ± S.E.M., P < 0.001)]. The percent correlation for the newly formed spines with synaptic markers VGLUT1, synapsin, or PSD-95 is shown in Fig. 7, D, and E. Dihexa and Nle1-AngIV treatment-induced spines did not differ from control-treated neurons in the percent correlation to VGLUT1, synapsin, or PSD-95 (P > 0.05), indicating that the newly formed spines contained the same synaptic machinery as already-present spines. The previous results suggest that the newly formed dendritic spines produced by dihexa and Nle1-AngIV treatment create functional synapses.hallucinogen comparison notes:
vglut1:
Colocalization of pre- and postsynaptic markers following treatment demonstrated that psychedelics promoted synaptogenesis by increasing the density, but not the size of synapses (Figure 2D–2F). This increase in synapse density was accompanied by an increase in the density of VGLUT1 puncta, but not PSD-95 puncta, following compound administration (Figures 2G and 2H).
* note dihexa doesn’t alter vglut1. It simply copied that which is already present. Need more research.
We treated mature rat cortical cultures for 24 hr with DOI, DMT, and LSD as representative compounds from the amphetamine, tryptamine, and ergoline classes of psychedelics, respectively. All three compounds increased the number of dendritic spines per unit length, as measured by super-resolution structured illumination microscopy (SIM) (Figures 2A, 2B, and S6), with LSD nearly doubling the number of spines per 10 μm. Additionally, treatment caused a shift in spine morphology, favoring immature (thin and filopodium) over more mature (mushroom) spine types (Figure 2C). Colocalization of pre- and postsynaptic markers following treatment demonstrated that psychedelics promoted synaptogenesis by increasing the density, but not the size of synapses (Figure 2D–2F).
Psychedelics Promote Spinogenesis and Synaptogenesis
In addition to dendritic atrophy, loss of dendritic spines is a hallmark of depression and other neuropsychiatric disorders (Christoffel et al., 2011; Duman and Aghajanian, 2012), so we next assessed the effects of psychedelics on spinogenesis. We treated mature rat cortical cultures for 24 hr with DOI, DMT, and LSD as representative compounds from the amphetamine, tryptamine, and ergoline classes of psychedelics, respectively. All three compounds increased the number of dendritic spines per unit length, as measured by super-resolution structured illumination microscopy (SIM) (Figures 2A, 2B, and S6), with LSD nearly doubling the number of spines per 10 μm. Additionally, treatment caused a shift in spine morphology, favoring immature (thin and filopodium) over more mature (mushroom) spine types (Figure 2C). Colocalization of pre- and postsynaptic markers following treatment demonstrated that psychedelics promoted synaptogenesis by increasing the density, but not the size of synapses (Figure 2D–2F). This increase in synapse density was accompanied by an increase in the density of VGLUT1 puncta, but not PSD-95 puncta, following compound administration (Figures 2G and 2H).
Psychedelics Promote Spinogenesis, Synaptogenesis, and Functional PlasticityEncouraged by our in vitro results, we next assessed the effects of a single intraperitoneal dose of DMT on spinogenesis in the PFC of adult rats using Golgi-Cox staining. We chose to administer a 10 mg/kg dose of DMT for three reasons. First, all available data suggested that this dose would produce hallucinogenic effects in rats with minimal safety risks (Glennon et al., 1980, 1983; Glennon, 1999; Gatch et al., 2009; Smith et al., 1998; Appel et al., 1999; Winter et al., 2007; Carbonaro et al., 2015; Helsley et al., 1998; Strassman et al., 1994; Nair and Jacob, 2016). Second, we have previously shown that a 10 mg/kg dose of DMT produces positive effects in rat behavioral tests relevant to depression and PTSD (Cameron et al., 2018). Finally, we wanted to directly compare the effects of DMT with ketamine, and seminal studies conducted by Li et al. (2010) had previously demonstrated that a 10 mg/kg dose of ketamine produced a robust increase in dendritic spine density in the PFC of rats. We observed a significant increase in the density of dendritic spines on cortical pyramidal neurons 24 hr after dosing with DMT (Figures 2I and 2J). This effect was comparable with that produced by ketamine at the same dose (Figure 2J). Importantly, this DMT-induced increase in dendritic spine density was accompanied by functional effects. Ex vivo slice recordings revealed that both the frequency and amplitude of spontaneous excitatory postsynaptic currents (EPSCs) were increased following DMT treatment (Figures 2K–2M). Interestingly, 10 mg/kg and 1 mg/kg doses produced similar responses despite the fact that they are predicted to be hallucinogenic and subhallucinogenic, respectively (Strassman et al., 1994; Nair and Jacob, 2016).
Because the half-life of DMT is exceedingly short (~15 min), these results confirm that structural and functional changes induced by DMT persist for hours after the compound has been cleared from the body. Moreover, they demonstrate that DMT produces functional effects on pyramidal neurons of the PFC that mirror those produced by ketamine (Li et al., 2010). Because the PFC is a key brain region involved in extinction learning (Quirk et al., 2006), and both ketamine and DMT have been shown to facilitate fear extinction (Cameron et al., 2018; Girgenti et al., 2017), our results suggest a link between the plasticity-promoting and behavioral effects of these drugs. Because fear extinction can be enhanced by increasing levels of brain-derived neurotrophic factor (BDNF) in the PFC (Peters et al., 2010), and ketamine’s behavioral effects have been shown to be BDNF-dependent (Lepack et al., 2014), we next sought to determine the role of BDNF signaling in the plasticity-promoting effects of classical psychedelics.
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Tiagabine:
The similarities of the perampanel spectra to those of tiagabine reported by Nutt et al. (2015) is notable. Both drugs increase slow wave activity and decrease faster rhythms, thus shifting the brain to a less excitable state, but have marked differences in their mechanism of action. Whereas perampanel decreases the actions of glutamate at the synapse via allosteric blockade of AMPA receptors, tiagabine is a GABAergic drug that is thought to potentiate GABAergic inhibition by blocking reuptake (Meldrum, 1996). Both drugs are most commonly used as an adjunctive treatment for refractory partial seizures in epilepsy, so the similarities in spectral power changes may reflect the seizure-controlling mechanisms of both compounds. However, there are also differences apparent between the profiles of the two drugs, with effects of tiagabine being more spatially diffuse in the delta and theta bands and more frontally focused in alpha and beta bands, compared to the overall posterior pattern observed with perampanel.
https://journals.sagepub.com/doi/10.1177/0269881117736915
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Tiagabine is an anti-epileptic drug, that selectively inhibits GABA reuptake, thereby decreasing glutamatergic activity. Common adverse effects seen in trials include dizziness, asthenia, somnolence, accidental injury, infection, headache, nausea, and nervousness. These were usually mild to moderate in severity and did not need medical intervention (168).
The largest tiagabine anxiety trial was an eight-week randomized placebo-controlled trial, on 266 subjects with GAD. The tiagabine treatment of upto 16 mg/d was associated with significantly lower HAM- A scores compared to placebo (119). An open-label trial with 54 patients demonstrated improvement in the Lieboweitz social anxiety scale, social phobia inventory and Sheehan Disability Scale after being administered 4-16 mg/d for 12 weeks (169).
Other trials on the use of tiagabine in anxiety disorders have been largely underpowered due to small sample sizes or lack of placebo groups or blinding. One open label trial on 28 subjects with panic disorder found statistically but not clinically significant reductions in panic disorder scales and HAM-A when they were administered 2-20 mg/day for 10 weeks (170). A later four-week RCT was conducted on 19 panic disorder patients in which the tiagabine group was started at 5 mg/d which was increased to a maximum of 30 mg/d depending on adverse effects. They found no difference between the tiagabine group and the placebo group in the clinical ratings. However, they also conducted panic challenges with CCK-4 in which the tiagabine treated subjects showed decreased sensitivity to experimentally induced panic (171). These mixed results may be disentangled by running larger studies that are better powered to pick up any possible effect. Another eight week, open-label study investigated the utility of tiagabine as an augmentation therapy for patients with anxiety that remained symptomatic despite appropriate anxiety drug trials. Tiagabine was started at 4 mg/d and flexibly increased to a maximum of 20 mg/d to optimize efficacy and tolerability, with a resulting mean dose of 13 mg/d. A response was reflected in the HAM-A scores were seen in thirteen (76%) of the subjects. This implies that patients who do not respond to the traditional first and second line anxiety may respond to tiagabine augmentation. However, this study only had eighteen participants and more adequate RCTs need to be conducted to confirm the results (172).https://www.frontiersin.org/articles/10.3389/fpsyt.2020.548505/full
immune support/microglia:Furthermore, upregulation of GABA signaling by tiagabine also prevents LPS-induced microglial activation and aberrant behavior. This study illustrates a mode of bidirectional constitutive signaling between the neural and immune compartments of the brain, and suggests that the mPFC is an important area for brain–immune system communication. Moreover, the present study highlights GABAergic signaling as a key therapeutic target for mitigating neuroinflammation-induced abnormal synaptic activity in the mPFC, together with the associated behavioral abnormalities.
https://www.sciencedirect.com/science/article/pii/S0889159121005614
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Topiramate:
Topiramate
The introduction of topiramate is arguably the most important recent advance in migraine prophylaxis. Topiramate is an anticonvulsant with a number of actions that include enhanced GABA activity, voltage-gated Na+and Ca2 + channel inhibition, reduced activity of glutamate at AMPA/kainite post-synaptic receptors, and inhibition of the presynaptic release of calcitonin gene-related protein (CGRP). The net result is a reduction in excitatory transmission and an increase in inhibitory neurotransmission.
https://www.sciencedirect.com/topics/neuroscience/serotonin-antagonist
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The following is a message I wrote to a user. Please excuse any misspelling or grammatical errors; I wrote this on mobile.
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— the pathogenic hypothesis.
only recently there was a study done on pigs that showed psilocybin altered many of their neuro immune genes; some for a few days and others persistently.
usually, infections of the pns stay there and are fiercely deterred from entering the cns. When they do, however, they can cause a symptom set that is not only different than that of a patient suffering from a pns infection, but much more severe.
an example of this is mononucleosis. In children, there have been reports that it can get into the cns. Imo, the reason this doesn’t happen often in adults vs children is children have different immune systems. Once it does, it can create a syndrome called Alice in wonderland syndrome, which is characterized by the growing and shrinking of objects. I have had Alice in wonderland syndrome, and I can tell you it is indistinguishable from hppd visuals from psilocybin (growing/shrinking). It is interesting to see non drug induced hppd symptoms.
so, when a person takes any hallucinogen there is a change in pns and cns immune functioning just due to its effects on the 5ht2a system. They are powerful immune suppressants and immune modulators. Lsd even causes a 50% decrease in 5ht2a function after its initial agonization in the days following.
why is this so interesting? Well Abraham did some studies interested in why it is patients can do hallucinogens dozens of times and not get hppd and that others can do it once and get it. He discovered that there were thresholds— if you do it 10 times you breach a threshold and increase the likelihood after that. 20 times. 50 times.
when you apply that to the idea that one must have an active infection and do the hallucinogen at the same time to get hppd, it really becomes interesting. One could do it many times and still not get it. But one time, unbeknownst to them, they had an EBV infection, or a few others I will get to, that was only loosely controlled, like all opportunistic viruses, bacterias, and fungi, spread and even get into the cns. This could happen during the trip or even in the days after— which helps explain some of the sudden onset in the days to weeks following the trip. The immune system is not functioning correctly to fight the pathogens. The hose is unaware that they are biologically different than the other times they tripped and don’t know it.
wouldn’t someone know they are sick? You would be surprised. Many people get mono and don’t know it. I have extremely bad lymes disease and I don’t have the physical symptoms that are traditional in lymes. I have plenty of neurological symptoms however. Same with bartonella— primarily neurological.
now, there are no studies on this. But I just talked to someone on Reddit who got hppd by taking psilocybin during their active bartonella infection. They had a bad time and got hppd. They also had a terrible reaction to cannabis with bartonella, which I have also experienced.
what’s so special about bartonella? Well for one it is exceedingly prevalent in populations and people have no idea. 30% of cats have it. It likely can be transmitted sexually (officially you will read this doesn’t happen however, through asking to experts, I was told that patients who were sexually active and both test positive have more similar bacterial strains on average than they would simply by traversing the same physical environment). Ticks also carry it along with most mammals. Most people get it and can get the infection in check within 4 months but a subset of the population cannot and it takes them years to get it under control without therapy if ever.
in terms of what bartonella does to the brain, it seems to be extremely excitatory. Or rather, it removes the brakes to stop excitatory activity from going unfettered. Bartonella patients require high doses of benzodiazepines— like really high— to become sedated. I was able to drink 24 beers on 6 mg of clonazepam when bartonella was in my system and I woke up 6 hours later fully conciousness with working memory. A feet even the most rambunctious of fraternity mates couldn’t achieve. It is simply not neurologically possible. I was told by a psychiatrist who works specifically with bartonella patients that the highest dose he has seen to achieve symptom relief was 20mg of clonazepam. Amazing. Now if this doesn’t directly cause hppd it would severely exacerbate it and increase the progression through further increasing excitatory tone in the brain.
not all people with hppd have bartonella, I would think. It just would make getting hppd much more likely due to its disinhibition of brain chemistry. This same level of disinhibition could be achieved through other measures and would similarly increase the rate of hppd, imo, but not many as badly as this one as it also brings in the immune system and messes around with it. This effects the neuro immune system too— which is a much longer conversation and I have written about it this past year on this website. The interplay between neurological function and cytokines is fascinating — particularly interleukin-1b which can alter the brain into an increased excitatory tone via cb1 and gaba a. One thing this leads to panic attacks if it get bad enough, basically.—-the excitatory hypothesis:
ampa, sv2a, neurological rewiring, excitatory tone of the pfc, and mtorc1.
it has recently been shown that psilocybin requires the pfc and creates an increase in excitatory activity (glutamate). This is one of the proposed mechanisms that it helps with depression. And it makes sense. But glutamate is a double edged sword and must be kept in check with gaba— some of the first info solo and educated neuro buffs learn.
additinally, there was a pig study that showed an increase in sv2a activity— which is connected to gaba a activity and is what one of the most totable drugs to help patients with hppd take— levetiracetam. Increased sv2a is implicated in excitatory neurotransmittion in epilepsy.
https://pubmed.ncbi.nlm.nih.gov/33467676/
in terms of ampa— see my most recent posts that talks about them and how various hallucinogens such as lsd, ketamine, and psilocybin effect this receptor system and how the typical drugs that help or exacerbate fit into ampa—
—and try, at the same time, to connect the dots between an increased excitatory tone, ampa agonization, increased sv2a activity, increased mtorc1, and pathogenic infections that can increase mast cell activation and thus increased glutamate release. Do you see the perfect storm?
There is hope though. Even if we have lost ampa function there may be a road to salvation. I have only recently started to research ways to control, improve, and create ampa receptors. This is the first thing I have found that may help us:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4201273/
it should be noted I believe one must have control over everything I have said may be increasing excitatory tone before establishing new neurons or bringing about new neuronal excitatory capabilities. Hypothetically, one would just be creating new ampa receptors that would be out of control. I couldn’t say. I am not versed well enough in this to know and tbh— I don’t think anyone is in the context of everything I have written here.
—-the immune component: mast cells
in patients with pathogenic infection, we see an increase in mast cell activation. Even without it, from speaking to the foremost minds the subject, they say mast cell activation syndrome is a spectrum disorder that effects up to 18% of the population. It is not a question of if people with hppd have mcas— it’s how many do if not all.
how does this relate to neurological symptoms? Especially the excitatory hypothesis? Well that gets us into the world of mast cell mediators— histamine being the most noteable.
usually, people associate histamine with just allergies. But it is also a neurotransmitter that can elicit the release of glutamate— and this is the step by step process.
neuronal mast cells release histamine that then activated microglia/astrocytes to release glutamate at an uncontrolled rate. This release damages the microglia/astrocytes and damages nearby neurons as well. In patients that have their mast cells stuck in the on position— whether from pathogenic infection or mast cell activation syndrome, or both—will see their brains are stuck in a hyper-excitable state. In that case, drugs such as lamotrigine and Keppra can seem to be helpful for their microglial, glutamate reducing effects, and mast cell stabilizing effects, respectively.
there is already a post hypothesizing that microglia activation plays a role in the etiology of hppd written by user fawkinchit. This activation of microglia by neuronal mast cells fits into his hypothesis as well.
please refer to my mast cell posts for more information.
the mtor mast cell connection:
I have written extensively about mtor and mast cells on this site and they can be found by searching. It is incredibly complex literature and not even fully studied— but there are links between mast cells, mtor, ampa functioning, and hallucinogens.
Mold: the most complex
mycotoxic mold is extremely detrimental to the immune system, the brain, the pns, and basically every function in the body. More and more I’ve been seeing a subset of people who arrive at the forums, and I tell them to check their environment for mold, tell me immediately they have mold in their environment and near their sleeping areas. This is interesting to me as many people with hppd sleep and then the symptoms start.
mycotixins in the system could cause other pathogens to come forth and when combined with a hallucinogen create a perfect scenario for hppd.
according to the expert I spoke with about mycotoxic mold, he said that it is the most common driver of mast cell activation he sees in new patients. It is incredibly prevalent, and it is highly likely that some people have mcas genetically, environmentally, and have bartonella who take hallucinogens and find themselves in an excitatory/immune clusterfuck
interesting anecdotal info:
I have been increasingly perusing the lyme/bartonella, hppd, candida, vs, Epstein bad virus, and vaccine long haulers Reddits and have found an amazing commonality between the symptoms of them as it relates to hppd. Sometimes it’s been eary— like the person I told you about who had the bad reaction to mushroom/weed while in a state of active bartonella infection. Other anecdotes have been the remission of visuals and vs by treating SIBO or small intestinal bacterial overgrowth. Active candida infections can cause every symptom Killing candida can cause every emotional symptom of hppd and hallucinations too, as, apart from the other ways it does, the body creates antibodies to it that can cross the bbb and antagonize serotonin receptors (this plays into the loss of serotonin receptors in the visual cortex hypothesis— which can be found in this website and is quite old. I do believe this scenario is possible as a factor in hppd but not the direct cause of the insult). If hppd doesn’t involve the immune system directly, the hampering of it may allow fungi to grow in the gut along with other viral and bacteria to come out of dormancy and start to proliferate unchecked.
another interesting fact is hppd isnt even always caused by traditional drugs. Antibiotics and ssris have been implicated. Even a heavy night of drinking I see occasionally. Some people say they were born with and have never even smoked weed.
—-Oh boy… the vaccine (don’t shoot me!):
This is a highly politicized topic so I hope you believe me when I am completely uninterested in that side of this and am a person of science. I hesitate to even bring it up in fear that one may discredit everything else written here just based on me talking about it. But I don’t believe politics or societal views have a place in science and the influence they exert upon the scientific process is negative. Science needs to be practiced unfettered, within ethical guidelines, to work properly. I hope that you and anyone else who reads this understands that I am removing myself from any sentiment or views on vaccination and am simply trying to report what I have experienced and what I have read or heard from medical experts.
there have been anecdotal reports of worsening of hppd symptoms— some just temporary and other for longer— due to vaccination of the Covid-19 vaccine.
Now, that being said, I have learned from talking to both infectious disease experts and mcas experts that both their patient populations have individuals who have had negative and long lasting effects from the vaccine— and believe this is in direct effect from the vaccine.
Additionally, there are just now reports and literature being written about the sudden onset/worsening of autoimmune conditions in the days post vaccination. This is particularly interesting to me in respects to those who have had worsening of hppd with the vaccine, as it may indicate and point towards the immune hypothesis for hppd. Could we have an autoimmune condition? It seems plausible— considering the changes in immune functioning we have brought upon ourselves and through the agency of other actors such as pathogens (long lasting increases in immune function is correlated with development of autoimmune disorders). Additionally, there huuave been case studies about the sudden remission of autoimmune conditions through the use of hallucinogens. Most notably rheumatoid arthritis and it has been known to help treat conditions such as cluster headaches
https://pubmed.ncbi.nlm.nih.gov/35378658/
https://pubmed.ncbi.nlm.nih.gov/34957554/
when I got the vaccine I had been exposed to the most mycotoxic mold varieties— penicillin, aspergillus, stachybatrus— I had an active Epstein Barr infection— and I had been using cannabinoids as my hppd was largely in remission after 7 years.
I. Went. Insane.
it was like hppd on crack. X1000. The only way I got it under control was prednisone and other drugs that are effective in autoimmune encephalitis (which I didn’t have but the therapy for autoimmune disorders and that are the same).
I still encourage that everyone gets the vaccine. In light of there very preliminary studies, one should consult with their doctors if they have an autoimmune condition.
——
as you can see, there seems to be many many paths to Rome. This is likely, imo, why responses to treatment is so varied. What helps one hurts another. This was a lot to digest I’m sure and it’s all a bit all over the place, but once you get it and start researching, the connections become so apparent it’s difficult to unsee them.
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DHA:
AMPA Receptor-Mediated Cell Death Is Reduced by Docosahexaenoic Acid but Not by Eicosapentaenoic Acid in Area CA1 of Hippocampal Slice Cultures
Omega-3 fatty acids deficiency aggravates glutamatergic synapse and astroglial aging in the rat hippocampal CA1
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Pramipexole
Here we show that the striatal NMDA/AMPAreceptor ratio and theAMPAreceptor subunit composition are altered in experimental parkinsonism in rats. Surprisingly, while L-DOPA fails to restore these critical synaptic alterations, chronic treatment with pramipexole is associated not only with a reduced risk of dyskinesia development but is also able to rebalance, in a dose-dependent fashion, the physiological synaptic parameters, thus providing new insights into the mechanisms of dyskinesia.
WARNING: DAWS RISK. LAST RESORT. Highly efficacious in my own use; I did not get daws but I calculated the risk may be as high as 50% based off of data on patients using it off label at high doses to treat major depressive disorder
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Corticosteroids, mtor, and ampa:
mTOR is essential for corticosteroid effects on hippocampal AMPA receptor function and fear memory
Flunarizine+Keppra old post question
in Medications & Other Treatments
Posted
Here is a population study. This drug is certainly not without risk but it is good to know what those risk % are and what it means if they happen.
Background: Flunarizine (Fz) is a first-line prophylactic medication that is widely used in migraine. However, Fz has been recognized as a potential cause of drug-induced parkinsonism for a long time. However, to our knowledge, there has been no population-based subgroup analyses for Fz-induced parkinsonism (FIP) in migraine patients.
Methods: Data were obtained from the Taiwan’s National Health Insurance Research Database. The study comprised 6,470 migraine patients who were divided into two groups, based on their exposure or non-exposure to Fz.
Results: During the study period (2000–2012), the incidence rate of parkinsonism was 1.92 and 8.72 per 1,000 person-years in the control and Fz -treated groups, respectively. In the study population, the adjusted hazard ratio was 4.07 (95% confidence interval CI: 2.84–5.85). In 45–64-year old subjects and ≥ 65-year old subjects, the risk of FIP was 3.18 times (95% CI = 1.63–6.20) and 4.89 times (95% CI = 3.09–7.72) more than that in the controls. The Fz-treated subjects with comorbidities also had a higher risk (4.54, 95% CI: 3.14-6.57). An average annual cumulative Fz dose > 445 mg was accompanied by the greatest risk of FIP; Fz use for >60 days is a cut-off point for predicting future FIP.
Conclusion: At the population level, this study showed a complete picture of FIP in migraine patients. FIP is associated with older age, history of comorbidities, exposure to high-dose of Fz, and longer duration of exposure to Fz.