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Ampa, HPPD, and Treatment Options (some glia thrown in too)


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This is a thread meant to expand upon the new research being done upon traditional hallucinogens, their effect on increased excitatory tone via hippocampus and pfc reorganization, the effects of these drugs on ampa/nmda receptors, and excitatory tone in general. The following is a list of drugs that anecdotally hurt/help that also fit into this hypothesis and any other drugs I find that may help as well. 
 

mall the best to you all out there.

 

——————-

 

AMPA/NMDA ratios in slices taken from psilocybin-injected CMMS-susceptible mice were significantly greater than those in slices taken from CMMS-susceptible animals injected with vehicle or ketanserin alone (Fig. 3B). 

Our preclinical results therefore suggest that 5-HT2ARs, and thus psychedelic responses in humans, may not be required for an antidepressant response to psilocybin, although that can only be definitively established with tests in human TRD. 

https://www.pnas.org/doi/10.1073/pnas.2022489118
 

——

 

5-HT2A activation and subsequent activation of postsynaptic α-amino-٣-hydroxy-٥-methyl-٤-isoxazole propionic acid (AMPA) receptors by psilocybin is associated with increased glutamate concentration.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8156539/

 

—-

AVOID:

 

How nicotine effects this and us. Interesting as many find nicotine to be anxiety inducing post hppd: 

 

“Selective coactivation of α7- and α4β2-nAChRs also sufficiently reversed Aβ-induced AMPA receptor dysfunction, including Aβ-induced reduction of AMPA receptor phosphorylation and surface expression in hippocampal neurons.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8156539/

 

 

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Levetiracetam inhibits glutamate (ampa+nmda) transmission through presynaptic P/Q-type calcium channels on the granule cells of the dentate gyrus
 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2801216/
 

Levetiracetam (100 µM) inhibited both evoked EPSCAMPA and EPSCNMDA to an equal extent (80%), altered the paired-pulse ratio (from 1.39 to 1.25), decreased the frequency of asynchronous EPSC and prolonged the inter-event interval of miniature EPSCAMPA (from 2.7 to 4.6 s) without changing the amplitude, suggesting a presynaptic action of levetiracetam.

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Would like to seE parampanel trial. If there is loss of receptors it should worsen symptoms. Need stabilizer of ampa without loss of function. Need insertion of new ampa receptors to accommodate potential loss. 

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Things that aggravate hppd and involve ampa contrasting to moa of drugs that help hppd. Avoid these drugs. 

 

nicotine:

https://pubmed.ncbi.nlm.nih.gov/26370265/

https://www.jneurosci.org/content/30/41/13814
 

ketamine:https://pubmed.ncbi.nlm.nih.gov/30075169/

psilocybin: https://www.pnas.org/doi/10.1073/pnas.2022489118

 

lsd: Social behavior (SB) is a fundamental hallmark of human interaction. Repeated administration of low doses of the 5-HT2A agonist lysergic acid diethylamide (LSD) in mice enhances SB by potentiating 5-HT2A and AMPAreceptor neurotransmission in the mPFC via an increasing phosphorylation of the mTORC1, a protein involved in the modulation of SB.

https://www.pnas.org/doi/10.1073/pnas.2020705118

 

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Drugs that can reverse loss of ampa neurons: 

 

dihexa:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4201273/

 

whatever is causing the overload of ampa function needs to be resolved before healing. Need a drug that inhibits ampa function only when it is overloading but not when it is in normal range. Dihexa, if beneficial, should only be used once the excitatory neuro transition is under control. 

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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 

https://pubmed.ncbi.nlm.nih.gov/23223310/

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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

 

https://www.researchgate.net/publication/23414762_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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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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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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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).

Figure 2
Psychedelics Promote Spinogenesis, Synaptogenesis, and Functional Plasticity

Encouraged 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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  • Onemorestep changed the title to Ampa, HPPD, and Treatment Options (some glia thrown in too)

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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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

 

https://www.researchgate.net/publication/323953215_Long-term_administration_of_Greek_Royal_Jelly_decreases_GABA_concentration_in_the_striatum_and_hypothalamus_of_naturally_aged_Wistar_male_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

—-

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. 


https://www.researchgate.net/publication/283967231_Sildenafil_reduces_neuroinflammation_and_restores_spatial_learning_in_rats_with_hepatic_encephalopathy_Underlying_mechanisms

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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

 

https://pubmed.ncbi.nlm.nih.gov/31473552/#:~:text=Vinpocetine is a nootropic phosphodiesterase,deficits by increasing BDNF expression.

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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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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

—-

 

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

 

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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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.

https://pubmed.ncbi.nlm.nih.gov/11070504/

Edited by Onemorestep
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