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Onemorestep

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Everything posted by Onemorestep

  1. 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.
  2. Gabapentin: Decreased AMPA receptor activation and norepinephrine release in the brain are observed due to the reduced calcium influx, which decreases excitatory amino acid (glutamate) release [24]. https://www.hindawi.com/journals/bmri/2014/631756/
  3. 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
  4. 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.
  5. 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.
  6. Personal anecdote: I got mild hppd from using psilocybin while blocking the 5ht2a receptor and not having trips. Suspecting hppd may not be mediated, or mediated entirely, via 5ht2a for some people.
  7. https://pubmed.ncbi.nlm.nih.gov/18248444/ Lamotrigine inhibits postsynaptic AMPA receptor and glutamate release in the dentate gyrus The dentate gyrus (DG) is a gateway that regulates seizure activity in the hippocampus.
  8. Discussion Our results provide evidence that psilocybin exerts a rapid beneficial action in well-studied and well-validated models of chronic stress-induced deficits in depression-relevant hedonic behaviors. Although depression is a uniquely human disease, findings from animal experiments can provide insights into psilocybin’s mechanisms of action that are challenging to obtain in humans, such as receptor pharmacology. Indeed, our results recapitulate the rapid antidepressant actions of psilocybin in humans (3, 4) and alterations in brain functional connectivity that outlast the presence of the drug, as reported previously (32). Although psilocybin has been reported to have delayed antidepressant-like effects in the forced swim test in some, but not all, strains of rats (13, 33), we were unable to replicate this finding in mice. Psychedelic compounds alter consciousness through activation of 5-HT2ARs. The prevailing view in developing psychedelic compounds for psychiatry is that the mind-altering effects of these compounds contribute to, or are responsible for, the therapeutic benefits (2, 9, 10). This assumption has never been tested, however. Our test of this hypothesis requires that the pretreatment with ketanserin sufficiently attenuated the activation of 5-HT2ARs at the time we administered psilocybin. We present two lines of evidence that indicate this is true. We observed that ketanserin blocked 5-HT2AR–dependent head twitching (Fig. 2A) and 5-HT2AR–dependent decreases in low-frequency oscillatory activity (Fig. 2 C and D). Our preclinical results suggest that 5-HT2ARs, and thus psychedelic responses, may not be required for an antidepressant response to psilocybin. We also found that mice with little or no evidence of psilocybin-induced head twitches, indicative of a lack of 5-HT2AR activation (12, 17), still exhibited a robust psilocybin-induced antianhedonic effect (Fig. 2B). 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. We cannot exclude that 5-HT2AR activation is required for some antidepressant activity at postpsilocybin time points longer than the 24 to 48 h we examined here. If 5-HT2AR activation is not necessary, then the combination of psilocybin and a 5-HT2R antagonist safe for human use, such as ketanserin, offers a potential means to eliminate, attenuate, or shorten the duration of psilocybin-induced alterations of perception while retaining its therapeutic benefits. This would reduce barriers hindering psilocybin’s widespread clinical use and perhaps increase its acceptance and utility. Use of nonhallucinogenic derivatives of psychedelic compounds (14) is another potential approach, although an antianhedonic response to these compounds has not yet been demonstrated. Resetting synaptic strength within cortico-mesolimbic circuits responsible for integration of reward and emotion, such as those demonstrated here, could provide a neurobiological substrate for lasting improvements in psychological and cognitive processing. In this study, we found a significant correlation between synaptic strength and change in hedonic state after psilocybin. Indeed, human studies with healthy volunteers and TRD patients reveal persistent increases in functional connectivity in these same circuits after psilocybin administration (11, 32, 35). The 5-HTRs underlying this synaptic response to psilocybin remain to be determined, but their definition could reveal a strategy for developing alternatives to psilocybin that are biased toward synaptic strengthening relative to perceptual alteration. Our previous work has suggested that 5-HT1BRs contribute to the synaptic and behavioral antidepressant-like actions of SSRIs (36). It is possible that psilocin and novel ibogaine analogs, which both have a high affinity for 5-HT1BRs (6, 14), exert their beneficial actions through activation of 5-HT1BRs. Although animal models cannot provide insight into the potential synergistic effects of the psychedelic experience and traditional psychotherapy, the effectiveness of these interactions may be improved with a better preclinical understanding of the pharmacological and physiological basis of psilocybin’s actions. https://www.pnas.org/doi/10.1073/pnas.2022489118
  9. 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/
  10. https://www.sciencedirect.com/science/article/abs/pii/S019701861530036X • α4β2-type nicotinic receptors are present on trigeminal caudal nucleus nerve terminals. • Pre-stimulation of α4β2 nicotinic receptors cause AMPA autoreceptor internalization. • The analgesic action of nicotine might depend on desensitization of AMPA autoreceptors.
  11. The psychedelic substance psilocybin appears to have antidepressant effects. In a study with [3H]UCB-J autoradiography, acute administration of psilocybin persistently raised the SV2A density measure in prefrontal cortex and hippocampus in pig brain. Psilocybin also induced an acute decrease in serotonin receptor levels in the same areas, which did not persist 7 days after the treatment. These findings could contribute to the explanation of how psilocybin produces its antidepressant action (Raval et al., 2021b). https://www.frontiersin.org/articles/10.3389/fnins.2022.864514/full
  12. https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-014-0222-3 We found that activation of TLR4 by lipopolysaccharide (LPS) reduces GABAergic synaptic activities through both presynaptic and postsynaptic mechanisms. Specifically, LPS causes the release of IL-1β from microglia. IL-1β in turn suppresses GABA receptor activities at the postsynaptic site through activating protein kinase C (PKC) in neurons. GABA synthesis at the presynaptic site is reduced upon activation of TLR4. Glial glutamate transporter activities are suppressed by IL-1β and PKC activation induced by LPS. The suppression of glial glutamate transporter activities leads to a deficiency of glutamine supply, which results in an attenuation of the glutamate-glutamine cycle-dependent GABA synthesis. These findings shed light on understanding synaptic plasticity induced by activation of TLR4 under neuroinflammation and identify GABA receptors, glial glutamate transporters, IL-1β and PKC as therapeutic targets to abrogate abnormal neuronal activities following activation of TLR4 in pathological pain conditions. —— question: how does inhibiting microglia effect glutamate-glutamine cycle-dependent GABA synthesis? It seems to be negative but overactivation of microglia damages glutamate neurons and nearby neurons. Hmm
  13. For those who need to take antibiotics, this should be of some help in deciding which is safer for those with hppd. clarithromycin seems a bad choice. minocycline is calming to microglia and promotes gaba. https://www.sciencedirect.com/science/article/pii/S2666354620301137
  14. I enjoy lyrica. I used to take it occasionally but found that the withdrawals were increasingly worse each time I stopped. The last time I was super anxious for a week if you stop, taper. I prefer Gabapentin.
  15. Imo you need drugs that decrease glial activation. There is a theory from several here that microglia/astrocyte activation causes persistent glutamate release. lamictal is the best and least risky one. But there are many others. Mast cell stabilizers: • over activation of mast cells leads to dysregulated histamine release which activates glia/astrocyte which activates glutamate ketotifen: mast cell stabilizer and h1 antagonist. you can buy this on https://www.americanresearchlab.net/product/ketotifen-fumarate-1mg-per-ml-x-30-ml/ I have had success with quetiapine and some others have too but others have had bad reactions. No idea why but the drug has other moas. The drug also antagonizes h1 receptors which stabilizes mast cells. h2 antagonists: otc drugs such as famotidine and cimetidine. Be wary— h2 antagonists boost immune function— th1 and th2 dominance. This can be bad in the long term for some with autoimmune issues
  16. There have been reports that quetiapine helps some of us with symptoms. It is my belief that part of the etiology of hppd, for those who are mast cell sensitive patients to begin with (upwards of 18% of population falls somewhere on this scale) benefit from quetiapine due to the antihistamine action on neuronal h1 receptors. For those of you that are unfamiliar, there is already a hypothesis on this website that the user Fawkinchit has written about concerning microglia and astrocyte activity releasing too much glutamate. Here I propose that for a subset of people with hppd, they also have mast cell activation— either through the direct action of the drug or through stress. The neuronal action is thus Histamine is NOT just for allergies. There are many histamine receptors and they do many different things in modulating immune response to giving erections. pns histamine, while unable to cross the blood brain barrier, does increase neuronal histamine levels. This article disputed that, however according to Dr Afrin, the most world rebound mast cell expert, there is a cascade that does in fact activate neuronal mast cells even though histamine does not cross the BBB . mast cell activation —> 2000 mediators release —> histamine is a major one; excitatory neurotransmitter—> activates microglia/ astrocyte—> induced rapid and uncontrolled/persistent glutamate release —> neuronal injury to glia/astrocyte and surrounding neurons —> the persistence of this mechanism does not allow the brain to heal. this is where quetiapine can be helpful for some: “Quetiapine is a tricyclic 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.” lamictal is another good choice for this same action
  17. Full link here. Calcium Channel Blockers *as this drug has been posted in the last two years as having some benefit, I thought I would pass this along. Whatever the etiology of hppd, glutamate seems to play a role in a large majority of people. Some find therapeutic benefit in drugs like lamictal, another calcium channel blocker, which also calms down microglia/astrocyte activation and this glutamate release. Now in to the drug: Verapamil is an L-type calcium channel blocker used to treat angina and hypertension, and is also used to treat cerebral vasospasm secondary to subarachnoid hemorrhage (46). It was the first calcium channel antagonist to be introduced into therapy (in the early 1960s) (47). As anti-hypertensive drugs, calcium channel blockers target a modifiable risk factor for stroke, but additional evidence indicate they have a neuroprotective action based on their ability to minimize carotid intima-media thickening (48) and the fact that intracellular calcium dysregulation can trigger ischemic cell death (49). A phase I clinical trial, completed in 2016, demonstrated neuroprotective activity of Verapamil when administered together with tPA and/or mechanical thrombectomy (NCT02235558). Combining the use of Verapamil with direct intra-arterial administration rapidly restored the cerebral artery, and may offer an opportunity to translate bench-side neuroprotective effects into bed-side success (46). This SAVER phase 1 clinical trial revealed the addition of Verapamil to thrombectomy, produced no thromboembolic complications. Due to the limited sample size of only 11 patients, this study did not have the power to demonstrate Verapamil's efficacy. Future studies should assess neuroprotection in regard to comorbidities and gender. There is an ongoing phase I study testing this agent for neuroprotection in stroke patients, which is estimated to be completed in the spring of 2020 (NCT03347786).
  18. Mast cells have always existed! They are one of the oldest cells in our bodies, genetically. We had them before we evolved into humans!
  19. Yeaaa that would be useful to know dosage. I mean it’s mice but if they were giving the equivalent of an oz of mushrooms it would be telling. It’s probably in the full article which I don’t have access too. there is an interesting study on how psilocybin alters neuro immune genes in pigs.
  20. Full study here • Psilocybin ameliorates stress-related behavioral deficit in mice • Psilocybin increases spine density and spine size in frontal cortical pyramidal cells • Psilocybin-evoked structural remodeling is persistent for at least 1 month • The dendritic rewiring is accompanied by elevated excitatory neurotransmission
  21. The only thing I can think of left for you to try is mast cell stabilizers such as ketotifen or imatinib. Cromolyn sodium. Quercetin is an herbal one but dirty in that it has other effects in the body. methylene blue may do something. all my love friend
  22. Lamictal is a immune suppressing drug. As is Gabapentin. I would screen yourself for viral, fungal, and bacterial infections. Check your living area for molds. Your case seems rather… unusual. I don’t know many who have found those drugs to make them worse.
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