[{"id":847,"title":"OCD, TRPA1s, AND THE VAGAL FEAR PATHWAY.","sha":"74ec27b32cf62e4025f328208bac3597","user_id":null,"state":"published","body":"As mentioned in articles in NPBR.1. and JBI.2., the crucial stage in MAOI and St John' s Wort OCD cures I have repeatedly found to be strong TRPA1 receptor activation by radicals, resulting in gut serotonin and CCK release. Matsuo et al.3. have pointed out that the TRPA1 vagal/trigeminal innate fear pathway, demonstrated in animals, is conserved in humans, including the vagal solitary tract nucleus path to the midbrain parabrachial nucleus. Vagal activation of this fear pathway leads to hypometabolism in brain areas due to suppression of pyruvate dehydrogenase activity by phosphorylation.\r\nOCD cure, as detailed earlier, appears to relate to disruption of vagal afferent feedback, and resulting reversal of brain hypometabolism in crucial areas could provide increased \"neural noise\", bringing back the ability to \"drown\" persistent thoughts and to \"mind wander\" i.e activation of the default mode network. This hypothesis is testable, given current research into new TRPA1 agonists.\r\n.1. Neurology,Psychiatry and Brain Research 5(4):181, 8(4):185, 10(4):149.\r\n.2. Journal of Brief Ideas. \"Oxidative stress, MAOIs and OCD\". \"OCD, St John's Wort and iron\".\"OCD, radicals and TRPA1 receptors.\"\r\n.3. Matsuo et al. Nature Communications. 2021 12(1):2074. / (bioRxiv posted May 19, 2020).    ","created_at":"2021-04-20T05:16:01.376Z","updated_at":"2021-05-21T06:01:19.734Z","zenodo_id":4775135,"doi":"https://doi.org/10.5281/zenodo.4775135","subject":null,"tags":["ocd","trpa1","vagal fear pathway."],"vote_count":0,"view_count":1,"score":0.1,"deleted":false,"muted":false,"tweeted":false,"attachment_file_name":null,"attachment_content_type":null,"attachment_file_size":null,"attachment_updated_at":null},{"id":462,"title":"OCD, ST JOHN'S WORT AND IRON.","sha":"829e23a13f3a464704c08167f974fab8","user_id":null,"state":"published","body":"MAOI and St John's Wort treatments for OCD may have a similar radical-based mechanism. Six years' unrelieved total compulsive thinking was cured by the MAOI Phenelzine, with also a role for radical-releasing phenols which enter the CNS very little .1. (Journal of Brief Ideas article \"Oxidative stress, MAOIs and OCD\"). Side-effects lead to a search for alternatives. St John's Wort extract proved ineffectual (at 5 x 333 mg whole herb equivalent per day), but cure was greatly improved when ferrous fumarate was added to St John's Wort (at 2 x 14 mg per day). This improved cure, just as on the MAOI, did not happen until after several weeks, but followed 24 - 48 hours after the advent of peripheral serotonin release patterns. This suggests that the enabling of radical-based releasing of serotonin is a crucial first stage, as on MAOIs, as excess iron ions are known to increase the radical effects behind gut serotonin release by cisplatin and pyrogallol, for example. .2. \r\n.1. Neurology,Psychiatry and Brain Research 5(4):181, 8(4):185, 10(4):149.\r\n.2. European Journal of Pharmacology: Environmental Toxicology and Pharmacology.(1993) 248:329-331.  ","created_at":"2018-06-23T19:39:23.672Z","updated_at":"2018-07-06T17:11:57.596Z","zenodo_id":1297179,"doi":"https://doi.org/10.5281/zenodo.1297179","subject":null,"tags":["ocd","iron"],"vote_count":1,"view_count":1,"score":1.1,"deleted":false,"muted":false,"tweeted":false,"attachment_file_name":null,"attachment_content_type":null,"attachment_file_size":null,"attachment_updated_at":null},{"id":931,"title":"OCD AND PYRUVATE DEHYDROGENASE","sha":"56a7903732671db85e9bce76cc731ece","user_id":null,"state":"published","body":"As set out in NPBR.1. and JBI.2., MAOI OCD cure involves gut TRPA1 activation by radicals*,and vagal/trigeminal change influencing the parabrachial and subthalamic nuclei.3. The subthalamic nucleus is implicated in OCD.4. with ventral subthalamic theta activity inversely-correlated with OCD severity.5. Vagal feedback disruption, with consequently increased pyruvate dehydrogenase complex(PDC) activation by dephosphorylation, reverses brain hypometabolism. Astrocyte dysfunction in OCD.6. suggests increased PDC activation may be significant for OCD cure not only for the TCA cycle and brain energy metabolism, but also linked glutamate-glutamine-GABA cycling, and resultant changes to excitatory/inhibitory balances in neurons. Neurons depend upon this cycling to replenish glutamate via glutamine from astrocytes. Disordered astrocyte/neuronal coupling is seen in the OCD-related Tourette's syndrome, with significant negative correlations between thalamic glutamate levels and premonitory urges.7. Further, pyruvate kinase M1 is an autoimmune target in Tourette's.8.;this immunoreactivity may be clinically relevant to Tourette's and OCD. \r\n*(Sleep deprivation, frequently found antidepressant in humans, has recently been found to cause large free radical increases in mammalian small and large intestines.9.,which may explain this.)\r\n1.Neurology,Psychiatry and Brain Research.5(4):181,8(4):185,10(4):149.                       \r\n2.Journal of Brief Ideas.\"OCD,TRPA1s and the vagal fear pathway\"                                             3.Nature.Communications.2021;12:2648.                                                                                                                                                                4.J.Neurol.Neurosurg.Psychiatry.2020;91:1349-1356.                                                                                                                                               5.Translational Psychiatry.2018.8:118.                                                                      \r\n6.Experimental \u0026 Molecular Medicine.2020.52:1028-1038.                   \r\n7.BRAIN.2017:140;218-234.                                              \r\n8.J.Neuroimmunol.2006;181(1-2):165-176.                                             \r\n9.Cell.2020.181;1307-1328.\r\n","created_at":"2022-04-10T15:07:30.729Z","updated_at":"2022-06-17T02:42:55.811Z","zenodo_id":6643857,"doi":"https://doi.org/10.5281/zenodo.6643857","subject":null,"tags":["ocd","subthalamic nuclei","pyruvate dehydrogenase","astrocytes"],"vote_count":1,"view_count":1,"score":1.1,"deleted":false,"muted":false,"tweeted":false,"attachment_file_name":null,"attachment_content_type":null,"attachment_file_size":null,"attachment_updated_at":null},{"id":792,"title":"Fenton reactions and OCD.","sha":"c9045df53b5e2b9d9fbdf6d89bee2041","user_id":null,"state":"published","body":"Fenton reactions and OCD.\r\n\r\nSt John's Wort treatment (5x333mg pd) only became anti-OCD when ferrous fumarate was added.1. (2 to 5x14mg iron pd), suggesting radical releasing of serotonin was crucial, as on MAOIs.2. Gut Fenton reactions in the presence of free iron produce hydroxyl radicals, (carbonate radical anions around pH7 in the duodenum.3.), activating TRPA1 receptors, releasing serotonin and CCK. Replacement of ferrous fumarate (70mg iron pd) by equivalent amounts of ferrous sulfate did not change the cure. Change to ferrous gluconate (70mg iron pd) increased anti-OCD effects strikingly. This suggests the greater comparative amount of labile iron on ferrous gluconate improves the cure, (iron pd is the same), due to much greater Fenton radical induction.4. Resulting serotonin (and also possibly CCK) release leads to crucial vagal changes, which affect the hippocampus et al, bringing back greater \"neural noise\" and consequent ability to \"change gear\" mentally, both into default mode, and out to externals.\r\n\r\nREFERENCES.\r\n1. Journal of Brief Ideas.\"Oxidative stress, MAOIs and OCD\", \"OCD, St John's Wort and Iron\", \"OCD, radicals and TRPA1 receptors\".\r\n2. Neurology, Psychiatry and Brain Research. 5(4):181, 8(4):185, 10(4):149.\r\n3. Free Radical Biology and Medicine. 131: 1-6.\r\n4. Basic \u0026 Clinical Pharmacology \u0026 Toxicology. 119:412.        \r\n","created_at":"2020-12-01T11:14:42.161Z","updated_at":"2021-05-21T06:01:19.620Z","zenodo_id":4775018,"doi":"https://doi.org/10.5281/zenodo.4775018","subject":null,"tags":["hydroxyl radicals","carbonate radicals","ocd"],"vote_count":0,"view_count":1,"score":0.1,"deleted":false,"muted":false,"tweeted":false,"attachment_file_name":null,"attachment_content_type":null,"attachment_file_size":null,"attachment_updated_at":null},{"id":612,"title":"\"OCD, radicals and TRPA1 receptors\".","sha":"d4dfa1a905c32f84b3c55fdc97b78fab","user_id":null,"state":"published","body":"Further to NPBR .1. and Journal of Brief Ideas papers on \"Oxidative stress, MAOIs and OCD\" and \"OCD, St John's Wort and Iron\", this paper concerns TRPA1 human gut receptors which respond to oxidative stress. The 1,2,3- and 1,2,4- benzenetriols are responsible for much of the gut release from coffee of radicals which act at TRPA1 receptors, resulting in serotonin release. However, a number of natural products are strong agonists at TRPA1 receptors notably cinnamaldehyde. On St John's Wort,(5 x 333mg whole herb equivalent per day),as on MAOIs, adding cinnamaldehyde produces the same post-serotonin release patterns (e.g alternating auricle high blood flow) observed when taking new batches of serotonin releasing coffees (the 1,2,4 benzenetriol is quickly oxidized in air to an inactive, insoluble form). Small true cinnamon bark quills have been found to work best,(cinnamaldehyde is quickly oxidized to TRPA1-inactive cinnamic acid in the human stomach), and daily cinnamaldehyde addition this way to St John's Wort has improved the OCD cure. The cinnamaldehyde TRPA1 agonist effect adds to the peripheral serotonin release which alters vagal systems, likely resulting in a resetting of the brain's default mode system, which is influenced by vagal stimulation via, significantly, the auricle .2., in treatment for depression, for example.\r\n\r\n1. Neurology,Psychiatry and Brain Research 5(4):181, 8(4):185, 10(4):149.\r\n2. Biological Psychiatry (2016) Vol. 79(4):266-273.","created_at":"2019-07-21T15:35:34.280Z","updated_at":"2019-11-14T00:46:22.604Z","zenodo_id":3445538,"doi":"https://doi.org/10.5281/zenodo.3445538","subject":null,"tags":["ocd","radicals","trpa1","vagus","auricle"],"vote_count":1,"view_count":1,"score":1.1,"deleted":false,"muted":false,"tweeted":false,"attachment_file_name":null,"attachment_content_type":null,"attachment_file_size":null,"attachment_updated_at":null},{"id":1234,"title":"Antidepressants, the gut microbiota, TRPA1 receptors and self-cooling.","sha":"5479cf237932e4c70ad63b1322598599","user_id":null,"state":"published","body":"Enhanced efflux pump expression and intracellular production of reactive oxygen species in gut bacteria has been\r\nobserved following exposure for sixty days to several antidepressants, at clinically relevant concentrations.1. This pattern has been shown to be associated with increased microbiota antibiotic resistance, but from another point of view this chronic effect of antidepressant use may over time increase radical levels in the aerobic (small) intestine by altering the gut microbiota, leading to OCD-curative radical action at gut TRPA1 receptors, releasing serotonin from enterochromaffin cells,(linked to anxiety modulation.2.), as outlined previously.3. \r\nThe peripheral release of serotonin and CCK due to gut TRPA1 activation causes blood flow changes repeatedly seen just prior to the onset of cure-points on MAOI treatment, most strikingly alternating hot, high blood flow red ears (followed by bilateral). This may relate to a reinstatement of more effective self-cooling systems, as possible defects of self-cooling systems and raised temperatures are positively correlated with depression severity in a large-scale recent study.4. The complex role of the vagus in metabolic regulation, and the need for vagal change in OCD cure referred to in earlier papers make this pattern understandable.5.\r\n\r\n.1.ProcNatlAcadSciUSA.2023.Jan31;120(5):e2208344120.\r\n.2.Nature.2023.Apr;616(7955):137-142.\r\n.3.Neurology,Psychiatry,andBrainResearch5(4):181,8(4):185,10(4):149.Journal of Brief Ideas.\"Oxidative stress,\r\n    MAOIs and OCD\",\"OCD,radicals and TRPA1 receptors\".\r\n.4.Nature.Scientific Reports.2024.5 Feb.\r\n.5.AnnalsofNYAcademyofSciences.2019.1454(1):42-55.      \r\n\r\n","created_at":"2024-06-17T06:53:13.205Z","updated_at":"2024-09-30T07:53:33.890Z","zenodo_id":12660254,"doi":"https://doi.org/10.5281/zenodo.12660254","subject":null,"tags":["antidepressants","ocd","gut microbiota","trpa1","self-cooling"],"vote_count":1,"view_count":1,"score":1.1,"deleted":false,"muted":false,"tweeted":false,"attachment_file_name":null,"attachment_content_type":null,"attachment_file_size":null,"attachment_updated_at":null},{"id":305,"title":"Oxidative stress, MAOIs and OCD.","sha":"ac24cf8b54f24d1203f552538a155693","user_id":null,"state":"published","body":"Cure of severe obsessional thinking by monoamine oxidase inhibitor* gave rise to “side” effects, meriting investigation as repeatedly linked to cure-points. Phenol-rich foods, particularly robusta coffees, release serotonin from gut enterochromaffin cells by phenol-generated free radicals. (Phenols don’t enter the CNS). Releasing effects appeared just before the first cure-point, and all subsequent improvements, suggesting restraints on gut free radical action are removed by MAOI treatment. As MAOI reduction of oxidative stress has been shown to diminish antioxidant activity, and excessive antioxidant activity repeatedly shown in research on human OCD, the hypothesis is that it is by reducing intracellular antioxidant activity over time that MAOIs enable the extracellular release of serotonin required for the OCD cure. In one waking cure-point pharyngospasm (found with peripheral serotonin injections) was followed by vagal lesion-like effects, and I found I had regained the ability to “drown” constant compulsive violent thoughts. Vagal activity, although peripheral, has been found to influence CNS memory storage, and to be essential for the maintenance of some CNS-originated stereotypies. This peripheral cure trigger involving further serotonin release is enabled by the prior radical gut release of serotonin. Testing of this hypothesis would be practical.\r\n*Refs.“Neurology,Psychiatry and Brain Research” 5(4):181, 8(4):185, 10(4):149\r\n \r\n","created_at":"2016-05-24T13:40:28.942Z","updated_at":"2022-06-17T02:44:02.760Z","zenodo_id":114128,"doi":"http://dx.doi.org/10.5281/zenodo.51955","subject":null,"tags":["ocd","cognition"],"vote_count":2,"view_count":1,"score":2.1,"deleted":false,"muted":false,"tweeted":false,"attachment_file_name":null,"attachment_content_type":null,"attachment_file_size":null,"attachment_updated_at":null}]