VisualDude Posted March 11, 2016 Report Share Posted March 11, 2016 First a few terms: Agonist – “a chemical that binds to a receptor and activates the receptor to produce a biological response” https://en.wikipedia.org/wiki/Agonist Antagonist – “blocks or dampens … responses rather than provoking a biological response” https://en.wikipedia.org/wiki/Receptor_antagonist Inverse Agonist – “induces a pharmacological response opposite to that agonist” https://en.wikipedia.org/wiki/Inverse_agonist Down Regulation – “decrease in the number of receptors” https://en.wikipedia.org/wiki/Downregulation_and_upregulation Drug Tolerance – “concept where a subject's reaction to a specific drug and concentration of the drug is reduced followed repeated use, requiring an increase in concentration to achieve the desired effect” https://en.wikipedia.org/wiki/Drug_tolerance Serotonin and HPPD - LSD While serotonin isn’t the only player in the game, it is important and studied. Some of the strongest hallucinogens (i.e. LSD, mescaline, psilocybin) involve serotonin. Much of the effect has been attributed to increasing activity of 5-HT2A receptors - scroll down to 5-HT2A in this table: https://en.wikipedia.org/wiki/5-HT_receptor#Subtypes . Also note that “5-HT2A antagonists block the psychedelic activity of LSD” https://en.wikipedia.org/wiki/Lysergic_acid_diethylamide#Pharmacology . So LSD is a 5-HT2A receptor agonist - 'tripping' is from over stimulation of these receptors. While perhaps a bit technical, it is important to note that in the visual cortex, 5-HT2A receptors are inhibitory - “5-HT2A may also have an inhibitory effect on certain areas such as the visual cortex” https://en.wikipedia.org/wiki/5-HT2A_receptor . Inhibitory receptors reduce neuronal firing rates. Because of these points, certain medications can also cause HPPD symptoms. For example, risperidone is inverse agonist of 5-HT2A https://en.wikipedia.org/wiki/Risperidone#Pharmacology Posthallucinogen-like visual illusions (palinopsia) with risperidone in a patient without previous hallucinogen exposure: possible relation to serotonin 5HT2a receptor blockade - http://europepmc.org/abstract/med/10721882 LSD-Like Panic From Risperidone in Post-LSD Visual Disorder - http://journals.lww.com/psychopharmacology/Abstract/1996/06000/LSD_Like_Panic_From_Risperidone_in_Post_LSD_Visual.8.aspx Moving on … developing tolerance is typical. There can be several mechanisms for this but of particular interest is downregulation. Note with LSD, “tolerance is probably caused by downregulation of 5-HT2A receptors in the brain and diminishes a few days after cessation of use.” - https://en.wikipedia.org/wiki/Lysergic_acid_diethylamide#Tolerance Neurons normally add (upregulate) and subtract (downregulate) receptors. That is the basis of neuroplasticity - the ability to learn/adapt. While there are many scenarios, in this context, LSD over-stimulates 5-HT2A receptors … so the brain responds by reducing the number of them. So the sequence of events is this: Over stimulation of 5-HT2A receptors causes hallucinations The brain compensates by reducing the number of 5-HT2A receptors 5-HT2A receptors are inhibitory in the visual cortex, therefore the reduction of them (without LSD) is synonymous with over stimulation (with LSD) Until a balance is restored, visual perception will remain altered With some HPPDers, the affected neurons fail to upregulate after the ‘trip’. There could be many reasons for this such as: the brain adopted the change, learned to ‘trip’ as normal the brain is unable to ‘restore’ quickly due to nutrition, genetics, and/or stressors the brain is injured too significantly to restore Dr Abraham hypothesizes that HPPD is a ‘‘disinhibition of visual processing related to a loss of serotonin receptors on inhibitory interneurons’’ https://www.erowid.org/archive/rhodium/pdf/hppd.review.pdf Whatever the case, the important point of this post is HPPD involves changes in serotonin activities. Link to comment Share on other sites More sharing options...
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