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Serotonin and HPPD

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First a few terms:

Agonist – “a chemical that binds to a receptor and activates the receptor to produce a biological responsehttps://en.wikipedia.org/wiki/Agonist

Antagonist – “blocks or dampens … responses rather than provoking a biological responsehttps://en.wikipedia.org/wiki/Receptor_antagonist

Inverse Agonist – “induces a pharmacological response opposite to that agonisthttps://en.wikipedia.org/wiki/Inverse_agonist

Down Regulation – “decrease in the number of receptorshttps://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 effecthttps://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 LSDhttps://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 cortexhttps://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


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:

  1. Over stimulation of 5-HT2A receptors causes hallucinations

  2. The brain compensates by reducing the number of 5-HT2A receptors

  3. 5-HT2A receptors are inhibitory in the visual cortex, therefore the reduction of them (without LSD) is synonymous with over stimulation (with LSD)

  4. 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.


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Took me ten years but i actually understand this post. Post when i was taking the pill of MDA  (Not MDMA) i got hallucinations with closed eyes and especially when i pressed my closed eyes i had incredible visuals. I know there is a report of the tolerance from LSD that visuals, when provoked, consisted for a week after use. The general idea is that LSD tolerance takes about a week to go back to baseline.


Long time ago people talked about this and how to upregulate the receptors. It would be interesting if natural VS cases had the same thing going on and could be proven. Even more, proven exactly what is the state of our neurons. Or what about people with hppd/Vs from weed or NDMA antagonists?


The three potential causes you mention are indeed interesting.

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Glad that you could understand it ... it is hard to simplify yet retain any meaning - "stuff just happens" doesn't quite explain anything.


Both MDA and MDMA act on 5-HT2A receptors.  Some of this stuff sounds worse than LSD

  • MDMA -> "use has been shown to produce brain lesions … neurotoxicity in serotonergic axon terminals.  Neurotoxic damage to axon terminals has been shown to persist for more than two years … Adverse neuroplastic changes to brain microvasculature and white matter also seem to occur in humans using low doses of MDMA. Reduced gray matter density in certain brain structures has also been noted in human MDMA users … produces persistent cognitive impairments in human users … Impairments in multiple aspects of cognition, including memory, visual processing, and sleep have been noted in humans …  the magnitude of these impairments is correlated with lifetime ecstasy or MDMA usage. ... increased rates of depression and anxiety… at high doses, MDMA induces a neuroimmune response which … making the brain more susceptible to environmental toxins and pathogens." https://en.wikipedia.org/wiki/MDMA#Long-term
  • MDA -> "Relative to MDMA, MDA is also a more potent releasing agent of norepinephrine and dopamine and hence is more stimulating in comparison, and is also notably several-fold more neurotoxic to serotonergic neuronshttps://en.wikipedia.org/wiki/Methylenedioxyamphetamine#Pharmacology

Whatever the case, there are clearly things people can do to manage HPPD better.  And its reported that most people recover from HPPD.  The 2-year thing was interesting, showing slow recovery - something common to most HPPDers.


It is also clear that many things are involved - even Dr A doing a dopamine drug trial.  Serotonin, Norepinephrine, and Dopamine get the most attention. [ will try to keep this thread focused on serotonin ].  But changes in blood-brain-barrior and vascular are noteworthy.  


There are so many drugs and effects out there.  In the end, understanding what is going on can help some ... its a matter of each person's outlook and makeup.  Some prefer not to know since it may feed fear.  Others find it calming to begin grasping the reasons for all the weird stuff being experienced.


The most important thing to realize is that their is hope of getting better, of 'management', and of developing a happy life.  The brain is very malleable and each person can learn to stack the odds back to their favor.

As for upregulation, it would be interesting to figure out how to do that.  If 'normal' is the base line and 'high'/'tripping' are downregulating ... what is the opposite of 'high' and 'trip'?  If down-to-earth is normal, what is below down-to-earth?  Can only imaging the 'treatment' would feel aweful, lol - the mythical hell.
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