This is a long story and it may sound like a manic delusion at the first sight. But PLEASE read on, if I am right it could be not less than a true breakthrough for a certain subgroup of immensely mentally suffering people who struggle in day-to-day life with society and feel in pain because they know they could do better, but they just can’t. Many will have various psychiatric treatments behind with little or no success, and it could explain many yet conflicting findings and theories.
I am sorry to flood you with information. I will try to contact persons in real life too who could be able to help me, but I have the feeling that this place here is maybe where some of the best-educated open-minded people might read it.
The facts are all there and some even well researched, but maybe no one has yet puzzled it all together....?? I have found so many references and have to sort them before posting.
Key part is an overactivity of NMDA receptor neurotransmission, possibly genetic and very probably related to quinolinic acid.
And that it's unusual, with only a fraction responding this way so it has been overlooked.
I for myself have been struggling more and more with sensory input, social interactions, emotional overload, inner tension, etc ... becoming stronger and more disabling with increasing age (I'm currently 28 years old). NMDA receptor antagonism brings me back to life, and I need to get opinions on this, to find professionals who know what they are talking about, to find a legal way to being able to live my life (with the current RC and drug legislation putting an immense pressure on me, time-related also as I will have to face a legal lawsuit for possessing MXE etc), to be in peace with myself and the world, to be productive ... and it could help others so much too ...
Mood disorders
The prefrontal cortices in the post-mortem brains of patients with major depression and bipolar depression contain increased levels quinolinic acid immunoreactivity compared to the brains of patients never having suffered from depression.[13] The fact that NMDA receptor antagonists possess antidepressant properties suggests that increased levels of quinolinic acid in patients with depression may overactivate NMDA receptors.[10] By inducing increased levels of quinolinic acid in the cerebral spinal fluid with interferon α, researchers have demonstrated that increased quinolinic acid levels correlate with increased depressive symptoms.[14]
Increased levels of quinolinic acid might contribute to the apoptosis of astrocytes and certain neurons, resulting in decreased synthesis of neurotrophic factors. With less neurotrophic factors, the astrocyte-microglia-neuronal network is weaker and thus is more likely to be affected by environmental factors such as stress. In addition, increased levels of quinolinic acid could play a role in impairment of the glial-neuronal network, which could be associated with the recurrent and chronic nature of depression.[13]
Furthermore, studies have shown that unpredictable chronic mild stress (UCMS) can lead to the metabolism of quinolinic acid in the amygdala and striatum and a reduction in quinolinic acid pathway in the cingulate cortex. Experiments with mice demonstrate how quinolinic acid can affect behavior and act as endogenous anxiogens. For instance, when quinolinic acid levels are increased, mice socialize and groom for shorter periods of time.[14] There is also evidence that increased concentrations of quinolinic acid can play a role in adolescent depression.[13]
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I for myself am heavily affected by this, I have lived since my early days as a child knowing that something is ‚wrong‘, that I’m ‚different‘ but that I couldn’t explain it and no yet-approved diagnosis would ever fully fit. I have gotten so many conflicted diagnosis and gone through half of a pharmacy without real success. I know that I am not delusional, and have the potential for high cognitive abilities, as well that I am so very overly sensible and too empathic for for most people.. From time to time I have met someone with whom it felt ‚right‘, and usually this were very intense contacts, the feeling to having finally found a soul mate, but eventually it became too intense for both sides. Maybe relevant, my mother is seriously suffering too, she has some sort of paranoid schizophrenia.
Ever since my adolescence I have been trying to understand this. I have had many unusual reactions to various drugs including prescription meds. The best fitting theory since has been inattentive ADD, but it did fit only half way, and the psychostimulants also helped only half way.
I have been reacting enormously positive to NMDA antagonists (dissociatives) with methoxetamine being the very best, used at very low doses, below any trippy or dissociative effects. But 3-MeO-PCP (the most manic), DXM (very pronounced and long-lasting, but also too psychotomimetic - related to sigma agonism? and too strong of an NRI), Ketamine (short-lived) and Memantine (the most sedating) had more or less the same truly beneficial effect with varying side effects. So I think serotonergic activity is relevant too, because of the unique effects of MXE and DXM (the latter being overshadowed by side effects) but I can be wrong of course and that it's another pharmacophore. Maybe related to calcium channels (NMDA receptors and calcium channels are interconnected if I'm right...(?) hyper excitability, sub-epileptic as it is suggested for some ADHD subtypes.. but enough to make one unable to function).
I have tried to explain this to doctors, but of course they mostly did not listen and say that I am a drug addict and/or mentally ill. Having to say that I never truly became addicted to anything, I hate to being dependent on anything and usually when tolerance set in, the negatives become to overweigh. Not so with the NMDA antagonists. I knew I was right, it was just too strong to be wrong, but I also knew nobody would believe me. I tried to convince myself that I was mentally ill, addicted to drugs and all that. It felt so utterly wrong, I know how other people react to drugs and how they are, but well.. I had no other chance. Until now.
I think of me that I am somewhat the ‚opposite‘ of a schizophrenic. Hypo-dopamine and hyper-glutamate. This leads to some kind of ADHD like symptoms, in that I get easily overwhelmed by sensory input and especially when being with other people. I can perform cognitively enormous well but only under the very right conditions. I have self-taught things like psychopharmacology, information technology, the English language, whatever. I was quite good at school with next to no efforts to actually learn thing, but I miserably failed in anything socially. Kind of social anxiety, maybe even a hint of autism, but it just wasn’t this. I am not asocial, but overly empathic. It is more than disturbing to be so emotional, too much for this world. Leading to impulse control disorder and anxiety, severe depression to the point of being suicidal.
There is a very intriguing link about highly sensitive individuals, endorphin difference and glutamatergic hyperactivity. It is from the Netherlands, so relatively unknown.
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Now the findings about ketamine and its possibility to relieve a good part of treatment resistant depressed people really excited and intrigued me. To be exact, I theorized about something like that even before it was public, back in 2005 when I made my first experiences with DXM.
That effect is known to be very acute, bringing relief within a few hours, and sometimes lasting for days or up to a week, but then people usually relapse. Afaik this is the current state of research.
Now - what if this would not apply to every depressed person, but more so to a specific sub group of people having depression as a symptom, not as the cause - because they have a genetic variant (a possibly gene is even known, I will research this more and post links) that makes them over-associated, over sensible etc. by over active NMDA receptors. So ketamine would not just ‚reset‘ the depression as it is said, but it would actually cure the underlying ‚disorder‘. But, unfortunately, only as long as the treatment is sustained.
These people would sometimes have tried various drugs on the desperate search for relief, usually struggling with the one or other substance, but they wouldn’t truly fit into the usual addiction raster. They would not get the strong psychotomimetic effects from (lower doses of) dissociatives, but respond very bad to neuroleptics with exacerbated side effects, making them extremely restless, in panic and maybe even psychotic (as it happened to me).
And they will find that dissociatives (when dosed exactly right and after one learns to get used to the sudden change in perception, thoughts and feelings) have an overly expressed relieving effect, stopping the omnipresent mental tension and that disturbing unstoppable train of thoughts and the chatter of mind. They will find themselves in a overwhelming state of peace, being flooded with will to live, hope and confidence. Social interactions will suddenly become easy, just as being more sober than while sober. (This has been called the 'Tussin Euphoria' but not linked together in the big picture probably.) It may look and feel like hypomania, just because one is used to feel so wrong and depressed all the time. Despite the usual reaction of 'regular' people who actually get manic, they will realize that with the right dosage, they are in so exciting full sober control of themselves and finally feel completely normal and like a regular human being.
They will get bad reactions to the racetam family of nootropics, exacerbating the inner tension and maybe impulse control disorder, possibly making them suicidal.
They will be overly sensible to caffeine, get more side effects from norepinephrine than the usual person (so amphetamine / methylphenidate is kind of a double edged sword, relieving part of the symptoms - these related to the hypodopaminergia, but also having unbearable side effects from the NE. Combining a stimulant with an NMDA antagonist will get better results, but the NE thing is still there. Isopropylphenidate is very promising here, but in really low dosages, with the NMDA antagonism being the key effect required.. maybe pure NMDA antagonism is sufficient for many. In fact, when the glutamate thing is relieved, the dopaminergics begin to work differently, leading to easy over-focus etc.. )
This could be associated with a generally low tolerance and 'irregular responses' to psychostimulants. For me, 5mg of d-amphetamine is already a decent dose, or 5mg of a -phenidate. I can't imagine taking these sky-high doses many users do, even with tolerance - I get different tolerance than the usual person.. dosing higher doesn't keep me more awake, but it over-wires me and exacerbates over-excitability... this is strong enough for me to consider dopaminergics / psychostimulants to be essentially non-addictive / self-limiting. And they are not sustainable as they should be in a person with ADHD, they only work for a few days and then I get drained and fatigued.. this is, unless the glutamate is re-adjusted.
I think many sufferers from social anxiety are among these.
Sleeping problems might be common, intense dreams (as they are associated with highly sensitive persons, as is very vivid imagination), problems to get rest at all and then when one's finally sleeping, one will feel to need too much sleep, waking up tired and having a hard time to get trough the day.. with becoming more awake when the day ends.. leading to a never ending circle. NMDA antagonists, or better their 'afterglow' or the K-related antidepressant effect suddenly relieves all this, sleep will become refreshing and one will need only 6-7 hours of sleep as a regular individual, waking up refreshed and confident..
Opioids will have an initially positive effect, but not that mind-blowing euphoria usually attributed to them, and it will very soon become the opposite, and also feel somewhat wrong and intoxicating, not comparable at all to the 'sobering' effect of dissociatives. Addiction is a truth here and you will really want to abstain from any opioidergic.
Naltrexone in ultra low dose could be beneficial by improving endorphins and/or Kappa modulation, but do not take a regular or full dose of an opioid antagonist (reverse agonist) like naloxone or naltrexone, as this will be an instantly horrific, terrifying hell-on-earth experience even when not being on an opioid at all! This is one more weird effect that happened to me repeatedly. It could be that it's either endorphin, enkephalin and/or dynorphin imbalance, hypo- or hyperactivity. That's really just guessing, but opioid receptors are probably a key relevancy and they are somewhat interconnected with NMDA receptors (-> modulating mu opioid receptors, leading to the theory that dissociatives alleviate opioid tolerance... in some, like me, but maybe not in everyone.)
The highly sensitive thing is (obviously) associated with hyperalgesia. Physically as well as psychically. But opioids don't work really, or at least they are not sustainable. To me, codeine for example doesn't really exhibit pain killing effects, it's just a weird sedative. NMDA antagonism alleviates the hyperalgesia.
The Russian nootropic peptide Selank is possibly somewhat promising too, but not a game-changer.
About tianeptine I am not yet sure. It could be very interesting but might not work at all.
This would fit all together why some have so very different reactions to dopaminergics, addiction at all, some responding to the tolerance-reducing effects of NMDA antagonists while it doesn't work for others.
GABAergics will also only work half way. They relieve the anxiety, tension and stress, but at the same time have a serious impact on motivation, cognition and drive, making one depressed. These people will get the physical addiction of GABAergics, but won't consider benzos as recreational / abusable drugs. Phenibut is somewhat more effective at the short term at least, because it is not just a GABAergic, but also enhances dopaminergic neurotransmission and is a calcium channel blocker, as pregabalin and gabapentin are (but their effects are too strong too and lead to cognitive impact again.) It's more the acute effect of pregabalin that feels relieving and somewhat similar to the antidepressant 'afterglow' of dissociatives, whatever the mechanism behind is.
Of course, this leads to interesting theories about ethanol, which is an NMDA negative modulator, GABAergic but also AMPA negative modulator (cognitive impairment - topiramate is horrific in this regard) etc. Overall, ethanol will have a slightly relieving effect but of course a bunch of negative or heavily negative side and after effects, and it's not the GABAergic effect to be the key for these specific people.
And they will have a difficult time to ever reach a ‚hole‘ state from a dissociative because the secondary effects (catatonia, amnesia, psychotomimesis with DXM, etc) will set in before they cross the threshold of dissociation. Reading through the DXM FAQ by W. White who described the different states of dissociatives very detailed - and I noticed a severe distortion between the usually experienced plateau effects and how it affected me. This would be entirely reasonable thinking of over-active NMDA receptors.
I was never able to hole from any dissociative, in any dose.
This could even mean that these people would have a very hard time if being anesthetized with a dissociative anesthetic, leading to horrific experiences of being halfway awake while surgery.
I am currently digging through publications and papers about highly sensitive personality and all that, and it all fits so incredibly much.
So, enough written for the moment.
I know that many of these effects and facts could and would apply more or less partially to many people. It is the thing as a whole that is so fucking exciting, and I think of it as a yet-do-be-defined subgroup of para-ADHD that could be literally life-changing for quite a few severely suppressed individuals.
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There are even more interesting connections ...
- Vitamine D3. I have felt repeatedly that exposure to sunlight, whilst living in the south, or on very warm sunny summer days, somewhat calms me down and makes me feel more at peace. This is linked to seasonal affective disorder.
- Vitamine B6 (Pyridoxine). Amazingly, there is the nootropic antioxidant Emoxypine, which is somewhat structurally related, and does great work in alleviating the hangover / rebound effects (waking up with headache, lethargy etc) from psychostimulants to me.
High levels of kynurenic acid (somewhat the counter-acting endochemical of quinolinic acid) have been identified in human urine in certain metabolic disorders, such as marked pyridoxine deficiency
- Inflammation and COX-2. Which showed some efficacy in treating depression. Intriguing is that there is evidence for chronic stress as well as exposure to drugs (tolerance development) has been linked to some sort of inflammation, leading to increased concentrations of quinolinic acid and a downward spiral. Memantine's opioid (and maybe dopaminergic) tolerance alleviating effects have been suggested to be partly due to alleviated inflammation markers. So this is an overall over-excitability inflammation thing.
It even continues with ALS, Parkinson's, Alzheimer's, Huntington's disease and all sorts of crazy stuff.
Levels of quinolinic acid in the CSF of AIDS patients suffering from AIDS- dementia can be up to twenty times higher than normal. Similar to HIV patients, this increased quinolinic acid concentration correlates with cognitive and motor dysfunction. When patients were treated with zidovudine to decrease quinolinic acid levels, the amount of neurological improvement was related to the amount of quinolinic acid decreased.
In the initial stages of Huntington's disease, patients have substantially increased quinolinic acid levels, in particular in the neostriatum and cortex. These areas of the brain that suffer the most damage at these stages.[15][17] The increase in quinolinic acid correlates with the early activation of microglia and increased cerebral 3-hydroxykynurenine (3-HK) levels. Furthermore, these increased levels of quinolinic acid are great enough to produce excitotoxic neuronal damage.[10] Studies have demonstrated that activation of NMDA receptors by quinolinic acid leads to neuronal dysfunction and death of striatal GABAergic medium spiny neurons (MSN).
Quinolinic acid levels are increased in the brains of children infected with a range of bacterial infections of the central nervous system (CNS),[17][19] of poliovirus patients,[19] and of Lyme disease with CNS involvement patients.[13][19] In addition, raised quinolinic acid levels have been found in traumatic CNS injury patients, patients suffering from cognitive decline with ageing, hyperammonaemia patients, hypoglycaemia patients, and systemic lupus erythematosus patients. Also, it has been found that people suffering from malaria and patients with olivopontocerebellar atrophy have raised quinolinic acid metabolism.
Could it be that some of the most intelligent, most sensible individuals have this sort of NMDA related overexcitability, leading to varying illnesses ranging from relatively mild inability to cope with day-to-day life up to truly destroying serious disorders like ALS, which usually develop with age and then it's too late to reverse the things ... and that this could actually been prevented / treated early enough with anti-excitotoxic agents?
- dopamimetic
Thank you so very much for reading this, and I am happy about any serious response!
Edited by dopamimetiq, 18 October 2015 - 11:23 AM.
