DMT is a fascinating neurotransmitter. May it be related to ‘Awe’?
RESPONSE TO Q4LT
While I was researching for my Pavlovian Prisons theory, I came across this beautiful post. And now I must do a response to it.
I really enjoyed this concept:
My first thought was that endogenous MAOIs could be released by the effect of one of the neurotransmitters binding to a receptor, perhaps serotonin, which mostly seems to fit due to its circadian rhythms functionality. I suspect that serotonin’s role beyond circadian rhythms would include many context-based responses, involving the glutamatergic system (contextual cue) and dopaminergic system (response) via heteromers, with serotonin at the center of design for each response-based, behavioral-memory sets. Perhaps this is what we know as mood, traditionally. There may be a way for certain contexts to trigger increasing MAOIs to release, having an effect of increased activity of monoamines, which may increase the amount of dopamine that goes into inhibitory mechanisms, such as D2 and D4.
We know that D2 forms heteromers with 5HT2a, and is also implicated in schizophrenia. I have written my hypothesis for how D2sh receptors may cause a difference in how attention is used.
Novel stimuli might cause more dopamine release than is typical, resulting in higher probability that D2sh receptor is activated.
Even without this mechanic, D2sh receptors stop dopamine flow and are inherently going to activate more likely if dopamine is higher. This means more stopping of dopamine flow.
The effects on normal linear dopamine signals would be disrupted more frequently if D2sh was more active. This means maybe the dopamine slips into neighboring neurons more likely than linear paths, that are typical. Even if it’s not literally linear, there are established common paths, perhaps what the default mode network represents, and D2 would logically derail dopamine signals to peripheral dopaminergic neuronal activity.
This would also be dose-dependent. Increasing D2sh activity would increasingly change consciousness to become less linearly-deep and more laterally-wide. The default mode network will likely dissolve as well, diffusing into what could appear as a more chaotic state.
The effect this would have on attention, would be diffusion. Diffusion of attention would mean not focusing on a singular thing. Eventually you’d become aware of many things. The purpose of this mechanic is to find things. This is so the source of novelty that causes a non-routine excessive dopamine release must be found, studied, and explained.
This seems to explain thought disorders and attention differences. It’s also worth noting that D4 and D2 receptors form heteromers. D4 receptors seem to decrease GABA in the prefrontal cortex, when agonized.
From the Wikipedia article on D4 receptors,
I have named the disorders here, creativity disorders, due to the links it has to novelty seeking. My theory on creativity claims that risk-taking and novelty-seeking are the fundamental core traits that cause creativity skills to develop. D4 receptors are associated with novelty-seeking. The paper suggests the D4 receptors are linked to the impulsive symptoms of ADHD and bipolar, and this makes sense considering my theory on creativity as well, which is partially explored below. Check out the full post for the complete concept.
First, my ideas on risk-taking and novelty-seeking:
Familiarity involves information or environments you know are safe or unsafe already. The familiar can be trekked safely. The unknown, or novel, is undetermined to be safe or unsafe as of yet. The more risky zones of reality have more potential for discovery than familiarity, because familiarity cannot lead to discovery, by definition, because it is the already-discovered. Novelty is the basis of discovery. Venturing into the unknown risks death, which poses evolutionary-survival problems. For example, exploring the dark may run the risk of meeting face to face with some nocturnal predator. There is still a genetic benefit for advancing society, via exploration of environments, ideas, and technologies, so these risky genes still benefit us, but we need most of society to fear change and the unknown. Fearing the unknown provides more evolutionary benefit than does craving exploration of the unknown/novelty-seeking. These traits operate on a gradient, rather than binary, trait/non-trait status.
. . .
This stigma usually discourages most people from attempting creative thinking. But creativity is linked with risk taking, and openness to experience. Rebelliousness is also linked to these traits, which makes sense, especially since grandiosity is arguably a form of rebellious mentality, and is linked to creative disorders such as schizophrenia and bipolar disorder. The stigma has even been historically linked to left-handedness. Left-handedness has been correlated to creativity, and schizophrenia. This bias may have even caused unique evolutionary developments, such as right-handed schizophrenics who’s language processing is atypically oriented, perhaps due to right-handed people surviving deaths due to discrimination. This may all come down to the fear of the unknown, and a bias against risk-taking.
And this is my concept of pattern recognition development:
Exploring is the concept of finding new paths and solutions to the same problem, or even to seek out new problems altogether. Try out this thought experiment that reveals how intuitive and creative thinking develops. Imagine you are taking a path to some destination A. You can take the same path every time for efficiency. Due to repeated exposure, you will memorize details of this path. With this scenario, the path becomes learned and environmental consciousness slowly fades out for autopilot because a pattern has been learned. While in automatic mode, the consciousness may rest or act leisurely and freely. This is why we dissociate when driving our commutes. But what if you took a novel path each time? Then you could not stay in this automatic state. Consciousness is required to sort out novel data for it to become habituated as well. You would not have exposure to the details of the same path each time. Instead, the only repeated details you are exposed to are the ones that are common among novel paths. This means you will learn how navigate novel paths by noticing patterns between novel paths due to memory of the repeated details among these paths. This is the basis for pattern recognition. This means that pattern recognition is not some special inherent trait, but moreso novelty-seeking, and thus also risk-taking, since novelty is inherently more risky.
If you find this creativity topic fascinating, as I do, check out my full podcast episode that goes a bit more in-depth on the topic! Also for future updates, subscribe on iTunes, Google Play, or Stitcher.
As previously stated, D2 receptors also form heteromers with 5HT2a receptors. The mechanic of this seems to be responding to novel stimuli by enhancing glutamate release, and also changing how attention fundamentally works. I think this potentially includes perceptual changes, either through an enhancement of glutamate release via 5HT2a-mGlu2 heteromer effects, essentially producing sensory enhancement by at least by the mechanism of increased NMDA receptor activity, that should produce effects opposite to NMDA antagonists effects, namely opposite of dissociation, numbness, anesthesia, at least initially before downstream mechanisms stabilize this effect. I would assume that the after-experience may produce anesthetic like effects, or that many other effects, such as dynorphin release, would cause dissociative effects in response to aversive stimuli that you are exposed to in such a state of sensitivity. More on this later, as Q4LT and Nichols mention endogenous opioids as possibly being implicated in hallucinations.
This is where things get very interesting. Agmatine, the endogenous neurotransmitter for imidazoline receptors, has NMDA antagonist properties. SSRI drugs are dependent on manipulation of imidazoline receptors, via agmatine, for their antidepressant effects. If it is not already apparent, I should state my stance now, basically all drug-induced perceptual effects will come down to modulation of glutamate activity. I have yet to see the possibility of perceptual effects that are not heavily linked to NMDA or AMPA activity ultimately. Anticholinergic hallucinations are likely mediated by inhibition of NMDA heteromers, NMDA antagonists obviously manipulate glutamate receptors, 5HT2a psychedelic effects are known to be blocked by the mGlu2 modulator N-Acetyl-Cysteine (you will have to ctrl-f for mGlu2), and THC seems to increase dynorphin levels, which of course bind to kappa receptors, which some seem to block NMDA activity (sorry for the Guinea pig study
THE STATE OF AWE
To me, it seems there must be a connection between D4 receptors and endorphin/dynorphin release or sensitivity. It is known that D4 decreases GABA release, as mentioned previously. It is also known that manic and ADHD disorders are both correlated to higher D4 genes, which are linked to novelty-seeking, and these disorders are also linked to creativity. I think that the state of mind, known as awe, is deeply relevant here.
And even more fascinating,
Humanistic/forensic psychologist Louis Sundararajan also critiqued Keltner and Haidt’s model by arguing that being in the presence of a more powerful other elicits admiration, but does not require mental accommodation because admiration merely reinforces existing social hierarchies. Sundararajan expanded upon Keltner and Haidt’s model by arguing that first, an individual must be confronted with perceived vastness. If an individual can assimilate this perceived vastness into her or his existing mental categories, s/he will not experience awe. If an individual cannot assimilate the perceived vastness, then s/he will need to accommodate to the new information (change her or his mental categories). If this is not accomplished, an individual will experience trauma, such as developing PTSD. If an individual can accommodate, s/he will experience awe and wonder. By this model, the same vast experience could lead to increased rigidity (when assimilation succeeds), increased flexibility (when assimilation fails but accommodation succeeds), or psychopathology (when both assimilation and accommodation fail). Sundararajan did not speculate on the evolutionary origins of awe.
Hypothesis: D4 receptors enhance sensitivity to both reward and fear, basically endorphins and dynorphins, during situations that are novel, possibly via GABAergic modulation. It also appears that a link between novelty states and D4-D2-5HT2a-mGlu2 heteromers, where the purpose of 5HT2a is to increase glutamate to enhance perception. Those with these creativity disorders are addicts of awe, and perhaps the schizophrenic merely experiences PTSD more frequently due to increased dynorphin:endorphin ratio resulting in an increased tendency towards fear responses such as PTSD. I also theorize that PTSD is the aversion equivalent to addiction, where addiction is typically a pleasure loop, PTSD is an aversion loop, that eventually results in dissociative effects due to dynorphin’s NMDA antagonist effects. The reason perpetual awe might exist in these disorders has to do with being less exposed to common stimuli due to favoring exploration and novelty-seeking rather than repeating stimuli within familiar realms.
To explain the perceptual increase, here as an excerpt from my post on Cannabis:
A case could be made, that all illusions are a form of memory, and they form for efficient processing. Using memory constructs to form perceptions of familiar and common images that we are exposed to, such as faces, the corners of rooms, and 3-dimensional data, would allow faster processing and less time spent deciphering data as if it were novel. The ‘motion aftereffect’ illusion occurs when staring at a source of consistent motion, where eventually when looking at a static image, the perception of motion continues after the stimuli has ceased (3). This would show that the illusion is developed via exposure to the stimuli, and this would make sense of cultural differences found with optical illusions (10). Being exposed to grid-roads vs being exposed to forests, reveal drastically different stimuli that each group is exposed to on a frequent basis. Illusions are in some sense, memory-based abstractions, created from familiarity and exposure to common stimuli. Illusions would allow for faster processing, reduction of details, assumption-recognition-based processing as opposed to sensory-observation-based processing and interpreting of observations.
There is correlation between illusions failing, and proneness to schizophrenia, such as the case of depth inversion illusions, or ‘hollow mask illusions’ (7). It may be that, increasing doses of NMDA antagonists, would decrease perception, and that illusions are the highest form of perception, relying on a combination of stimuli and memory, as opposed to stimuli alone. So, with increasing doses of NMDA antagonists, we could expect the highest forms of perception to vanish first, which would put pressure on visual processing, and eventually visual failure, where an excess of details are surpassing the ability to distinguish and process the details.
By increasing illusions, visual data may be increasingly abstract and simplified, resulting in faster processing of novel stimuli, or simply that there is less novel stimuli to process, as it has been turned into illusions/memories already.
What is interesting here, is that agmatine, the endogenous imidazoline agonist, seems to be actually implicated in near death experiences (NDE). This paper suggests that increasing agmatine levels may treat schizophrenia, but suspiciously, this paper suggests that agmatine concentration was increased in schizophrenics. It is known that agmatine is an NMDA antagonist, and these tend to be psychotomimetic. Agmatine tends to boost the effects of cannabis, especially by restoring psychedelic effects to an immense degree, at least according to many anecdotes. Agmatine supplementation is commonly used with opioids and cannabis to boost its effects, among reddit users. Personally, I have mixed agmatine at doses of 500mg-1g with vaporized cannabis, and the effects were beyond anything I could have gotten alone. There is some research indicating reactions between cannabis and agmatine. Imidazoline inhibits NMDA activity as well, showing an overlapping psychotomimetic mechanism. I have written a post that discusses the interactions and heteromers that may produce the psychoactive effects of cannabis.
It is known that serotonergic drugs are capable of inducing mania. In the supplement and nootropic culture, it is commonly reported that melatonin induces depression on the day after ingestion. This has been backed in the literature as well, as melatonin is thought to be a biomarker of depression. Dynorphin is also implicated in stress and depression, which makes sense as it seems to be the aversion neurotransmitter, mediating our negative response to pain, fear, and anything we seem to feel aversion to. It is known that there are circadian rhythm mechanisms involved in bipolar disorder, and that both serotonin and melatonin play a massive role in maintaining circadian rhythms. The idea that serotonin provides a ‘wake-up’ signal, and melatonin a ‘go-to-sleep’ signal, seems to give intuitive evidence to the idea that serotonin induces mania, and melatonin possibly inducing depression. Lithium has been shown to treat mania, and also increase dynorphins. Kappa agonists, such as pentazocine, have been shown to reduce manic symptoms in bipolar patients. More interestingly, bipolar disorder is linked to lunar cycles, and also linked to the genetics involved in our biological clocks.
The pineal gland that houses and synthesizes our DMT, is also heavily associated with our biological clocks. Typically, the third eye, or parietal eye, of animals that still have an externally expressed third eye, responds to the color of the sky, to induce wake or sleep signals, which are context-based responses.
I strongly suspect that psychedelics better represent mania, rather than psychosis, as traditionally hypothesized. This would make sense of why psychedelics reduce PTSD and fear of death, likely by reducing dynorphin activity somehow, leading to increased freedom from fear-based conditioning, one of our Pavlovian Prisons. It could also be that the lack of fear, allows you to explore ideas and experiences that are more risky, and potentially traumatizing, which may actually facilitate the development of new PTSDs once the fear creeps back in, after a dose wears off. Psychedelics lead to increased openness to experience which is presumably implying less fear of the unknown, and/or more willingness to explore the unknown, which is inherently more risky in terms of decision-making as compared with making decisions using known information or familiar factors, because you cannot predict error (and generally cannot predict) when you are exploring the unknown.
This could also explain the risks of suicide in manic states, as a suicidal person who suddenly decreases their fear of death would be at higher risk to taking action, and if dynorphin activity were suppressed, it might also mean some form of amygdala activity suppression, since dynorphin activity in the amygdala seems to be what controls fear-based behavior, presumably inaction towards fearful activities. It is known that prefrontal 5HT2a activity is correlated with amygdala reactivity. In this study, they found that rapid increases in 5HT release caused fear behaviors. I suspect that a rapid increase in serotonin in natural environments would occur during exposure to deeply novel stimuli, whereas regular serotonin activity may have a sort of stability of the inputs and outputs of serotonin neurotransmission. The purpose may be to put you on guard, when in unfamiliar territory. This paper found that increased receptor density of 5HT2a in the prefrontal cortex is correlated to decreased reactivity of the amygdala. This is in contrast to the idea that increased general serotonin would increase fear-based behavior.
These findings also support the idea that reduced fear is the mechanism for suicide in general. SSRI drugs increase manic symptoms in bipolar patients, and they also seem to upregulate 5HT2a. Although suicide is common in bipolar, it was not found that 5HT2a receptor density is increased in patients with bipolar disorder, and in fact might be decreased in bipolar patients. Though, a mechanism involving heteromers could exist, since higher D4 receptor density is related to bipolar disorder. Reduced prodynorphin mRNA was found in bipolar and depressed post mortem patients, which makes sense since drugs that increase dynorphin tend to treat bipolar disorder, though this finding seems to contradict the paper posted earlier that suggests increased dynorphin activity is a possible mechanism in depression. Though, it is possible that increased dynorphin activity might downregulate prodynorphin mRNA, while bipolar patients have less production of dynorphinergic neurotransmitters, but I cannot seem to find info on this. Comment below if you have any studies.
It is known that chronic administration of 5HT2a agonists downregulates the 5HT2a receptors, and that bipolar patients are shown to have less 5HT2a receptors, and correlations to circadian rhythm genetics. Our circadian rhythms are heavily implicated in pineal gland function, which relates to DMT production and neurotransmission. It is also thought that psychedelics (5HT2a agonists) reduce amygdala reactivity and fear of death in the terminally ill, and reduce PTSD which is mediated by dynorphinergic neurotransmission. Psychedelics also have been emerging as a treament option for addiction, which is mediated by dynorphinergic pathology. Those with bipolar disorder are also shown to be treated by kappa receptor agonists, and lithium, which increases dynorphin levels, as previously shown. It is also known that MAO activity is decreased in those related to bipolar patients, and more exciting is this study which suggests a specific gene variant related to reduction of MAO A in bipolar patients. All of this points to a possibility that bipolar disorder is based on hyperactivity of endogenous DMT neurotransmission.
Is bipolar disorder really third eye disorder?
As a counter possibility, the D4 receptor causes a decrease in GABA which might have some implication for dynorphinergic transmission. It is also known that the D4 receptor is involved in novelty-seeking, which is in some sense chasing the state of awe on some level, where awe is really a state of profound novelty. Knowing that psychedelics decrease fear, even of death, it could make sense that D4 receptors somehow modulate endogenous DMT activity, either by the previously described endohuasca system or by downstream modulation of DMT release or maybe both. Many symptoms that are related to D4 receptors, such as impulse control issues and novelty-seeking seem like symptoms of bravery on some level, which seems very relevant to the effects found with 5HT2a agonists. Could it be, that 5HT2a agonists might upregulate D4 receptors or modulate them through the heteromer (D4-D2-5HT2a) systems, and that this is how dynorphins are reduced (if they are) by 5HT2a agonists?
Hypothesis 1: Some relationship between melatonin and dynorphin exists, and is implicated in the fear of the darkness. If you read my theory, Exploring Darkness: Theory of Creativity, it is even more interesting, as it binds a behavioral and pharmacological explanation for how risk-taking and novelty-seeking are the primary drivers for the development of creativity.
Hypothesis 2: The endohuasca system is triggered somehow in this chain of D4-D2-5HT2a-mGlu2 heteromers and elevates endogenous DMT levels to a degree that can produce enhanced awareness of surroundings that allows better survivability in unknown environments. Also, I theorize that psychedelics somehow decrease dynorphin, and could explain its efficacy in treating disorders linked to dynorphin, such as PTSD, or arguably, fear of death (studies in terminal patients). The increased risk-taking and thus novelty-seeking promotes the increase of openness to experience that is observed in psychedelic users, and the increased creativity commonly associated to psychedelics, bipolar disorder, schizophrenia, and ADHD. This study might reveal some evidence for the possibility that psychedelics (and perhaps SSRIs) may reduce dynorphin sensitivity via downregulation of serotonin or some similar mechanism.
Hypothesis 3: Since bipolar is linked to lunar cycles and circadian processing, I think the disorder may also be linked to geography, in terms of daylight hours, seasons, perhaps altitude as well. Further research here may help us find proper environmental intervention to increase the quality of life for those with bipolar disorder.
Hypothesis 4: Endogenous DMT hyperactivity is a possible mechanism for bipolar disorder.
If you enjoy the cover photo, I also filmed a music video in that room, for my song Above Awe, which very appropriately fits with this topic of psychedelics!
To Be Added
As a farewell note. . .
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