Most of this is taken straight from Psychedelics and Schizophrenia, but without much of the added bulk. The hope is that this can be the landing page for the dynorphin hypothesis of schizophrenia.

Schizophrenia appears to be a condition of extreme stress with issues in stress recovery, leading to an accumulation of negative consequences. There is evidence that extreme levels of stress may be hallucinogenic via Kappa Opioid Receptor (KOR) agonizing and NMDAr blocking mechanisms. It may be that anyone can suffer psychosis with enough prolonged stress and suffering while those with schizophrenia are more susceptible to the effects of stress, less able to recover, and there may even be genes that predispose someone to seek out stressful and nonconformist situations naturally. In this section we will look at the hallucinogenic stress mechanisms.

Dynorphin seems to be capable of binding many theories of schizophrenia together. Dynorphins are a family of endogenous opioids that primarily bind to kappa opioid receptors (KORs). This article will refer to this family of endogenous opioids as dynorphin, like this paper does. Dynorphin is involved in stress-induced dysphoria, anhedonia, anxiety, addiction, depressive and even psychotic effects. Dynorphin directly blocks NMDAr which would produce NMDAr hypoactivity, satisfying the glutamate hypothesis of schizophrenia. Chronically elevated dopamine is thought to play a role in schizophrenia and upregulates dynorphin, likely through interactions at D1 and NMDAr complexes. Dynorphin potentiates D2 receptors and reduces dopamine release, satisfying the dopamine hypothesis of schizophrenia. Dynorphin is implicated in trauma, explaining the association of schizophrenia with trauma. Dynorphin mediates the effects of social defeat stress and upregulates from early childhood social isolation, satisfying the social defeat theory of schizophrenia.


The link of social defeat and schizophrenia may represent how crucial social support is for dealing with symptoms of stress, potentially from any cause. If you are persecuted, it is likely an even worse stressor because not only can you not get social support, but you have social stress and offense. The severity of symptoms in schizophrenia correlated with a lack of friends. Frequent interactions with friends was found to be crucial to recovery in schizophrenia, more than the self-reported quality of friendships although this likely doesn’t mean that abusive friends are better than none. Reducing loneliness reduces paranoia while inducing loneliness increases paranoia. A genome-wide association study found coheritability of loneliness and schizophrenia. Those with schizophrenia often feel excluded due to stigma. Differences in status, social class and political views was found to generate paranoia. Experimentally induced social threat induced paranoia. It may be that social exclusion, otherness, loneliness are all very stressful and hindering to stress recovery. The picture of social defeat may often begin with interest in the taboo and social deviance, which is found to occur before any psychotic symptoms in schizophrenics. Then as stigma and social exclusion sets in, symptoms get worse, perpetuating further exclusion. Socializing may be key to treating our stresses in life and for those who lack a social support system, they may be unable to recover and cope. Lacking a social support system may be one of the worst possible stressors when living in a society of humans.

Solitary confinement produces many schizophrenic symptoms in prisoners, including hallucinations, ideas of reference, persecutory delusions, and more. It seems likely that psychotic effects could emerge in anyone who is in an extremely aversive and helpless environmental condition, such as solitary confinement or torture, but those who are born with some set of genes linked to schizophrenia are more sensitive to aversive and helpless scenarios, or even more likely to find themselves in aversive and helpless living situations. This is further supported by the association found between low socioeconomic status and schizophrenia. Those with low socioeconomic status will be more likely to experience harsher living conditions, stress, and helplessness. One might wonder if solitary confinement in prison is at least a more predictable living situation than isolation in the outside world. Those living in solitary confinement would sit without obligations or tasks to complete, without the fears of one’s live collapsing since it already has. Living in isolated conditions in the real world may still come with the obligations of paying rent, dealing with potential social threats, many stressors, fears of homelessness and life collapse.

Another genome-wide association study found strong evidence of genetic overlap between PTSD and schizophrenia. This supports the idea that individuals with schizophrenia are born with a higher sensitivity to stress.

A genome-wide association study found extensive overlap with gene loci associated with poor cognitive performance and schizophrenia. Low IQ also correlates with schizophrenia and dynorphin may be able to help explain this. Microinjections of dynorphin into the hippocampus produced spatial memory deficits. Individuals with schizophrenia also face spatial memory deficits. Dynorphin levels rise with aging and spatial memory declines with aging. Knocking out dynorphin prevents age-related cognitive decline. Alcohol-related memory and learning impairment is mediated by dynorphin upregulation. Stress-induced deficits in learning and memory are mediated by dynorphin. Occlusal disharmony, a painful condition, also involved memory and learning impairments mediated by dynorphin, which could be due to a role that dynorphin may play in pain aversion.

Speaking of pain, dynorphin plays a role in PTSD which is also linked to low IQ. The linked research on PTSD and IQ has noted that premorbid IQ being lower also made PTSD worse, but this may be due to early life stress or that prior trauma is limiting IQ and even promoting more severe stress reactions in adulthood. For example, it was found that exposure to domestic violence suppressed IQ. Prior trauma is a risk factor for experiencing further trauma. So it seems likely that prior trauma and stress may be at play here with premorbid IQ scores. This article explores research showing up to a 14 point IQ difference based on stress

On top of all of that, social exclusion was found to drastically decrease IQ (25%) and reasoning ability (30%) in the short term. This is important as social defeat stress is mediated by dynorphin. The low IQs found in schizophrenics might be explained by chronic rejection for being socially deviant.

Psychosis and dynorphin have been explored very lightly in the research so far. Kappa Opioid Receptor (KOR) agonists like dynorphin produce psychosis in healthy humans. It is thought that dynorphin releases during seizures to curb overactive glutamate activity, but also induces a psychosis post-seizure. Receptor complexes of dopamine D1 and D2 localize on dynorphin neurons in schizophrenia and meth users. Dynorphin levels were found to be increased in the cerebral spinal fluid of schizophrenics and correlated with their psychotic symptom severity. Stimulants like cocaine, amphetamine, and nicotine upregulate dynorphin activity which could explain related psychotic symptoms such as stimulant psychosis. There is something known as ‘coke bugs‘ which is formication, an effect that dynorphin injections were found to produce in 1 out of 4 people.

Exogenous KOR agonists have shown psychosis inducing effects. A quote from this study,

The inhalation of vaporized salvinorin-A led to very strong psychotropic effects of rapid onset and short duration. Perceptual modifications included the visual domain, and in contrast with 5HT2A agonists, auditory hallucinations were very common. Also in contrast with the classical serotonergic psychedelics, loss of contact with external reality was prominent with the participants being unreactive to external visual and verbal cues, especially after the medium and high doses. While at the low and medium doses there was an increase in bodily sensations, at 1.0mg there was an almost complete loss of body ownership and an increase in out-of-body experiences. These results suggest that the dynorphins – KOR system may play a previously underestimated role in the regulation of sensory perception, interoception, and the sense of body ownership in humans.

This study is great because it distinguishes the dynorphin-like psychotic effects such as hearing voices from serotonergic psychedelic states, which don’t often contain auditory voice hallucinations.

To recap, dynorphin is a KOR agonist similar to the drug Salvia Divinorum. It is essentially the body’s endogenous Salvia. This means social defeat and even stress, in general, should promote salvia-like hallucinogenic and psychotic effects. Those with genes related to schizophrenia likely have a natural sensitivity to stress, a decreased ability to recover from stress, a higher likelihood of living stressful lifestyles or engaging in potentially socially defeating behaviors.

Neurogenesis and Plasticity

Neurogenesis is the process of neuron birth. Neuroplasticity is the ability to reorganize synaptic connections, especially in response to learning. Neurogenesis in adults takes place primarily in the hippocampus and dentate gyrus. Individuals with schizophrenia have impaired neurogenesis and neuroplasticity. Impaired neurogenesis and stress were found to differentially lead to reduced hippocampal volume. Hippocampal volume was found to be reduced in schizophrenic and schizoaffective individuals but not bipolar 1 individuals. Neurogenesis is enhanced by Long Term Potentiation (LTP) which relies on NMDAr function. There is evidence that schizophrenics have impaired LTP, likely mediated by NMDAr hypofunction. It is thought that this hypofunction of NMDAr seen in schizophrenia may explain the reduced neurogenesis. The NMDA receptor also plays a critical role in plasticity, so hypofunction of these receptors could also explain the reduced plasticity seen in schizophrenia.

Stress was found to reduce neurogenesis which might involve dynorphin, since it is implicated in stress reactions. Blocking dynorphin may lead to stress resilience and functions as a rapid-acting and pronounced antipsychotic. Dynorphin reduces LTP and reduces excitatory signaling in the hippocampus and also the dentate gyrus, likely at least partly explaining the stress-linked reduction of hippocampal volume. Chronic opiate use both upregulates dynorphin activity and inhibits neurogenesis. It isn’t clear that dynorphin inhibits neurogenesis itself, but it seems likely due to the above research. Some studies mention a hypothesis that dynorphin increases neuroplasticity. Addiction may certainly involve dynorphin upregulation, neuroplasticity, learning and LTP, but it also involves so many different mechanisms and fluctuations due to repeated dosing and withdrawals.

It is thought that increasing neuroplasticity may have potential in treating schizophrenia. Theanine is an NMDAr partial agonist that was found to function as an antipsychotic and also enhances neurogenesis

Glycine Switch

This mechanism is less well understood but is likely a crucial part of understanding what conditions influence the hallucinogenic effects of dynorphin. NMDAr has a glycine subsite which is a necessary cofactor for NMDAr stimulation. Glutamate can bind NMDAr if glycine is occupying the subsite receptor.

Dynorphin binds not only to the main receptor site of NMDAr as an antagonist, but also appears to bind on the glycine subsite of NMDAr. Normally binding at the glycine subsite allows glutamate binding at NMDAr. When extracellular levels of glycine are low, dynorphin seems to replace glycine’s function, potentiating NMDAr activity. This suggests that dynorphin’s NMDAr blocking effects occur when glycine subsites are occupied either by glycine or dynorphin. When glycine is low, much of the dynorphin may be replacing glycine’s function. It could be that very high levels of dynorphin leads to the occupation of both the glycine subsite and the NMDAr main site by dynorphin, while when glycine levels are high, dynorphin occupies mostly the NMDAr site. If glycine levels are low, dynorphin probably functions as both NMDAr enhancer and antagonist, but primarily an enhancer at first. 

Dynorphin may differentially produce dissociative or pain-sensitizing effects depending on extracellular glycine levels. If NMDAr activity is potentiated we should expect increased pain and excitotoxic effects. It may be that schizophrenics experience both of these depending on their glycinergic tone.

This becomes important in the KYNA section, but first we must understand the connection to:


Psychedelic drugs induce neurogenesis in the hippocampus, a region that has reduced volume in individuals with schizophrenia. Serotonin is also able to induce neurogenesis. Psychedelics promote structural and functional neuroplasticity, which, as previously mentioned, is impaired in schizophrenia

LSD was found to attenuate the depressive effects of dynorphin/KOR agonism. On the other hand, a 5HT2a inverse agonist (opposite of agonist) were found to potentiate KOR signaling. 5HT2a receptor agonism was found to inhibit aversion in the DPAG, a region of the brain in which KORs are located and PTSD is implicated in. CBD was found to have antipsychotic properties and is a 5HT2a agonist and thought to reduce aversion in the DPAG as well. Psychedelics have also recently been considered as treatment for PTSD.

Dynorphin has been implicated in depression. As mentioned before: a single large dose of psilocybin produced long-lasting (6 months+) strong decreases in depression in 80% of patients who were dying of terminal illness. In another study on psilocybin for depression, all patients showed benefits at 1 week after the dose, and many of them showed benefits many weeks later. The fMRI scans revealed that reduced blood flow to the amygdala induced by psilocybin correlated with reduced depressive symptoms. Dynorphin is known to control the gain on an amygdalar anxiety circuit, which further implies an interruption of dynorphin. On top of that, dynorphin plays a major role in addiction and psilocybin was able to get 80% of long-term smokers off of nicotine using only a single dose. A 2018 study found that psilocybin even reduces the pain of social exclusion which has implications for the connection of dynorphin, social defeat, and schizophrenia. All of this together suggests that psychedelics may interact with dynorphin, reducing its’ mechanisms and effects. 

Dynorphin and psychedelics relate to fear extinction. Fear extinction is impaired in schizophrenics. During fear extinction, KOR mRNA is found to be dramatically downregulated while fear conditioning shows a dramatic upregulation of KOR mRNA. Blocking dynorphin/KOR was found to block conditioned fear. DMT microdosing in mice was found to enhance fear extinction. Low doses of psilocybin were found to increase neurogenesis and enhance fear extinction. High doses appear to do the opposite. D-cycloserine was found to facilitate fear extinction and is studied for treatment of schizophrenia. There are studies on psychedelics (MDMA) exploring fear extinction in relevance to PTSD, which involves altered fear extinction like schizophrenia. During fear recognition tasks that measure amygdala response, schizophrenics show hyperactivation of the amygdala to both fearful and even neutral faces while with LSD users there is a reduced response of the amygdala.

This altered fear extinction brings us back to the idea that individuals with schizophrenia may be less capable of recovering from stressful events, leading to an accumulation of negative effects. It seems that serotonin and dynorphin function with opposing and interconnecting roles in resilience and stress. This interaction relationship between dynorphin and serotonin seems to occur at p38 MAPK, KOR signaling induces the serotonin transporter (SERT) to reuptake serotonin, producing a hypo-serotonergic state. This induction of SERT was necessary for dynorphin to produce some of its effects which may be due to the anti-dynorphin/KOR effects of 5HT2a receptors. Blocking SERT is known to produce stress resilience. The removal of p38 MAPK on serotonergic neurons also produces stress resilience, likely by disrupting dynorphin. Blocking dynorphin directly leads to stress resilience as well. Serotonin itself is known to downregulate SERT, so when dynorphin levels are high its’ induction of SERT will lower extracellular serotonin levels and prevent SERT from downregulating. This should be expected to perpetuate a stressed tone, until something else either decreases the stressful trigger or increase serotonin levels and disrupt the low serotonin tone. Repeated doses of the KOR agonist, Salvia, were also found to upregulate SERT. Schizophrenics also appear to have increased SERT levels. Ultimately, a pattern of low serotonin activity and high dynorphin activity seems to be consistent. It may be that disruption of KOR mediated effects invoked by psychedelics stops this loop in which SERT is induced, thus allowing serotonin to accumulate again and restore a resilient state of mind.


In recent years, a novel kynurenic acid hypothesis of schizophrenia emerged after it was discovered that schizophrenics have elevated kynurenic acid in their CSF. Like dynorphin, stress-induces a rises in KYNA. Kynurenic acid (KYNA) is a metabolite of L-tryptophan that blocks NMDAr, AMPAr, and Kainate glutamate receptors, and also blocks the glycine site of NMDAr. This has special implications for the dynorphin glycine switch because, by blocking the glycine site of NMDAr, it means glutamate cannot bind the NMDAr and glycine is not being utilized. This may displace other glycine molecules which then creates an environment of high extracellular glycine, in which dynorphin is more likely to act directly on NMDAr as an antagonist, rather than replacing glycine’s role in enhancing glutamate binding on the NMDAr. KYNAs other mechanisms are to block glutamate activity as well, functioning as another endogenous dissociative-like mechanism to stack with dynorphin’s dissociative hallucinogenic effects.

This also connects the strange association of niacin and schizophrenia, since niacin is a precursor to L-tryptophan. In some cases niacin has functioned as an effective treatment for schizophrenia. Psychosis is also a symptom of niacin deficiency. A study found that a lack of niacin flush is an indicator of schizophrenia, the same results were found in a second study as well. A more recent 2016 study noted that this attenuated response to niacin was dependent on the phase of schizophrenic, as ultra high-risk for psychosis patients had an exaggerated flush response. Delusional parasitosis and formication has been effectively and rapidly treated by niacin in the past.

Since L-tryptophan is a precursor to serotonin synthesis, KYNA hyper-production may be a product of a failure to synthesize serotonin, or that serotonin synthesis is turned off because of frequent reuptake induced by dynorphin.

Why might KYNA synthesis increase?

L-tryptophan has two pathways to metabolize, either the one leading to serotonin and melatonin, or the one leading to KYNA. Toxoplasmosis has been implicated in schizophrenia and was found to involve the secretion of an enzyme that leads to the degradation of tryptophan towards the KYNA pathway and away from the serotonin pathway, leading to a decrease in serotonin and increase in KYNA. Below is an example of the metabolic pathway taken from this paper. If it’s confusing, don’t worry just trekk on.


KYNA has also been linked to ketogenic diets, where increased levels of KYNA occur. This is significant because ketosis is considered a starvation state. There is evidence that ancestral famine leads to higher occurrence of schizophrenia in later generations. Ketosis is also associated with diabetes, which is associated to schizophrenia as well. Dynorphin levels are found to be increased in diabetes. Since serotonin suppresses hunger and regulates feeding and dynorphin induces hunger, there may be an adaptation that occurs to prevent rising serotonin levels by interrupting the metabolic pathway of L-tryptophan to serotonin, instead favoring the KYNA pathway to dominate. This would keep one in a state of starvation and hunger, leading to seeking out extra food and surviving better than others during a famine. In this sense, some cases of schizophrenia may be a state similar to a perpetual starvation mindset.

This is further supported by the association of hibernation, feeding, and dynorphin. It could be that this starvation mechanism functions to induce hibernation eating patterns of storing food for the winter, which might be a natural recurring famine period in historic times. Protein consumption may be able to inhibit KYNA production, likely being one of the mediators that distinguishes the KYNA-serotonin pathway fork and functioning as a starvation switch. Individuals with schizophrenia also have higher BMI on average, which supports this famine hypothesis. Some of this ties into the recent post I did titled Junky Minds where you can read about how junk food may reduce our cognitive ability through dynorphinergic mechanisms.

KYNA also might antagonize nAch7 receptors which has been shown to induce dynorphin release. The nAch7 receptors have been implicated in schizophrenia as well. The activation of these receptors is linked to a decrease in dynorphin release, suggesting that impairment of these receptors would disinhibit dynorphin release. Therefore KYNA may enhance dynorphin release by inhibiting nAch7 receptors.

KYNA may aide in binding the glycine switch and dynorphin parts of this hypothesis and also adds another stressor like sleep deprivation, may induce psychosis as well. Dietary, social, and/or sleep problems may begin one’s trend towards psychosis.

Dietary Influence

Relevant clips from Junky Mind:

A Plos One paper discusses the role that serotonin plays a role in insulin excretion from the pancreas. The authors note that diabetes occurs in the absence of serotonin. Because dynorphin has anti-serotonergic effects through inducing reuptake of serotonin, it seems likely that the rapid induction insulin-resistance due to pain and stress may be related to dynorphin, which is also implicated in both pain and stress aversion. In relation to schizophrenia, this could mean that pain and stress begin the loop of bad eating.

Dynorphin is further connected to dietary patterns through the orexin system, which regulates feeding behavior and energy balance. Dynorphin was found to induce feeding, putting a physiological touch to the notion of stress-eating. On the contrary, serotonin decreases hunger and is also implicated in energy balance. In regards to energy balance, this may be related to the role that dynorphin plays in depression, while serotonin seems capable of inducing mania, again, on the contrary. This fits within the hibernation and starvation KYNA hypothesis.

On the other hand, carbohydrate consumption is shown to mediate how much serotonin is released from neurons, how much serotonin synthesizes and induces a satiety effect. The paper notes that, unlike carbohydrates and proteins, fats are not associated with the production of any neurotransmitters, though this study was from 1995. Serotonin activation in the hypothalamus was found to reduce the consumption of fatty foods. Low fat and high carbohydrate diets have shown efficacy in reversing type II diabetes. On the other hand, the high-fat ketogenic diet has been associated to insulin resistance, even while increasing energy expenditure and not leading to weight gain. Since ketogenic diets are low carb diets, they may limit serotonin synthesis and promote rising KYNA levels. 

Despite this, ketogenic diets are being explored in treatment for schizophrenia, with seemingly good results. It may be that niacin deficiencies, low protein consumption, or junk food habits are resolved by the change in diet. There are cheese-derived and gluten-derived opioids that are thought to play a role in schizophrenia. Many paleo-style ketogenic diets recommend against dairy or bread consumption, so this may be a factor as well. PsychologyToday noted that ketones may be providing energy to insulin-resistant brain cells. It is also possible the change to a low-carb diet halts the supply of energy to gut microbiota that are linked to schizophrenia

One might consider how social factors play a role in junk food addiction. Social defeat stress was found to be mediated by dynorphin and linked to weight gain and increased food intake. Like cocaine addiction and stress, social defeat upregulates the serotonin transporter, likely partly due to dynorphin. Socially subordinated monkeys had increased vulnerability to addiction to cocaine compared to dominant monkeys. In the article Serotonism, we explored how serotonin is implicated in social hierarchy of many species, revealing further contrary patterns in dynorphin and serotonin research. Low social rank is thought to be a risk factor for diabetes as well

This further paints a picture of how general stress and bad experiences may accumulate and play together to manifest symptoms of schizophrenia. In this light, schizophrenia may be a low consciousness state that is focused on saving energy but also detecting potential threats, which paranoia may aide in. Major cities may be a hub for schizophrenia because of being such a place that requires constant higher consciousness while also being a very stressful place that slowly brings you into the depressive power-saver half-conscious state. Cities may also be a hub for junk food consumption among the poor.

The disorder may often begin to show up in the transition to adulthood because the individual loses their familial support such as money, resources, and general aide, while also gaining the freedom to stay up late at night, eat what they want, and live without rules to keep them in line. Many of the at-risk individuals may have already been living problematic lives with dwindling support from their families as they are given up on and left with less support. There are also toxic family dynamics that may occur, as I’ve described in Nexus.

Moving back to


Individuals with schizophrenia were found to have less functional 5HT2a receptors. A gene related to less 5HT2a receptors was linked to schizophrenia (warning: this is a candidate gene study). This receptor forms complexes with mGlur2, which is thought to be a key to the psychedelic effects. Another study showed reduced function of these psychedelic receptor complexes in post-mortem brains of schizophrenic patients. They also show reduced 5HT2 receptor binding in the prefrontal cortex. Since mGlur2 agonism enhances 5HT2a binding, the reduced binding of 5HT2a may be explained by the reduced number of mGlur2 that are seen in post mortem schizophrenics. With less mGlur2, 5HT2a receptors will be less enhanced. This could mean they have a lower ability to activate the 5HT2a/psychedelic mechanism, and thus a lower ability to attenuate dynorphin/KOR mediated effects.

In older studies this is backed up. Schizophrenics appear to be less sensitive to LSD and also showed reduced effects from DMT, experiencing a lack of visual effects at doses that worked in non-schizophrenics. Glycine-type drugs that can treat schizophrenia through NMDAr enhancement increase serotonin in the prefrontal cortex where 5HT2a receptors are. Another study found that low thalamocortical plasticity is modulated by dysfunctional 5HT2a receptors in schizophrenia. A major predictor of schizophrenia is low cognitive function. Individuals with schizophrenia also show impaired associative learning. Psychedelics were found to be cognitive enhancing and increase associative learning ability. 5HT2a receptor antagonists were able to reduce verbal memory and spatial memory in SSRI pretreated individuals. Taken together this could mean that the lower functioning of the 5HT2a receptors may allow un-attenuated dynorphin activity to disrupt cognitive function in schizophrenia, in similar ways that is seen with stress-related cognitive decline. Since psychedelics attenuate the effects of dynorphin/KOR, it might be that cognitive impairments related to dynorphin are also attenuated.

This would include aging, which I recently explored on a post about Alzheimer’s and Psychedelics. Curiously, the brains of schizophrenics were found to be 8 years older than their true age. Another study revealed mGlur2 loss to correlate with age, rather than schizophrenia diagnosis. 5HT2a receptors are also lost with age. Also, when dynorphin producing genes are removed from mice, age-related loss of mGlur1 was attenuated, along with age-related cognitive decline. Somehow dynorphin activity leads to the loss mGlur1 in aging, so perhaps dynorphin may be implicated in the loss of mGlur2 that is seen in aging as well. The loss of mGlur2 with aging would mean that 5HT2a binding decreases, allowing dynorphin’s effects to increase, in what seems to be a vicious cycle. This might provide a model for cognitive aging as a dynamic between serotonin, dynorphin, and glutamate. In the case of schizophrenia, it may explain some of the accelerated aging

A lot of research has focused on the idea that psychedelics are an axiomatic model for schizophrenia. Recent studies on schizophrenia that utilized an mGlur2 agonist drug failed phase 3 trials. This drug worked as an agonist of mGlur2 which is one of the receptors involved in the 5HT2a effect. The relationship here is that 5HT2a binding decreases mGlur2 binding which allows for increased glutamate release that is normally inhibited by mGlur2. This experimental drug functioned on the mGlur2 receptor in the opposite direction as psychedelics, enhancing the receptor rather than decreasing activity. This drug was found to correct some NMDAr antagonist mediated deficits in gamma oscillations but not restore NMDAr antagonist mediated cognitive function deficits. It was found that mGlur2 agonists prevent the neurotoxicity induced by NMDAr antagonists, but there is evidence that psychedelics also prevent the neurotoxicity associated with the typical NMDAr antagonists that model psychosis. A study found that mGlur2 binding causes enhanced dynorphin signaling, which means the experimental drug may also enhance dynorphin signaling. The dynorphin enhancement via mGlur2 agonism may also help explain how psychedelics attenuate dynorphin/KOR signaling and why 5HT2a inverse agonists enhance dynorphin/KOR signaling. It could be that this drug failed partly due to enhanced dynorphin activity but helped with certain symptoms by enhancing 5HT2a signaling, but also preventing some of the mechanisms of 5HT2a signaling by functioning in the opposite way.

Tolerance and receptor downregulation might be an issue. Short lasting psychedelics like DMT might produce less tolerance hypothetically, thus be preferred to longer lasting psychedelics like LSD. It was noticed that the later phase of LSD intoxication became more paranoid and seemingly psychotic which led to research show that chronic LSD use may be a model for psychosis. In this study, they mentioned changes to gene expression as an explanation. An alternate explanation could be that 5HT2a binding is reduced. Chronic administration of LSD was found to reduce 5HT2a binding in the brain and produce tolerance to the effects, which is a pattern seen in schizophrenics, both reduced binding and less sensitivity to the psychedelic effects. It was found that both acute and chronic dosing of LSD produced increases of serotonin levels. This increased serotonin activity may be able to downregulate the serotonin transporter, thus reducing the ability of dynorphin to exert effects and allow a higher tendency towards increased serotonin tone in general. In a way, it may reverse the sensitivity to stress and enhance a tendency towards resilience. Chronic use of psychedelics might produce a withdrawal like state, leading to enhanced dynorphin signaling, which may worsen problems. Use of DMT infrequently might be able to avoid some of these problems due to its short duration.

All of this taken together suggests psychedelics may be able to treat schizophrenia by disrupting psychotomimetic KOR signaling. It isn’t clear if frequent dosing would be required or, if like depression, a single dose might show lasting effects. I suspect that it will be a matter of stress exposure as the psychedelic system of mechanisms may help in resilience and adaptation. The next thing we should do is look for those diagnosed as schizophrenic who have had experience with psychedelics and do not use cannabis or hopefully any other drugs. 

Lastly, I’d like to thank Mr. Nobody (username) from the discord server for helping to collect sources in our database and discussing some of these ideas. Another special thanks to the two patrons, Abhishaike Mahajan and Charles Wright! Abhi is also the artist who created the cover image for Most Relevant. Please support him on instagram, he is an amazing artist!

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A 2020 study found further evidence of this hypothesis, namely, KOR plays a key role in the symptomology of schizophrenia, including the cognitive dysfunction.

One thought on “Dynorphin Theory

  1. I’ve noticed this pattern in my life that whenever I take psychedelics recreationally my depression is lifted for one or two months and I become stress resilent. The first and second time it happened I thought that I was cured “forever”, but I’ve since realized that it always creeps back in. This week I’ve taken LSD for the first time with the primary intent of treating my recent descent into chronic stress and suicidal ideation. It worked better than I expected it to, even though the dose was low (around 40 micrograms). So according to your theory my depression could be related elevated dynorphin. I wonder if doing this consistently could be a sustainable way to manage mood.

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