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.
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.
The next step to understanding this would be to explore what environmental conditions and endogenous mechanisms influence extracellular glycine levels. It is also worth noting that regardless of the direction of influence on NMDAr, dynorphin still reduces glutamate release through separate mechanisms which may still have antiglutamatergic effects.
Psychedelic drugs induce neurogenesis in the hippocampus, a region that has reduced volume in individuals with schizophrenia. Serotonin also is able to induce neurogenesis. Psychedelics also 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 well. 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.
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.
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