A hypothesis of schizophrenia is presented that proposes a psychopharmacological model as an addition to the diathesis-stress model. The opioid peptide dynorphin may help bridge together various hypotheses of schizophrenia. The dopamine, glutamate, serotonin, and social defeat hypotheses of schizophrenia are explored. Mechanisms underlying hallucinogenesis and stress overlap, specifically in the opioid system. A psycho-bio-social model for stress-induced psychotic symptoms is explored. As stress impacts one’s affect, amplified salience for affect-congruent memories and perceptions may factor into the development of aberrant perceptions and beliefs. As another mechanism, stress-induced dissociation from important memories about the world that are used to build a worldview may lead one to form conclusions that contradict the missing memories/information.
Later comparisons and contrasts are made with classical psychedelics and THC. Psychedelic mechanisms are explored in relation to this model, notably with clarifications whether they may or may not produce states that mimic endogenous schizophrenic states.
One of the older theories of mental health is one known as the diathesis-stress model. Its’ basic premise is that increased stress and increased vulnerability to stress through genetics (and probably prior experiences) can manifest in mental health problems. The endogenous opioid system may be involved in determining the valence of experiences, from euphoria, to the dysphoria of stress. Most interestingly, one of the most potent hallucinogens to have ever been found in nature is predominantly an opioid agonist. Specifically, Salvia Divinorum contains salvinorin A which is a kappa opioid receptor (KOR) agonist and powerful hallucinogen. The kappa-opioid receptor system is implicated in the stress response and many of the KOR agonists induce very many symptoms of common mental health problems. Dynorphin is the endogenous agent that binds to the KOR system and may help in connecting pharmacology to the diathesis-stress model. At the deep end of the stress response may reside the psychotic state, dissociation, and eventually hallucinogenesis.
The dynorphins are a group of opioid neuropeptides that are like endorphins but in some sense opposite. Instead of producing effects like euphoria and reinforcement of reward (Roth-Deri, Green-Sadan, & Yadid 2008), the dynorphins induce effects like dysphoria and aversion conditioning (Land et al 2008; Al-Hasani et al 2015). While endorphins predominantly interact with the mu-opioid receptor (MOR) system, the dynorphins interact predominantly with the kappa-opioid receptor (KOR) system. If endorphins are seen as a rewarding mechanism, the dynorphins can be viewed as a punishment (aversion) mechanism. Dynorphins seem to be a key component of the dysphoric component of stress and possibly even pain (Land et al 2008; Massaly et al 2019). Expectedly, the dynorphins seem to play a role in many dysphoric and stressful mental health problems including depression, anxiety, drug withdrawals, PTSD, and schizophrenia (Tejeda & Bonci 2019; Knoll & Carlezon 2010; Crowley et al 2016; Chavkin & Koob 2016; Rabellino et al 2018; Clark & Abi-Dargham 2019). The dynorphins seem to play a major endogenous role in fear conditioning and avoidance behaviors (Knoll et al 2011; Donahue et al 2015).
Drugs that stimulate the KOR system are rarely used in medicine due to inducing many problematic effects such as psychosis, anxiety, dysphoria, depression, and hallucinations (White & Roth 2012; Coursey 1978). The infamous hallucinogen Salvia Divinorum appears to work through KOR agonism as its’ main mechanism (Butelman & Kreek, 2015). Many other KOR agonists are hallucinogenic as well, such as ketazocine and pentazocine, which has limited their use in medicine (White & Roth, 2012; Morris & Wallach, 2014; Coursey, 1978). Ketamine also stimulates this system, although it is not its’ main mechanism (Nemeth et al., 2010). It is even thought that acute KOR agonism and subsequent KOR desensitization are required for ketamine’s protracted antidepressant effects (Jacobson et al., 2020). On the other hand, KOR antagonists are found to be euphoric and antidepressant acutely (Jacobson, Browne, & Lucki, 2020). While KOR agonists may have some potential uses in the treatment of psychiatric problems, they often haven’t been favored in medical use due to their depressive and psychosis-like effects.
Schizophrenia is a condition characterized by episodes of positive (hallucinations, delusions, paranoia) and negative symptoms (anhedonia, cognitive problems, memory issues). There is evidence that dynorphin may be useful to understanding schizophrenia. Dynorphin A was found to be elevated in the cerebrospinal fluid of schizophrenics and the levels of dynorphin A correlated with symptom severity (Heikkilä, Rimón, & Ternius, 1990). A newer study found elevated serum KORs in schizophrenia which associated to all symptom dimensions (Moustafa et al., 2020). It is worth noting that another study found decreased dynorphin (1–8) (D 1–8) in the CSF of schizophrenics (Zhang et al., 1985). This might suggest a role for specific types of dynorphin in schizophrenia.
The proposed role of dynorphin/KOR in schizophrenia may be region-dependent, specifically, regions that are hyperdopaminergic in schizophrenia may also show elevated dynorphin/KORs. Another consideration is that there are differential mechanisms that converge on schizophrenic symptoms. Such regional specificity of increased KORs has been observed in a post-mortem study on cocaine overdose cases. The researchers observed double the KORs in the striatum of cocaine overdose victims (Mash & Staley, 1999). Most interestingly, they also observed that those who had delirious effects had elevated KORs in the amygdala. Since cocaine has been observed to induce psychotic symptoms (Tang, Martin, & Cotes, 2014), this is of particular interest. In this article, most focus is on the potential role of striatal and amygdalar dynorphin/KORs in cases of schizophrenia, although other regions are touched upon as well.
DELUSION AND HALLUCINATION
Delusions may be partly mediated by the effects of affect on cognition. Specifically, one’s affect may amplify the salience of affect-congruent memories and perceptions. Reward processing is impaired in schizophrenia, with an observed diminished reward processing and intact aversion processing (Cheng et al., 2012; Strauss, Waltz, & Gold, 2014). Individuals with schizophrenia also appear to have a decreased density and availability of mu-opioid receptors (MORs), a receptor-type involved in reward processing (Ashok et al., 2019). This may suggest that dynorphin/KOR agonist signaling is functional, but not MOR agonist signaling, ultimately biasing perceptions towards aversive processing and interpretation, causing one to view the world through a lens of fear, pain, and threat. The negative affective state may induce memory biases that filter judgment towards threatening conclusions and paranoia (Lepage et al. 2007). Paranoia induced by cannabis appears to be “fully accounted for” by the negative affective state (Freeman et al, 2015), which is thought to be mediated by kappa-opioid receptor activity (Ghozland et al., 2002; Zimmer et al., 2001). In later sections, THC is explored. The negative affective state may bias recall of memories and cause one to form conclusions that are biased and absent of information that is key to non-delusional judgment. Dynorphin may play a role in this affect-mediated cognitive process via its’ role in dysphoria.
The striatum seems to be implicated in delusional and hallucinogenic processes. In a small study, the ventral striatum was found to have increased activity in those experiencing active delusions (Raij et al., 2018). The study found that dopamine activity in the striatum plays a role in the delusional process, which the authors argue is related to altered salience of stimuli. This altered salience of stimuli may be similar to the altered access to episodic memory during affective states, which is arguably a form of altered memory salience. Again, it may be that affect produces self-congruent amplifications of salience. In other words, a negative affect may enhance the salience of negatively affective memories and perceptions. An individual who feels threatened may look at the world with a confirmation bias to discover relevant threatening aspects of the world.
Hallucinations may stem from the impact of belief on perception and affect may mediate the strength of belief by promoting the development of delusions through the processes previously outlined. One study found that increased expectations during uncertainty were associated to hallucinations (Cassidy et al., 2018). The authors also found that this was linked to striatal dopamine.
Delusions and hallucinations may be conditioned and involve mechanisms in the striatum and amygdala. Some research has found that auditory hallucinations can be conditioned (Powers, Mathys, & Corlett, 2017). The striatum is involved in conditioning (O’Doherty et al., 2004), so it may be that the salience of stimuli or memories are conditioned by prior experiences and our beliefs. More arousing or strongly valent experiences or beliefs may alter the conditioning of salience. The amygdala plays a role in arousal and valence (Anders et al., 2008) and has been linked to incentive saliency which the authors argued to involve opioid mechanisms (specifically mu-opioid receptors in this particular study) (Mahler & Berridge, 2012). Since KORs exist in the amygdala (Tejeda et al., 2015) and KORs/dynorphin play a role in fear processing and conditioning, KORs may similarly play a role in incentive saliency processes in the amygdala like MORs seem to. These processes may play a role in conditioned saliency and perceptual memory biases that may help explain delusions and hallucinations in schizophrenia.
Dissociation is often experienced by those with schizophrenia. Dissociation could be defined as subtraction of subjective experience (or potentially also function). This may occur as a muting of components of subjective experience on a particulate level (perceptions, empathy, feelings, sense of self, etc.). It is thought that trauma can induce dissociative disorders (Lanius et al., 2018). This may be because of the way attention to some stimuli are essentially “punished” by the traumatic experience. Attendance to empathy or certain feelings may cause suffering and escaping this may be protective to one’s feelings. One could also dissociate from external stimuli and become withdrawn into their imagination.
It is important to note that this idea is separate from affect-congruent saliency of stimuli. In this case, it may be that we turn away from certain kinds of undesirable stimuli because we are rewarded or negatively reinforced to do so.
Dynorphin could play a role in endogenous dissociative states, considering that salvinorin A, a dynorphin agonist, produces dissociative states. A recent review paper has explored evidence that dynorphin is a mechanism for trauma-induced dissociation (Lanius et al., 2018). Those with the dissociative disorder known as depersonalization have muted salience for emotional stimuli (Medford et al., 2006). Since dynorphin plays a role in aversion/fear conditioning, it may be involved in conditioned/learned dissociation from extreme stress. Specifically, dynorphin may be implicated in avoidance of attendance to aversive stimuli and may be negatively reinforcing due to the relief that non-attendance provides in the stressful situation. In the case of depersonalization, an individual may learn how to mute the emotional components of stimuli as a way to reduce stress.
KOR agonism may suppress the salience of memories. Salvinorin A seems to cause a suppression of memory for one’s life during the experience. People often forget that they consumed a drug, forget who they are, and even that they are human. Salvinorin A might indiscriminately target KOR neurons, while endogenous dynorphin might target specific neurons based on contexts. For example, memory suppression that seems to occur from traumatic events might be a highly selective form of dissociation, meanwhile salvinorin A might suppress memories indiscriminately. It is possible that certain endogenous conditions cause dynorphin release that is poorly discriminate. This may be especially the case if one becomes hypersensitive to stress, which is explored in the diathesis stress kindling section later.
This memory suppression could change how we form conclusions about reality, as if we forget to account for information that we should be aware of. For example, the trauma victim may conclude that they have not been abused, when in fact they have. This may set the stage for delusional belief formation.
Another thing to consider is that individuals may develop tolerance to the subjective feeling of stress or dysphoria, while still maintaining their effects on the salience of memories or perceptions. In this sense, one may not subjectively notice their affect but it may still influence their perception and cognition. Chronic dysphoria may result in mostly behavioral effects such as the flat affect, anhedonia, and altered perception/thinking. I suspect that the subjective noticing of dysphoria is most prominent during the initial transition to the feeling, after which a tolerance to the subjective feeling of the affect develops and one loses the ability to notice their affect.
There have been a multitude of biopsychological hypotheses of schizophrenia over the years. This section explores the unification of the dopamine, glutamate, serotonin, and KOR hypotheses of schizophrenia. In the later sections, research on the diathesis stress model, social stress, drug-associated psychosis, and seizure-induced psychosis is explored.
The KOR antagonist buprenorphine was found to be acutely and potently antipsychotic in un-medicated psychotic subjects, with effects lasting about 4 hours before the psychotic symptoms returned (Schmauss, Yassouridis, & Emrich, 1987). Other KOR antagonists like naloxone and naltrexone have also been explored with some beneficial effects (Clark, Van Snellenberg, Lawson, & Abi-Dargham, 2020), though I would suggest that MOR antagonism may be pro-psychotic as well, since there is an observed decrease in the rates of schizophrenia among users of MOR agonists (Chiappelli, Chen, Hackman, & Hong, 2018) and due to the nature of the MOR system having almost diametrically opposed effects to the KOR system (Pan, 1998). Furthermore, KOR agonists are popularly known to be hallucinogenic (White & Roth, 2012; Morris & Wallach, 2014; Coursey, 1978) and produce some of the negative symptoms of schizophrenia, such as anhedonia (Tejeda & Bonci, 2019). Dynorphin has been experimentally tested as a treatment for heroin addiction in humans, in which 25% of the participants experienced crawling hallucinations known as formication (Wen & Ho, 1982). This is interesting because the authors were not exactly testing to see if dynorphin would produce hallucinations, in fact they would hope it doesn’t because this could be a hindrance to the therapeutic potential of their experimental treatment for addiction.
It is important to consider that, even if endogenous schizophrenic symptoms are mediated by KOR agonism, using KOR agonists as an experimental animal model may not be sufficient. This is because endogenous KOR agonism is not arbitrarily stimulated, but instead is part of a larger context and cause-and-effect stream. As we will explore in the following sections, dopamine, glutamate, and other neurotransmitter activity may be an earlier step in the process and also contribute to the symptomology of schizophrenia too. KOR agonism alone may only partially mimic certain aspects of schizophrenia and be missing other more causal elements that alter the experience. In that sense, KOR agonism alone may produce an extracted or purified set of symptoms that aren’t character of the cocktail of symptoms and mechanisms implicated in endogenous schizophrenic states. As an example, later we will explore how stimulants may produce KOR-mediated hallucinations and psychotic effects, but obviously the subjective effects of stimulants differ greatly from those of salvinorin A. Individuals with schizophrenia are likely living a life that contains some or many of the things that can potentiate KOR-mediated hallucinations, which also produce many other effects than pure salvinorin A alone would. It is likely that a dopamine-induced KOR-mediated hallucinatory state is subjectively different than a simple KOR-mediated hallucinatory state.
Stimulant drugs are known to produce psychotic effects, often with repeated use rather than acutely, except in those who have been previously sensitized or have already experienced psychotic effects in the past (Grant et al., 2012; Ujike, 2002). This has helped to contribute to the dopamine hypothesis of schizophrenia along with dopamine receptor antagonists, known as antipsychotic drugs. Stimulant drugs like amphetamine or cocaine commonly work by stimulating dopamine activity. One dopamine receptor of particular interest is the D1 receptor, which actually stimulates dynorphin increases in the striatum (Solís et al 2021; Hanson et al., 1995; Steiner & Gerfen, 1995). Cocaine, alcohol, nicotine, methamphetamine, and morphine all produce an increase of dynorphin in the striatum after use (Shippenberg, Zapata, & Chefer, 2007; Isola et al 2009; Hanson et al 1988; Nylander et al 1995). Dynorphin is often used to explain the withdrawal symptoms of drugs as well as playing a crucial role in the development of addictions (Bruijnzeel, 2009; Chavkin & Koob, 2016). This connection of dopamine to KOR activity provides a possible mechanism for stimulant-induced psychotic effects, which usually don’t show up on the immediate effect of the drug (except in those previously sensitized), but often after repeated use (Grant et al., 2012; Ujike, 2002). Meanwhile, KOR agonists are acutely psychotic and hallucinogenic.
The dopamine hypothesis of schizophrenia often focuses on D2 receptor hyperactivity and KOR agonism can potentiate the effects of D2 receptor agonism (Escobar et al., 2017). This may help to explain how D2 receptor hyperactivity becomes prominent in schizophrenics. In animals, knockout of D2 receptors prevents the rise in dynorphin in the striatum induced by D1 receptor stimulation (Solís et al 2021). D1 and D2 heteromers localize in dynorphin dense neurons in the striatum. The formation of these heteromer complexes between D1 and D2 in dynorphin neurons is promoted by amphetamine and exists in an elevated state in schizophrenics as well (Perreault et al 2010). It isn’t clear how, but this indicates that D2 receptor activity may somehow facilitate this dynorphin release. It may be the co-agonism of D1 and D2 simultaneously that induces dynorphin release, although this is something that warrants further exploration.
KOR agonism in the striatum may help explain how hallucinations occur in schizophrenia. Dopamine in the striatum has been implicated in hallucinations (Schmack et al., 2021; Cassidy et al., 2018). Dopamine-mediated hallucinations may occur via dopamine-induced dynorphin activity, possibly via the upregulation of these D1-D2 heteromers on dynorphinergic neurons in the striatum. Since stimulants often seem to require some kind of sensitization process in order to induce hallucinations and dynorphin agonist drugs produce strong hallucinogenic effects acutely, the hallucinations caused by dopamine might be related to dynorphin instead. During periods where dopamine activity peaks strongly, we may observe a consequential peak of dynorphin activity that is strong enough to produce positive symptoms like hallucinations and delusions. When this dopamine activity declines, dynorphin activity may also subsequently dip, but still produce negative symptoms like anhedonia, due to excessively diminished dopamine activity, especially in the prefrontal cortex.
My hypothesis is that the striatum plays a role in managing whether perceptions and thoughts are rewarded or punished (likely through conditioned salience), then facilitating perceptions and thoughts that are successful. As an example, when a child is new to the world, they may have not yet calibrated their visual perception. The erroneous perceptions may lead to failures of reaching goals, such as bumping into a wall because it was closer than expected. Spatial acuity may be conditioned by rewards when we successfully reach goals that we are aiming for. When we fail, perception may be primed for elimination by suppression of the salience of a representation or stimuli. Visual perceptions may stem from reward/aversion-conditioning that tells the brain which perceptual predictions were useful or problematic. Disruptions in detecting reward/aversion may then disrupt perceptual processing as well.
Blocking out memories that contradict a rewarding belief might be negatively reinforcing. If perceiving or thinking something is aversive or punishing, dissociation may suppress the salience of stimuli that lead to the perception or thought. The relief induced by this dissociation could become negatively reinforcing. Dopamine might reinforce delusional ideas and hallucinations, while dynorphins may subtract from stimuli that would ordinarily prevent such delusional or hallucinatory thoughts and perceptions from arising. Dynorphin may suppress information that is critical for developing accurate perceptions or thoughts. Strange hallucinations may also stem from delusional beliefs.
There is a distinction between dissociating from harmful stimuli to be rewarded and being rewarded for avoiding harmful stimuli via successful anticipation. Affect-congruent saliency may especially play a role in the avoidance of anticipated harmful stimuli, while actively harmful information, such as information that contradicts your belief in a way that leads you to suffer, is dissociated from or loses its’ saliency. In both of these cases, avoidance of harm is shared. One strategy is to manipulate the environment to avoid harm and the other is to dissociate as if the harm is not occurring. There may then be a mix of becoming hypersensitive to detecting threatening stimuli and also dissociation to protect oneself from threats.
It is important to note that salvia divinorum is acutely hallucinogenic and likely does not seem to rely on conditioned responses. Though, repeated salvia use might induce conditioned responses hypothetically. Acute hallucination and delusion might come from suddenly suppressed internal or external stimuli that leads to an altered view of reality. Important stimuli that inform our conclusions and perceptions of reality could go missing and allow for conclusions and perceptions that contradict the missing information. It may be that salvia strongly disrupts our conditioned salience or even enhances our reaction to already conditioned stimuli. Undergoing repeated episodes of this might lead to conditioned responses.
Another popular hypothesis for schizophrenia proposes a major role of the neurotransmitter glutamate, specifically an involvement of NMDA receptor hypoactivity (Moghaddam & Javitt, 2012). This led to the use of NMDA receptor antagonists in the study of an animal model of schizophrenia. KOR agonism appears to suppress glutamate release in the prefrontal cortex, nucleus accumbens, and in a pathway between medial prefrontal cortex and the basolateral amygdala (Tejeda et al., 2013; Hjelmstad & Fields, 2003; Tejeda et al., 2015). Besides producing anti-glutamatergic effects through KOR agonism, dynorphin has also been shown to directly block glutamate NMDA receptors (Chen, Gu, & Huang, 1995). This effect seems to depend on extracellular glycine levels, which determine whether dynorphin will potentiate NMDA-receptor-mediated excitotoxicity or suppress NMDA receptor activity (Zhang et al., 1997). Dynorphin has been found to inhibit neuroplasticity in the hippocampus of animals (Xu et al., 2021; Terman, Wagner, & Chavkin, 1994), something that is also thought to play a role in schizophrenia (Stephan, Baldeweg, & Friston, 2006; Stephan, Friston, & Frith, 2009). This makes sense as NMDA receptors are the key mechanism for certain types of plasticity, such as long-term potentiation (Stephan, Baldeweg, & Friston, 2006).
So, as dopamine activity increases, dynorphin releases which reduces glutamate function through KOR and NMDA receptor inhibition. High activity of glutamate may also play a role in the dynorphin release, as it was mentioned above that the NMDA receptor seems to play a collaborator role along with dopamine D1 receptors in the release of the peptide.
DIATHESIS STRESS KINDLING
The diathesis stress model proposes that stressful experiences produce a vulnerability to schizophrenic symptoms (Jones & Fernyhough, 2007). An older neural rendition of the diathesis stress model focused on cortisol and the stress response (Walker & Diforio, 1997). In this current paper, the focus is on dynorphin since it is part of the stress response and targets the same mechanisms that KOR agonistic hallucinogens stimulate to produce hallucinogenesis. This tweak to the model may better explain stress-related symptoms and schizophrenia.
General support of the diathesis stress model comes from research showing that those with schizophrenia have often had trauma (Larsson et al., 2013; Lommen & Restifo, 2009; Lysaker & LaRocco, 2008). As much as 82% of those diagnosed with schizophrenia spectrum disorders reported experiencing childhood trauma, particularly emotional neglect (Larsson et al., 2013). Other support for the model comes from the observation of stress-induced schizophrenia symptoms. One case study has explored 3 soldiers’ stress-induced hallucinations, which occurred without other psychopathology (Spivak et al., 1992). The soldiers’ symptoms were both acute and transient. A small study interviewing severe trauma survivors found that subjects experienced hallucinogenic effects from their stressful events, particularly those who experienced life-threatening situations and isolation (Siegel, 1984).
The diathesis stress model may be explained partly by the dynorphinergic effects of stress. In essence, some level of stress may produce hallucinogenic or psychotomimetic effects through dynorphin activity, possibly mimicking the effects of the KOR agonist hallucinogenic drugs like Salvia, Pentazocine, Ketazocine, and Ketamine. Repeated stress events may induce plasticity in the KOR system that eventually upregulates its’ function and sensitivity (Knoll et al., 2011), biasing one to find the dysphoric, stressful, and phobic elements of life as a protective mechanism against threatening environments. While it is only anecdotal, there have been reports that salvinorin A produces “reverse tolerance” in which taking the drug repeatedly produces an increasingly potentiated hallucinogenic response. Traumatic and stressful events may also be capable of a similar potentiation mechanism and this may underlie the diathesis stress model. We could term this phenomenon stress kindling. The term kindling usually refers to epileptogenesis that occurs from repeated stimulation of the brain or from repeated withdrawals from benzodiazepine sedatives. The idea is that smaller levels of stimulation produce a potentiated response later, in essence, reverse tolerance. This isn’t to say that stress always results in a kindling effect, but it may be a possible effect. Stress kindling may be a kind of aversion sensitization, similar to how there is reward sensitization that is often explored in addiction research.
To give an example of how stress sensitization may work, consider alcohol. Alcohol appears to induce fear and aversion sensitization via activation of the dorsal periaqueductal gray (Cabral et al., 2006). KOR agonism in this same brain region induces panic effects, while blocking KOR in this region has anti-panic effects (Maraschin et al., 2017). This may occur due to the stress of withdrawals, which may induce lasting sensitivity to KOR responses. Repeated alcohol use has been observed to induce plasticity in the KOR system, upregulating the dynorphin/KOR system (Sirohi, Bakalkin, & Walker, 2012), which supports this idea. In summary, repeated stress of alcohol withdrawal may sensitize aversion and fear responses via plasticity of the KOR system in the dorsal periaqueductal gray. This may generalize to many forms of stress, such as bullying, drugs, sleep loss, and traumatic events. Social stress and drug use are further explored in the following sections.
Imaginably, frequent or strongly negative experiences are expected to shape our judgment. If one has been in multiple car accidents, a fear of driving may emerge. Negative and positive life events may shape how negative or positive we expect life to be. Having strong or many negative events could lead one to anticipate more negative events, thus biasing one’s judgment towards expecting negative events. We anticipate a future that is derived from our understanding of our past and the world as we have experienced it. Events involving intentional harm towards an individual, such as parental betrayal and peer bullying may prime an individual to distrust people or worry about future harmful behaviors. Paranoia may often stem from the expectation or bias that other people intend to harm oneself. Those with schizophrenia may often have a genetic predisposition either to view experiences as negative or to have negative experiences. They may also be predisposed to discount positive experiences. Early life events may particularly influence the development of general distrust in people, since children have a smaller sample of normal human behavior. Trust-breaking events and betrayal may lead to further social avoidance and problems developing trusted bonds with peers. This may cause social conflict, isolation, and a failure to conform to social norms, beliefs, and other memetically-transferred behaviors, specifically because an individual would be less exposed to such memes if they are asocial.
Social stress is particularly relevant to both schizophrenia and the diathesis stress model and the effects of social stress may be partly mediated by endogenous opioid mechanisms.
Individuals with schizophrenia very often face social issues and this may produce stress responses that lead to KOR-mediated symptoms. The social issues in schizophrenia often precede the onset of schizophrenic symptoms (Ballon, Kaur, Marks, & Cadenhead, 2007). One study found that children of those with schizophrenia frequently had poor social adjustment, being unpopular with peers (Hans et al., 2000). Number of friends is negatively correlated to symptom severity in schizophrenia (Giacco et al., 2012). Experimental induction of loneliness seems to induce paranoia, while reducing loneliness decreases paranoia, effects that were moderated by proneness to psychosis (Lamster et al., 2017). Social isolation in childhood is linked to a potentiated KOR system in later life (Karkhanis, Rose, Weiner, & Jones, 2016). Social deprivation through solitary confinement also appears to produce nearly all symptoms of schizophrenia (Grassian & Friedman, 1986). This would suggest that negative social experience or social deprivation induces stress that may facilitate symptoms of schizophrenia and this may be in part due to dynorpinergic mechanisms.
Due to noticing trends in the schizophrenic population, namely that those who generally face more prejudice experience schizophrenia more commonly, a social defeat hypothesis of schizophrenia was once proposed (Selten, Van Der Ven, Rutten, & Cantor-Graae, 2013). This is surprisingly corroborated by dynorphin research in animals. In the animal models of social defeat, dynorphin activity is increased and seems to determine whether the animal becomes defeated or expresses resilience (Bérubé, Laforest, Bhatnagar, & Drolet, 2013). Further studies indicated that dynorphins role during social defeat is primarily in acute social defeat stress responses (Donahue et al 2015). In humans, social status is negatively correlated with KOR density, specifically in areas that process reward and aversion (Matuskey et al., 2012). Opioid neurotransmission is thought to play a role in social reward processing in humans (Loseth et al 2014; Nummenmaa et al 2018; Manninin et al 2017; Trezza et al 2011). It is possible that social punishment or aversive experience is mediated by dynorphinergic opioid activity. This would fit with dynorphin’s more general role in stress and aversion. Social defeat (abuse, bullying, isolation, rejection) in humans may stimulate dynorphinergic aversive processing that may elevate the risk of developing dynorphinergic hallucinogenic and cognitive effects.
Paranoia and persecutory delusions may develop from conditioned salience of threatening stimuli due to repeated negative social experiences like being bullied (actual persecution).
A more recent paper argued that the social defeat hypothesis may have problems with reverse causality (Selten, van Os, & Cantor‐Graae, 2016). Specifically, that schizophrenia may cause low social status. Rather than it being one hypothesis or the other, it may be both. Being born with genes associated to schizophrenia may both increase the risk for social defeat and social defeat may increase the risk of worsening symptoms. This seems clear when observing the benefits that socializing appears to have in those with schizophrenia. Those with schizophrenia may also have genes that make them more susceptible to the negative effects of social defeat and stress-induced symptoms like hallucinations. They may also have genes that cause them to face prejudice or defeat as well, making it more likely that the person will experience trauma or stress in their lifetime.
Challenging of one’s beliefs can be stressful. This is especially true when the social cost for having a “bad” belief is high. We often tend to shame people for believing the wrong things or disagreeing with our beliefs. An implicit assumption that often accompanies this is that the wrong believer is stupid or insane. In essence, one is harmed for holding the belief. This often drives people to avoid believing ideas that go against their subculture, although in some cases a person can protect themselves from this pattern of dissent by trying harder to prove that they are not stupid or insane. One may then conclude that the opposition is the stupid or insane one.
Schizophrenia and drug addiction very frequently coincide. This may be due to shared genetic liability between schizophrenia and drug use (Pasman et al., 2018) and it may also be due to drug use increasing the risk of schizophrenic symptoms (Howes et al., 2004). Dynorphin and the KOR system may help explain this connection. Dynorphin has been implicated in addiction, likely contributing to withdrawal symptoms and aversion that occurs when ceasing drug use (Bruijnzeel, 2009; Chavkin & Koob, 2016). Many commonly used drugs lead to enhanced dynorphin signaling via dopaminergic mechanisms. A rise in dynorphinergic activity has been observed as a consequence of the use of cocaine, alcohol, nicotine, methamphetamine, and morphine (Shippenberg, Zapata, & Chefer, 2007; Isola et al 2009; Hanson et al 1988; Nylander et al 1995). Dynorphin may even be implicated in food addiction (Karkhanis, Holleran, & Jones, 2017). As mentioned earlier, this dynorphin activity is likely induced by D1 receptor stimulation (Solís et al 2021; Hanson et al., 1995; Steiner & Gerfen, 1995). Normally, this dynorphin release may curb excess dopamine activity via dopamine release inhibition (Tejeda & Bonci, 2019), but when the dopaminergic drug wears off, dynorphin may remain elevated and produce dysphoric antidopaminergic symptoms such as anhedonia (Chavkin & Koob, 2016).
The use of stimulants like cocaine and methamphetamine has been associated with psychotic symptoms (Curran, Byrappa, & McBride, 2004) and have contributed to ideas like the dopamine hypothesis of schizophrenia (Baumeister & Francis, 2002). As mentioned before, amphetamine users and schizophrenics have elevated D1-D2 heteromers located on dynorphin dense neurons (Perreault et al 2010), which may contribute to psychotic symptoms that emerge from dopamine activity via the release of dynorphin. The study by Perreault and colleagues also suggests that becoming addicted to dopaminergic drugs (at least amphetamine) may lead to physiological changes that resemble those observed in schizophrenic patients and that also line up with the same mechanisms stimulated by the hallucinogenic drug salvinorin A.
It is important to note that nicotine use among schizophrenics is exceedingly high, with some studies suggesting as much as 80% of those diagnosed with the condition use the drug, which has often been explained as self-medication (Chambers, 2009). The self-medication hypothesis may be partially true, but we cannot neglect the possibility that nicotine is contributing to the symptoms as well. Some researchers have actually written about this possibility, noting that schizophrenics do not self-medicate with antipsychotic drugs, but in fact they often will refuse their antipsychotic medication likely because of their demotivating and flattening effects (Quigley & MacCabe, 2019; Juckel, 2016).
Drugs like nicotine may be ubiquitously desired by humans due to their rewarding and motivating effects. Those with schizophrenia may suffer from insufficiency of reward and motivation at baseline, possibly in relation to the decreased MOR receptor density and availability mentioned earlier, thus they may be driven to consume drugs that improve motivation and give a sense of reward more than those without schizophrenia. When these drugs are consumed, including nicotine, they may increase the risk for psychotic states via enhanced dynorphinergic signaling. In essence, those with schizophrenia may be more prone to seek out self-medication for the negative affective state but at the cost of risking more symptoms after tolerance and potentially psychosis eventually. These rewarding and motivating drugs may acutely resolve the diminished reward capacity in schizophrenia, but after tolerance sets in, they may experience elevated problems, particularly when the drug wears off and their reward capacity sinks below baseline, inducing a stronger bias towards threatening memories and stimuli. Hallucinations may stem from enhanced dynorphin signaling, potentially during the peak of dopamine spikes that induce dynorphin release via D1-NMDAr heteromers which is possibly facilitated by D2 receptor stimulation as well.
Interestingly, opioid (MOR agonist) use was found to be much less in those diagnosed with schizophrenia than those with other diagnoses, while alcohol, cocaine, and cannabis use was more frequent in schizophrenia than those with other diagnoses (Chiappelli, Chen, Hackman, & Hong, 2018). Since MOR agonism has effects that are oppositional to KOR agonism (Pan, 1998), MOR agonists might treat schizophrenia to some degree or prevent diagnosis. Meanwhile, alcohol, cocaine, and cannabis might facilitate diagnosis by amplifying symptoms to the point of psychosis, leading to hospitalization and eventually diagnosis.
Seizures were briefly mentioned in the context of kindling earlier and interestingly, seizures can invoke psychotic episodes. Some researchers have noted that dynorphin may help explain this tendency for seizures to bring on psychotic effects (Bortolato & Solbrig, 2007). Dynorphin seems to be a potent anticonvulsant and releases during seizures. This makes sense, as NMDA receptor hyperactivity and general glutamate hyperactivity is linked to seizure episodes (Bausch, He, & Dong, 2010) and dynorphin is capable of stopping both of these functions (Bortolato & Solbrig, 2007). The role of D1 receptors in producing a dynorphin response from stimulants also seemed to involve not only D1 but also NMDA receptor activation (Hanson et al., 1995), so this may partly be due to a role of dynorphin to stop excitotoxic and epileptic events that are related to NMDA receptor hyperactivity. Stimulants are also known to reduce the seizure threshold (Sheth & Samaniego, 2008; Hanson et al., 1999), possibly by stimulating mechanisms like NMDA receptors (often times indirectly).
The role of dynorphin targeting effects in psychedelic states, especially the kind induced by the so called classic psychedelics (serotonergic in nature; LSD, Psilocybin, MDMA), is likely to be controversial. It has been observed that LSD, both in acute and chronic dosing, suppressed the behavioral effects of KOR agonism (Sakloth et al., 2019). There are also mechanisms that may help in explaining this: LSD binds to 5HT1a and 5HT2a receptors as a partial agonist.
5HT1a serotonergic receptors may play a role in schizophrenic symptomology via dynorphin modulation and agonists may provide therapeutic value. 5HT1a receptor agonism is able to diminish the increase of dynorphin that occurs in response to L-Dopa, a dopaminergic substance (Tomiyama et al., 2005). In line with this, 5HT1a receptor agonism has been suggested to have antipsychotic effects, possibly by enhancing cognition and restoring neurogenesis (Schreiber & Newman-Tancredi, 2014). 5HT1a receptor agonism is thought to be antidepressant and induce activity of endogenous MOR agonists (Navinés et al., 2008), which might work to stabilize negative affect-mediated symptoms like memory biases and delusions.
5HT1a receptors in the amygdala and neighboring regions may be implicated in schizophrenia. 5HT1a agonism reduces aversion processing in the periaqueductal gray (Nogueira & Graeff, 1995). This brain region works with the amygdala in fear learning (Keifer Jr, Hurt, Ressler, & Marvar, 2015), something that dynorphin plays a role in (Knoll et al., 2011). From a small study, individuals with schizophrenia appear to have a hyperactivity of the amygdala (Pinkham et al., 2015). In tasks that measure fearful face processing, schizophrenics had overactivation of the amygdala even when presented neutral (non-fearful) stimuli (Hall et al., 2008; Dugré, Bitar, Dumais, & Potvin, 2019), suggesting a hyperactive fear-processing system. Schizophrenics also seem to have decreased 5HT1a receptor binding in the amygdala (Yasuno et al., 2014), which tsuggest unchecked fear/aversion processing and learning. This could help explain symptoms like paranoia. This decrease in 5HT1a receptor binding may allow dynorphin to accumulate, producing dysphoric, dissociative, and hallucinogenic effects that resemble the dynorphin-mimetic drug salvia.
The reduction of 5HT1a binding in schizophrenia may help explain the impairment of neuroplasticity (Balu & Coyle, 2011), as well as aberrant neurogenesis thought to be implicated in schizophrenia (Weissleder, North, & Weickert, 2019), since 5HT1a receptor agonism appears to induce neurogenesis (Borroto-Escuela et al., 2015; Klempin et al., 2010; Zhang et al., 2016; Schreiber & Newman-Tancredi, 2014) and neuroplasticity (Albert & Vahid-Ansari, 2019; Aguiar et al., 2020). Dynorphin is also known to have antiplastic effects (Polter et al., 2014; Huge et al., 2009; Terman, Wagner, & Chavkin, 1994), so the inhibition of dynorphin by 5HT1a receptor agonism may help restore the plasticity that is observed to be diminished in schizophrenics as well. The schizophrenic’s loss of 5HT1a receptor function may allow an antiplastic state to emerge via disinhibited dynorphin activity and 5HT1a receptor agonism may help to inhibit antiplastic mechanisms and improve function in schizophrenia.
Some important notes: those with schizophrenia may have increased binding of 5HT1a receptors in the prefrontal cortex (Burnet, Eastwood, & Harrison, 1997).
Differences in 5HT2a receptor density and binding may exist in schizophrenia and have implications for learning and memory. A meta-analysis and systematic review from 2014 found reduced binding of the 5HT2a receptor in post-mortem studies on schizophrenic patients and in molecular imaging studies in unmedicated schizophrenics, although the studies analyzed in this paper often had mixed and contradicting results (Selvaraj, Arnone, Cappai, & Howes, 2014). Reduced 5HT2a receptor binding has been associated with reduced cognitive ability in humans (Hasselbalch et al., 2008), which might help in explaining reduced cognitive ability in schizophrenic patients. Schizophrenics also appear to show reduced responsiveness to DMT and LSD in very old studies (Cholden, Kurland, & Savage, 1955; Böszörményi, 1958), supporting the observation of reduced binding. The date these studies were published aligns very closely to the earlier uses of the first antipsychotic drugs and it is unclear whether these patients were medicated. Since the results of the studies seem counterintuitive, one would expect that the authors considered the possibility that antipsychotic medication could also be antipsychedelic as well. Since there is no mention of this as an explanation for their observations, this could suggest the patients were not medicated with antipsychotics.
This receptor has been argued to be the ‘main’ mechanism of the serotonergic psychedelic drugs and may modulate KOR activity. It is thought that the receptor produces its’ psychedelic effects by suppressing glutamate mGlur2 receptor binding which results in a disinhibition of glutamate release, and thus a subsequent increase in glutamate activity (Delille et al., 2012). Besides LSD suppressing the behavioral effects of KOR agonism, there is evidence that 5HT2a receptors alter the effects of the KOR/dynorphin system. Blockade of 5HT2a receptors induces potentiation of the KOR activity of morphine (Peiró et al., 2011). Presumably, activity at 5HT2a receptors may then attenuate KOR activity. The 5HT2a receptors have also been implicated in anti-aversive effects in the periaqueductal gray (Nogueira & Graeff, 1995). This might be due to an interaction between 5HT2a receptors and the dynorphin/KOR system.
There are a few speculations that could be made as to the possible anti-dynorphin mechanisms of 5HT2a receptors. One is the induced release of acetylcholine in the hippocampus and prefrontal cortex (Nair & Gudelsky, 2004), which may promote agonism of the nAch alpha7 receptor, which suppresses dynorphin release from microglia (Ji et al., 2019). Interestingly, there is some (weak) evidence that mGlur2 stimulation facilitates KOR activity (Liu et al., 2017), though this seems still unclear as the researchers were studying diestrus. If this is true, then inhibition of mGlur2 via 5HT2a receptor agonism may suppress the dynorphin activity mediated by mGlur2 agonism. These mechanisms may be a good place to look 5HT2a receptor and dynorphin system interactions in future research.
It is possible that 5HT2a receptors are antidynorphinergic similarly to 5HT1a receptors, although it is less clear in this case. There is a section further down titled “Do Psychedelics Promote KOR Activity?” that explores the opposing argument, that 5HT2a receptor agonism may actually enhance KOR activity.
5HT2a AND COGNITION
Since dynorphin may play a role in learning and memory impairments and since schizophrenia involves learning and memory impairments, it is worth exploring the role of 5HT2a receptors in learning and memory.
There is evidence that drugs targeting 5HT2a receptors enhance learning and memory (Zhang & Stackman, 2015; Morales-Garcia et al., 2020; Barre et al., 2016), though there is also evidence that psilocin can impair learning and even acquisition at higher doses (Rambousek, Palenicek, Vales, & Stuchlik 2014). 5HT2a receptor agonists have been observed to enhance reversal learning in both animals (King, Martin, & Melville, 1974) and possibly humans (preprint experimental study) (Kanen et al., 2021). The 5HT2a receptor has been purported to play a role in plasticity and neurogenesis (enhanced in neocortex, inhibited in hippocampus) (Barre et al., 2016; Vaidya, Marek, Aghajanian, & Duman, 1997). These patterns of learning and plasticity are significant as schizophrenics show impairment in these areas, which could be explained by their reduced receptor counts. Unmedicated schizophrenics have impaired reversal learning (Schlagenhauf et al., 2014). These individuals also show impaired learning and memory (Diwadkar et al., 2008), and seem to have seem to have impaired plasticity and neurogenesis (Hall et al., 2015; Daskalakis, Christensen, Fitzgerald, & Chen, 2008; Stephan, Baldeweg, & Friston, 2006; Stephan, Friston, & Frith, 2009; Reif, Schmitt, Fritzen, & Lesch, 2007).
An important note: 5HT2 receptor agonism seems to oppose neurogenesis induced by 5HT1a receptor agonism (Klempin et al., 2010). This might suggest that the neurogenesis enhancing effects of psychedelics are related to 5HT1a receptor agonism rather than 5HT2 receptor agonism. Interestingly, there is also evidence that 5HT1a receptor antagonism potentiates the subjective psychedelic effects of DMT, a 5HT2a agonizing psychedelic (Barker, 2018). The neurogenesis topic is likely more complicated than it seems, so 5HT2a receptors may still play an important role. The study finding that 5HT2 receptor agonism decreases neurogenesis induced by 5HT1a receptors also found that 5HT2 receptor agonism promotes cell differentiation (Klempin et al., 2010), so it may play an important and useful role here as well. This study also didn’t distinguish 5HT2a and 5HT2c unfortunately.
DO PSYCHEDELICS PROMOTE KOR ACTIVITY?
It is even possible that some of the popularly known psychedelic effects are due to KOR-mediated effects at higher doses. While the low doses of psychedelics seem to produce an enhanced connection to reality, the senses, and the mind, on high doses of psychedelics people begin to dissociate away from reality (consider the DMT breakthrough, which appears very dissociative). The KOR agonists seem to generally disconnect one from reality dose-dependently, without the enhancement phase. Psychedelics may emulate the dynamics of seizures, where first an increase of sensation or some aspect of experience occurs, then a depression and disconnection occurs afterward as dynorphins flood into the brain to compensate for excess glutamate or dopamine activity. Besides this hypothesis, there are also mechanisms explored below that could underlie distinct psychotic or non-psychotic states
Another possibility is that 5HT2a receptor agonism actually promotes either KOR or dissociative (NMDAr antagonist) mechanisms under certain conditions. As mentioned previously, 5HT1a antagonists enhance the subjective effects of DMT. DMT itself is a 5HT1a, 5HT2a, and 5HT2c receptor agonist (Barker 2018). Since the agonism of the 5HT1a receptor was found to suppress increases of dynorphin due to dopamine D1 receptor stimulation (Tomiyama et al 2005) and antagonists of 5HT1a receptors potentiate the subjective effects of DMT in humans (Barker 2018), it is possible that blocking 5HT1a receptors is facilitating dynorphin release via another mechanism like 5HT2a. 5HT1a receptor antagonists also facilitate NMDA receptor inhibition via serotonin agonism at 5HT2a receptors, mimicking the 5HT2a receptor partial agonists studied (Arvonav et al 1999). These together suggest two possibly distinct (although they could be convergent) mechanisms underlying the “intensity” of subjective effects on psychedelics.
It is possible that 5HT2a receptors promote dynorphin release by enhancing D2 receptors. The increase of dynorphin via D1 receptor stimulation seems to rely on the presence of the D2 receptor and fails in D2 receptor knockout animals (Solís et al 2021). As mentioned before, D1-D2 heteromers colocalize on dynorphin neurons in a high affinity state in amphetamine abusers and schizophrenics (Perreault et al 2010), suggesting the cluster of these mechanisms may drive psychotic-like effects perhaps via potentiated KOR activity and NMDA receptor inhibition. 5HT2a receptors potentiate D2 receptor activity (Borroto-Escuela et al 2014), which might actually increase dynorphin release. This may suggest that 5HT2a receptor agonism is suppressing NMDA receptor activity by enhancing dynorphin release, although this is unclear still and would need to be explored in further research. From this research it does seem that 5HT2a receptor agonism has differential effects on NMDA receptors depending on 5HT1a receptor activity.
Clearly there are aversive and even frightening effects that can occur with the use of psychedelic drugs. This might be explainable partly by 5HT2c receptor binding. Dynorphin mRNA colocalizes strongly in 5HT2c dense neurons, while it was found lowest in the 5HT2a receptor dense neurons (Ward & Dorsa, 1996). 5HT2c agonism seems to facilitate CRF activity (Heisler et al., 2007) and CRF appears to induce dynorphin activity as part of the stress-response cascade (Bruchas, Land, & Chavkin, 2010). Both CRF and dynorphin are cofactors for the aversive effects of stress (Land et al 2008). This makes some sense, considering that 5HT2c receptors have been implicated in anxious responses to serotonergic drugs (Burghardt et al., 2007). Increasing the density of 5HT2c receptors in animals produces sensitivity to developing PTSD-like behavior (Règue et al., 2019). Though the connection between 5HT2c receptors and anxious reactions seems complicated, as it sometimes seems to produce an anti-phobic reaction (Jenck et al., 1998). It seems to depend on whether the anxious stimuli is a conditioned one or an unconditioned one. The conditioned anxious stimuli are enhanced while the unconditioned anxious stimuli are diminished (Mora, Netto, & Graeff, 1997). Though, it isn’t clear if that is really the case.
Important note: 5HT1a, 5HT2a, and 5HT2c all appear to increase CRF synthesis (Jørgensen et al., 2002), which might mean that 5HT2c isn’t especially CRF facilitating over the other serotonin receptor subtypes. Although the other receptor subtypes seem to be anti-aversive and the 5HT1a receptor seems to suppress dynorphin activity, so they may not all induce anxiety. 5HT2a receptors do seem to produce anxiety-like responses in animals (Weisstaub et al., 2006). Another study found that blockade of 5HT2a receptors increases CRF and the authors suggested that 5HT2a receptors may downregulate CRF (Nonogaki, Nozue, & Oka, 2006). It could be that the 5HT2a receptor’s effect is dependent on the state of 5HT1a receptors similarly to the case of 5HT2a receptor’s effects on NMDA receptors described earlier.
The cannabinoid known as THC is used by as much as 25% of schizophrenics have been diagnosed with cannabis use disorder at some point (Koskinen et al., 2010). THC appears to produce more classically schizophrenic effects, such as hearing voices, conspiratorial thinking, paranoia, and dissociation (PsychonautWiki). Interestingly, THC and other CB1 agonists actually reduce the commonly studied head twitch response that animals have when ingesting psychedelics (Darmani, 2001). Darmani also notes that CB1 antagonists induce a head twitch response, even without application of a psychedelic drug. This head twitch response has been associated especially to 5HT2a receptors, though 5HT2c may have some modulatory role (Canal & Morgan, 2012). This is significant because it suggests that THC and CB1 agonism generally may have anti-5HT2a effects. There is a study claiming that chronic use of THC enhances hallucinogenic signaling of 5HT2a receptors through heteromeric processes between CB1 and 5HT2a receptors (Ibarra-Lecue et al., 2018). This may not apply to acute use of THC. Usually, chronic use of LSD or similar psychedelics does not produce an enhancement of 5HT2a receptor mediated effects, they actually downregulate the receptors (Buchborn, Schröder, Höllt, & Grecksch, 2014). So THC may produce such an upregulation by inhibiting 5HT2a receptor activity through some mechanism, likely suppression via heteromeric processes, since 5HT2a receptors and CB1 receptors form heteromers. One complication of this idea is that users of psychedelics report a great potentiation when adding THC to a psychedelic trip. This potentiation may stem from other mechanisms besides facilitation of 5HT2a receptor agonism, such as alterations to GABA or glutamate release.
THC is also observed to induce dynorphin A (Mason Jr, Lowe, & Welch, 1999) and this induction of dynorphin seems to be necessary for THC-induced aversion, as mice lacking dynorphin do not experience THC induced aversion like normal animals (Zimmer et al., 2001). The euphoric effects of THC seem to be mediated by MOR agonism while the dysphoric effects seem to be mediated by KOR agonism (Ghozland et al., 2002). THC’s induction of paranoia seems to be strongly tied to negative affect induction (Freeman et al., 2015), which seems to be mediated by dynorphin release. THC may produce its’ hallucinogenic effects through indirect KOR stimulation rather than 5HT2a receptors. The reduction of 5HT2a receptor mediated effects by THC may potentiate KOR activity like what is observed in 5HT2a receptor antagonists. This may also mimic the reduced 5HT2a receptor binding observed in schizophrenics.
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