Infectious Loss of Sense

Upon the coronavirus’ descent on humankind, some have noted fears of losing neurological function (evidence of this is emerging now), fears of IQ loss, and some patients noticed a loss of smell after being infected, even after recovering. It is known that viruses sometimes have long-lasting impacts on people’s brain function, notably people have reported chronic fatigue syndrome (CFS) as a post-viral syndrome, which may be likened to immunological PTSD. Neurodegeneration has been linked to many viruses in the past as well, including influenza. To me it seems that there is an underlying commonality with neural damages and neural protective measures that remain consistent across most diseases and situations of nervous system harm. Namely, dynorphin may be a protective mechanism in most scenarios or at least sometimes, while glutamate leads as an excitotoxic neurotransmitter in the disease state. Here we will explore loss of sense, as the loss of reason, cognition, and literal sensation.

Viruses have been associated to brain dysfunction before, some being permanent and functioning as risk factors for neurodegenerative diseases such as Parkinson’s and Alzheimer’s. General infection have been associated to a drop in IQ scores by as much as 10 points. which seems to last years after the infection has ended. This may be a cause for concern with the new coronavirus pandemic that is wreaking havoc on society. Human respiratory coronaviruses have been shown to be neuroinvasive and lead to neurological problems in the past. SARS coronavirus enters the nervous system through the olfactory system (the nose), which seems highly relevant since a loss of smell is reported from the novel coronavirus. Influenzas have shown similar patterns as well.

Something to consider: Might we have increased our intelligence as a species by cooking food and ridding ourselves of regular exposure to pathogens?

Let’s start with a possible mechanism for both brain damage and neuroprotection. Dynorphin is an endogenous dissociative anesthetic (situationally) that blocks NMDA receptors (and reduces AMPAr too). In a sense, dynorphin increases during states of disease, danger, stress, pain, injury, and excitotoxicity (seizure) in order to shut down brain function to protect it. In relevance to viral infection, it may be that dynorphin plays a role once CNS injury occurs through increased glutamate activity that occurs due to inflammatory cytokines that are part of the immune reaction (including COVID-19). This is supported by the fact that NMDA receptor antagonists prevent neural degeneration induced by viruses. There are cases of viral-induced seizures, which are thought to occur when dynorphin activity is too low.

If your computer gets wet and you fear short-circuit and permanent damage, simply unplug it as fast as possible.

The mechanism for neural short-circuiting or excitotoxicity is overstimulation of NMDA receptors. I’ve spoken of this in the past in the article Cognitive Atomization, which argues that dynorphin atomizes neural networks into more disparate and disorganized streams in order to prevent damage of organized neural patterns and protect them from seizures. If we were to wonder what the brain equivalent of short-circuiting is, it seems like seizures would be a good candidate. Dynorphin in this case would be a cognitive unplugger, a dissociative, an anesthetic that numbs out our senses, thoughts and cognitive abilities in order to mitigate the damages.

I suspect that post-seizure brain fog is not much different than CFS, except that in the case of seizures, the person experiences ramping up of stimulation, of glutamate, to the point of overstimulation in a recurring pattern, rather than getting stuck in the haze phase long-term. Meanwhile, those with CFS may experience some intense viral sickness to which their brain undergoes its’ immune response and protective measures, including dynorphin to protect neurons (again, sometimes), and the person is left stuck with lingering low neuron activity long after the disease has halted. The problem of post-seizure haze may not linger as long, because the seizure is essentially the opposite side of that spectrum, an increase of glutamate activity, whereas dynorphin is blocking this activity and inducing cognitive and perceptual reduction, functioning as an endogenous anticonvulsant.

Right before seizures it is often reported that phantom smells occur, most often a burning odor. Instead of assuming that this odor is an illusion, might it be an actual smell is there, one that has always been filtered and ignored? Perhaps our bodies typically smell like a burning smell but we cannot usually identify this because most of our senses of smell are at least somewhat muted, then as a seizure comes, sensation enhances to a point that allows us to sense the previously undetectable odor. Perhaps humans smell like a burning smell because they eat so much cooked food. Others may not notice such a smell because everyone else has a muted sense of smell, possibly due to such ubiquitous exposure to the burning smell. It may also be that the burning odor is from a common environmental smell that is typically ignored as well. Heightened sense of smell is in fact linked to pre-seizure auras. A heightened sense of hearing is often reported as well. 

This enhancement of the senses likely doesn’t only amplify subtle senses, but also turn boosting inactive sensory neurons as if there was environmental stimuli when there wasn’t. This is why auras often involve scintillating scotomas, noise, or phosphenes.

On the other hand, the brain releases the NMDAr antagonizing peptide dynorphin which curbs the seizure, but can leave a person in a fog or even psychosis. NMDAr antagonists are known to induce the loss of smell. The anesthesia of dynorphin may not be exclusive to just the senses, but may include general cognition too. This would explain the brain fog of CFS, the diminished cognition in schizophrenia, pain, and stress. Anesthesia (NMDAr antagonism) is often used to simulate schizophrenia in animal research due to the overlapping mechanisms and effects that it has with endogenous psychotic states. It’s possible that schizophrenia is a reaction to extreme stress or excitotoxic problems and the following dynorphin that comes on to anesthetize the brain and protect neurons (although remember, dynorphin is neurotoxic through glutamate mechanisms too). NMDAr antagonism is actually shown to reduce virus-induced brain damage (and here), suggesting either dynorphin and/or glutamate mechanisms are involved in the brain damage mechanism, but also suggesting that dynorphin may play an endogenous role in preventing virus-induced neurodegeneration to a point, while in higher levels may enhance or cause damage.

This anesthetic protective mechanism likely occurs in the face of many sicknesses and physiological threats, including pain, fear, seizure, and consumption of toxins. It shouldn’t be a surprise if COVID-19 comes along with dynorphinergic symptoms as well. This means we should also expect dynorphinergic symptoms to follow viral illness, symptoms such as dissociation, depression, decreased intelligence, hallucination, trouble walking or maintaining balance, and impaired senses should be expected.

There have been fears circulating around these symptoms with the rise of the pandemic but these symptoms might not be as scary as we think. These symptoms may be partly transient, regardless if they seem to last forever after the sickness. Part of their lasting effects might be similar to conditions like depression or schizophrenia, which are both thought to involve immunological mechanisms. Dynorphin is both immunological and implicated in depression and schizophrenia.

Many disease states involve rising levels of dynorphin, for example CNS injury, neuropathic pain, drug addiction, spinal cord injury. Dynorphin is both neuroprotective and neurotoxic depending on complex mechanisms involving glutamate and kappa opioid receptors (KORs).

Let’s consider chronic fatigue syndrome. CFS has been associated to viruses in the past (also here and here and even with prior coronaviruses). It is likely that the disorder involves equifinality, meaning that multiple causes may lead to the same kind of symptoms. It seems to me that there isn’t a real distinction between CFS and major depressive disorder except that CFS is viewed under a lens of physiology while major depressive disorder is more often viewed as a psychiatric problem. CFS has been linked to immunological problems as has depression, CFS is linked to dynorphin as is depression, CFS is linked to elevated inflammatory cytokines as is depression, and the symptoms are nearly, if not entirely the same. So, as you could imagine, many possible causes could be at play, not only viruses but trauma, stress, or probably any kind of unsolved physiological or psycho-social problem.

CFS has been correlated with elevated dynorphin levels. Although the researchers’ hypothesis was that low levels of endogenous opioids might explain the hyperalgesia (heightened pain sensitivity) found in CFS patients, instead they found elevated levels. Later research has found that dynorphin may mediate pain and hyperalgesia through glutamatergic mechanisms. Another paper found that biological markers associated to CFS were reversible by an opioid antagonist, with the authors suggesting that the endogenous opioid system plays a role in the pathogenesis of CFS.

It makes sense that the body and brain would enter a kind of low power mode, using the most minimal amount of brain power and energy, in order to spare more energy to fighting disease later, especially since encounter with a virus might suggest future encounters are more likely. Dynorphin has been implicated in hibernation, which could help explain seasonal affective disorder (SAD). It would be interesting to consider whether this tendency evolved partially to avoid viruses which are more prevalent in cooler weather. Besides as an avoidance of dangerous weather and energy-saver during starvation season, seasonal depression may function as an evolved social distancing mechanism and self-quarantine behavior.

Becoming depressed for some time after a virus may also act as self-quarantine that helps prevent the spread of the virus, even after the virus is no longer expressing symptoms. Post-viral illness may then have evolved to stop contagion to the community, since many viruses can still be infectious many days after one ‘feels better’. This could also be viewed as an evolved immunological PTSD caused by infectious traumas. Perhaps Post Infection Reaction Disorder is an apt title for the syndrome.

There is some evidence of this virus-social distancing behavior evolution. There is something known as sickness behavior which cytokines can induce and tends to reduce social behavior. Viral infections are related to depression and involve cytokine activity. Neonatal Borna disease viral infections in mammals seems to reduce adult social behavior and might have implications for autism. There is also suggestion that seasonal asthma may begin the pattern of seasonal depression, so perhaps those who became overreactive to bronchial asthma and began to self-isolate out-survived those who continue to socialize during increasingly risky colder times. One mechanism for this might be seasonal changes to vitamin D which normally suppress cytokines more during the summer. Thus the increase of cytokines that occurs in darker weather may promote sickness behavior such as social withdrawal.

Interesting Tangent: This kind of behavior seems to mirror the social distancing behaviors of ants under sickness. When ants become sick they often drift away from the colony and end up spending more time outside the colony, especially avoiding the queen. Depression may invoke a similar self-excluding tendency, similar to the patterns we see in ants. Sometimes ants take a strategy akin to herd immunity, where they dose themselves with small amounts of the pathogen while social distancing from the queen. This is similar to vaccination in humans. For deadly fungi, they may inject formic acid into infected ants, to disinfect but also kill the infected ant and its’ fungus.

Another possible post-viral effect is the loss of smell and taste. This has been reported now with the novel coronavirus. Luckily, in past studies on other viruses, people seem to recover a year after infection passes. There have been fears rumoring around that the coronavirus might induce permanent neurological damage and that such damages might underlie the loss of smell found with the coronavirus. This seems unlikely, but of course very possible. Instead, more hopefully, it might be that dynorphin or similar protective mechanisms shut off function of non-critical neurological functions, in order to preserve them in case of excitotoxic damages, acting as an endogenous anticonvulsant). Some viruses (NSV, influenza, and HCoV-coronavirus) have been shown to induce neuron death via excitotoxic glutamatergic mechanisms and even induce seizures.

In the case of dynorphin shutting down seizures, psychosis has been a reported post-seizure phenomenon. Rather than only seizures, we may predict that increasing depressive and cognitive dysfunction occurs in response to physiological threats, as dynorphin release increases to protect neurons through what I’ve termed Cognitive Atomization, or ultimately a quarantining of neurons in order to prevent the spread of excitotoxic mechanisms that rely on active glutamatergic neuronal activity. Seizures may be the most clear demonstration, as it is often reported that senses increase, and then diminish greatly after presumably the dynorphin kicks in, sending the person into such an anesthetic and amnesiac state that they are nearly psychotic.

While not all viral infections may result in seizures or intense neurological threats, there may be a constant more mild threat that viruses pose to neurons, thus inducing neuroprotective mechanisms that just so happen to decrease cognitive ability and perception. There is evidence of cognitive disrupting powers of dynorphin in the research.

From Dynorphin Theory:

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.

This also matches the research on viral-infection induced cognitive deficits, as the picornavirus family of viruses has been found to induce spatial memory impairments, like dynorphin. Unfortunately, the impairment to memory correlated to damage in the hippocampus. Borna disease virus showed similar patterns. In this study the researchers found that a lack of inflammatory process worsened the damage, which may be due to dynorphin’s role in the inflammation process, possibly as a neuroprotectant.

Although, since dynorphin is capable of both neuroprotective and neurotoxic effects, one might wonder if this is a case of dynorphin-induced excitotoxicity. The fact that dynorphin has anti-inflammatory properties is even more telling, as this suggests the brain-damage in the hippocampus that correlates with decreased inflammation could be explained in part by dynorphin activity. It seems likely that the anti-inflammatory effects may depend on neurochemical contexts, that dynorphin may exhibit differential effects depending on the situation, since the evidence provided by that study supported the claim about anti-inflammatory effects with research showing dynorphin could treat inflammatory hyperalgesia, which as mentioned earlier, dynorphin can both treat or aggravate hyperalgesia. If there is more intense anti-inflammatory response, it may be that dynorphin levels are high and also producing excitotoxicity through glutamatergic mechanisms.

Even if there is brain damage and it correlates to the severity of memory problems, it may not be a causal relationship, even though it may at least partially be. If dynorphin activity is high, so might damage levels, but also so might transient brain fog, psychosis, depression, and even motor dysfunction (abnormal gait). The far end of sickness behavior may involve a kind of drunken delirium, psychosis, amnesia. Besides support of this coming from associations to schizophrenia and hallucinogenic mechanisms, there are researchers exploring whether HIV related dementias may involve dynorphinergic mechanisms.

There is a condition known as anti-NMDAr encephalitis which seems to be a lot like dosing NMDAr antagonists. This condition involves antibodies of NMDAr attacking the receptors, causing sensory and cognitive problems. It has been found that some viruses can induce the condition, such as herpes and the Epstein-Barr virus. Steroids were found to treat the case induced by herpes. Perhaps most people have some degree of anti-NMDAr encephalitis but so minor that it is simply considered normal. This would explain why very many people become manic upon steroid drug administration, since reducing NMDAr function can treat mania, while NMDAr enhancing drugs tend to induce mania.

Moving back to this loss of smell,

Dynorphin is involved in fear and trauma and PTSD sometimes involves the loss of smell. Amphetamine is able to induce a loss of smell at low doses and increases dynorphin. Nicotine is linked to a loss of smell and also increases dynorphin activity. Cocaine and alcohol produce loss of smell as well as increasing dynorphin. Deficits in smell have associated with schizophrenia, which again, associates to dynorphin. Cytokines have correlated to viral-induced loss of smell.

Post-Viral Treatment

So how can we fix this problem? One’s first impulse might be to grab dynorphin antagonists, but this doesn’t totally work since the rebound effect seems to be psychosis inducing, indicating that such drugs likely ramp up dynorphin levels in the long run.

NMDAr antagonists are reported to curb viral-induced neurological damage, so perhaps something like memantine could be given in small doses during infection. Although this is too risky to really recommend, thorough investigation is warranted before trying something like this. It is worth noting that the common cough suppressant, DXM, is an NMDAr antagonist, which is a fancy coincidence to say the least.

UPDATE: An epic r/DrugNerds reader found that memantine has actually been studied in coronaviruses before. The researchers found that glutamate-mediated excitotoxicity could be curbed by dosing memantine in mice. They also found that memantine reduced replication of the virus and even attenuated mortality rates. Note, this isn’t the novel coronavirus, it isn’t COVID-19. It was an enhanced coronavirus that was so excitotoxic that it produced a paralytic disease, which sounds terrifying. 

Drugs of the same class as memantine also worked in SARS coronavirus, preventing viral replication of the coronavirus. There is even a 2020 paper discussing the use of memantine and similar drugs in COVID-19, so it appears that this may become a reality quite soon.

Luckily, the majority (85%) of patients with post-viral loss of smell regained some restoration of smell (30%) after a year follow-up. Part of this may be due to the fading out of dynorphin anesthetic mechanisms and another part of this may be due to the fact that the olfactory bulb in the brain is one of the only regions to undergo neurogenesis in adults. Serotonin has been shown to mediate neurogenesis in the olfactory bulb, as well as the hippocampus, the other region that experiences damage from viral infections, through 5HT1a and 5HT2c receptor stimulation. Psychedelic drugs typically bind to both of these targets and induce neurogenesis. Anosmia (loss of smell) induced by dexamethasone was reversible by the serotonergic agonist and dynorphin blocker known as gingko biloba.

Anecdotally, some people who’ve consumed psychedelics sometimes report an increase in their sense of smell that persists long after the drug intoxication has ended. There are also reports of increased visual sensation that lasts after the drug has worn off (and here). These effects could be based on an increased capacity to process more information and less filtering of information. In the posts Cognitive Atomization, Dynorphin Theory, and Junky Mind I’ve argued that serotonin activity essentially signals environmental security and abundance, whereas dynorphin oppositely signals scarcity, stress and trauma. It may be that psychedelics induce a chronic state of abundance, treating trauma, stress, depression, and the scarcity mindset by attenuating dynorphin’s effects (while antagonists enhance dynorphin). This may clear the anesthetic effects of dynorphin that suppress cognition and perception, essentially convincing the body that it can afford to spend more energy on higher states of consciousness which are typically too expensive for those in states of disease, starvation, dangerous environments (trauma), and possibly disease, viral and otherwise.

Essentially the psychedelics may induce higher consciousness by turning off the low-power mode (the opposite of cellular quarantine?). Before you go off trying to treat your illnesses with psychedelics, it must be warned that this is very risky. The loss of neurological function during sickness may be critically functional. 5HT2ar agonists have been shown to facilitate the spread of various viruses such as JC virus, HIV, while on the other hand, serotonin agonists have prevented reovirus infection. Shutting down these mechanism during sickness might be critical. Serotonin antagonists have been explored for prior coronaviruses, although I could not access the chapter to read the full context here.

Sidenote: The JC virus infects people through 5HT2a receptors. Can you imagine if there were ancient plagues of this kind of virus? The disease induced by this genetic strand strips your nerves of the myelin coating, with increasingly problematic brain symptoms until you die. You could imagine that this would force humans to evolve reduced 5HT2a activity. Luckily (or not), this virus mostly only targets people whose immune system is suppressed.

Once we become sick, this may indicate to our body that potential future sicknesses will occur and so it should be prepared beforehand by reducing the potential of the virus to become infectious through serotonergic mechanisms and also by increasing cytokines (which reduce monoamine activity, including serotonin) long after, maintaining a sickness state even when the viral effects have ended. Depression may be an evolved immunological PTSD state in which our body predicts future infections based on how common they have been previously. Dynorphin and cytokines may play a role in cellular social distancing, or as we may term, (social) Atomization.

Psychedelics may be able to help reverse the immunological PTSD, as their efficacy for treating depression with psychedelics seems to be very high (80%). Psychedelics suppress inflammatory cytokines as well, which may disrupt feedback loops that perpetuate the fatigued state. There is a page detailing anecdotal reports of CFS being treated by psychedelics, but many of them report only temporary benefit. A reddit user has collected reports of people claiming their CFS disappeared after DMT use. A study found increased sensitivity to psychedelics is linked to CFS in animal models. The researchers found increased 5HT2a receptor levels, which doesn’t necessarily mean that 5HT2a receptor activity causes the symptoms of CFS, but instead it might be that the neglected receptor increases in numbers. It is unclear whether psychedelics would help, but it seems interesting. Whether they are useful may depend on the specific causes of the person’s fatigue syndrome. 

Next, we must focus on finding ways to prevent the economy’s chronic fatigue after this pandemic passes. The societal immunological response might be very relatable.

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