There is a new 2020 study published in The Royal Society Publishing that explored the impact of a western diet on the hippocampus, learning, memory, and appetite control. The authors showed impairment in learning and appetitive control in the group assigned to eat junk foods a few times a week. They back up the claim that it is hippocampus-dependent with animal studies as well. This article will be focused on explaining the possible mechanisms involved in the cognitive decline shown in the study. Mechanisms such as dynorphin, serotonin, insulin, orexin, dopamine, among others are explored in an attempt to explain how junk food consumption may lead to cognitive impairment, partially through the same mechanisms as drugs of abuse.
First let’s establish some of the relevant effects of junk food. When we think of what foods are bad, it’s usually salty, fatty, sugary, and nutritionally empty foods. We sometimes include MSG with junk foods as well.
Fat stimulates dynorphin, along with other endogenous opioids. Knocking out dynorphin lead to fat loss during fasting in mice. Sugar consumption leads to the secretion of dynorphin through a pancreatic B-cell dependent mechanism.
So let’s sink in to the mechanism!
Dynorphin
This blog has focused quite a lot on dynorphin in relation to schizophrenia, a disorder that involves both reduced hippocampal volume and learning impairment. A 2020 preprint supports this theory by noting an association of dynorphin and all symptom dimensions of schizophrenia along with the cognitive impairment that is linked to schizophrenia. Dynorphin has been implicated in stress, aversion, schizophrenia, trauma, addiction, social defeat, and depression.
Dynorphin serves as a prime candidate for explain the cognitive impairment associated with junk food consumption. Microinjections of dynorphin into the hippocampus produced 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, insulin resistance rapidly develops in response to pain and also stress, bringing us to the next key in the puzzle:
Insulin and Serotonin
Dynorphin’s role in this problem involves its’ effects on serotonin. 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 serotonin 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, further supported this observation of dynorphin and serotonin functioning as opposing systems.
What about food?
A Plos One paper discusses the role that serotonin plays a role in insulin excretion from the pancreas. The authors note that diabetes occurs in the absence of serotonin. Because dynorphin has anti-serotonergic effects through inducing reuptake of serotonin, it seems likely that the rapid induction insulin-resistance due to pain and stress may be related to dynorphin, which is also implicated in both pain and stress aversion.
Dynorphin is further connected to dietary patterns through the orexin system, which regulates feeding behavior and energy balance. Dynorphin was found to induce feeding, putting a physiological touch to the notion of stress-eating. On the contrary, serotonin decreases hunger and is also implicated in energy balance. In regards to energy balance, this may be related to the role that dynorphin plays in depression, while serotonin seems capable of inducing mania, again, on the contrary. The orexigenic effects of ghrelin were found to be modulated by dynorphin.
Furthermore, dynorphin was actually found to inhibit insulin secretion in response to glucose, while another study found that endogenous opioids have much more nuanced and variable effects on insulin. In this study on opioids, dynorphin did not raise insulin in lean mice, only in obese mice. Perhaps the insulin response to dynorphin in obese mice is a conditioned response due to sugar consumption that normally stimulates dynorphin. It would make sense that compensatory adaptions of insulin response to cues would be made for repeated overeating in order to control blood glucose problems and maintain homeostasis. The authors noted there was even a paradoxical hyperglycemia in response to dynorphin in the obese mice, despite the raise in insulin. It could be that the increase of insulin is a response to the hyperglycemia that emerged due to an initial inhibition of insulin. Hypocretin, the endogenous agonist of the orexin system was found to have opposing effects compared to dynorphin in many ways and also prevented insulin resistance.
Taken together this information suggests that dynorphin is at least sometimes inhibitory on insulin secretion, possibly through indirect actions on serotonin.
Insulin resistance and diabetes have both been linked to cognitive problems, including Alzheimer’s disease. Everything we have covered here is stuff I wanted to cover in my post HypoCognition, which is about Alzheimer’s and dynorphin, but the connection to insulin wasn’t included. Insulin resistance has also been associated to schizophrenia, even researchers noticing the association before the invention of antipsychotics, suggesting it is not merely induced by the drugs. This seems to fit ever so perfectly with the strange association of ancestral famine events and later generational schizophrenia. I’ve also explored the connection between schizophrenia, dynorphin, and addiction in Nicotine Disorder, bringing us to:
Addiction
Cocaine addiction involves increasing dynorphin levels by co-stimulation of glutamate NMDAr and dopamine D1 receptors. Dynorphin stimulates serotonin transporter activity, reducing extracellular serotonin. Upregulation of serotonin autoreceptors and transporters were found from repeated cocaine dosing. The autoreceptors function by reducing serotonin release while the transporter functions by decreasing extracellular serotonin, both mechanisms that would further decrease serotonin activity. Decreased extracellular serotonin increased cocaine cravings. As expected, psychostimulant use impairs insulin signaling, possibly by disrupting these serotonergic mechanisms. Drugs that bind to serotonin have even been suggested for us in food addictions.
Connecting back to junk food, intense sweetness was found to be more rewarding than cocaine and as previously mentioned, induces dynorphin secretion from pancreatic B-cells. Consumption of fat both impairs insulin signaling and is associated to many markers of addiction, including changes of dopamine and opioid signaling. It is also plausible that NMDAr binding by MSG may induce dynorphin release. MSG has also been linked to insulin resistance in animal studies. Salt has even shown similar pharmacological patterns as addiction. Since dynorphin is associated to addiction and drug cravings in particular, the dynorphin stimulating effects of fat and sugar consumption may promote similar cravings and addiction.
On the other hand, carbohydrate consumption is shown to mediate how much serotonin is released from neurons, how much serotonin synthesizes and induces a satiety effect. The paper notes that, unlike carbohydrates and proteins, fats are not associated with the production of any neurotransmitters, though this study was from 1995. Serotonin activation in the hypothalamus was found to reduce the consumption of fatty foods. Low fat and high carbohydrate diets have shown efficacy in reversing type II diabetes. On the other hand, the high-fat ketogenic diet has been associated to insulin resistance, even while increasing energy expenditure and not leading to weight gain.
People often liken type II diabetes to a food addiction. The drop in appetitive control that was observed in the study from The Royal Society Publishing could be partly explained through addiction mechanisms. With everything covered in this post, it does seem almost true. Keep in mind, this isn’t a full picture of the biology implicated in diabetes or food addiction, in fact it is a somewhat unconventional exploration of the topic, mostly looking into how mental health, neurotransmitters, and food intake overlap.
One might consider how social factors play a role in junk food addiction. Social defeat stress was found to be mediated by dynorphin and linked to weight gain and increased food intake. Like cocaine addiction and stress, social defeat upregulates the serotonin transporter, likely partly due to dynorphin. Socially subordinated monkeys had increased vulnerability to addiction to cocaine compared to dominant monkeys. In the article Serotonism, we explored how serotonin is implicated in social hierarchy of many species, revealing further contrary patterns in dynorphin and serotonin research. Low social rank is thought to be a risk factor for diabetes as well.
Social defeat is a topic commonly explored on this blog, if you are interested to read more on that, check out Delusion, Nexus, and Dynorphin Theory.
Tip: Diets that include high amounts of turmeric and garlic may produce resilience to social defeat.
Here is where it gets truly strange. Since most of my articles exploring the contrary catastrophes of serotonin and dynorphin have suggested that serotonin 5HT2ar and 5HT1ar stimulation may be key to restoring serotonin tone and diminishing the tyrannical influence of dynorphin, it is only fair to wonder if that is the case here. If you don’t already know, 5HT2ar stimulators are also colloquially known as psychedelics.
It seems to be an inescapable nexus of my research rabbit holes.
Psychedelics
Leave it all behind
Inspired by the facts that serotonin promotes the secretion of insulin and psychedelic serotonergic drugs rapidly cure addiction, I went to my search engine.
When I went to Google to find out if psychedelics were ever explored in diabetes research, I was shocked. There are actually researchers looking into treating diabetes with Ayahuasca to seemingly great effect. It was noted that the psychedelic cocktail produced the fastest ever recorded regeneration of pancreatic insulin-producing beta cells ever recorded. That said, it doesn’t seem to be clear that the compound that actually produces the effects are at all related to the psychedelic effects. The scientists narrowed down critical effects to harmine, the MAOA inhibitor, which has more general serotonergic effects that aren’t specific to the receptors involved in psychedelia but still include them.
During my recent experience with psilocybin mushrooms it seemed apparent that something had occurred to my glucose metabolism. It felt as though the mild ‘bad trip’ effects were partly a kind of hypoglycemic effect. It seemed similar to experiences I’ve had sober when my blood sugar was low or even when I dosed intranasal insulin as an experiment. Then as I consumed sugar in the form of Cacao Soylent, there was a pronounced positive effect on my cognition and mood. There was an almost immediate occurrence of clarity, but this effect didn’t last too long. The spikes of mood and clarity benefits lasted around 30-45mins after the food, at which point the residual effect began to diminish slowly over the course of a few hours. During this experience I wondered to myself if this how eating is supposed to feel, if we hadn’t ruined our bodies with stress and junk food. In connection to harmine, recent research has found that mushrooms do actually contain MAOIs and not just psilocybin and psilocin.
There is research that suggests psychedelics could improve cognition though and part of this may be related to the insulin-dynorphin-serotonin dynamic. Psychedelic drugs induce neurogenesis in the hippocampus, the same region of the brain that junk food impairs. Serotonin, too, is able to induce neurogenesis. Psychedelics also promote structural and functional neuroplasticity. 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.
In both Psychedelics and Schizophrenia and Dynorphin Theory I’ve outlined mechanisms by which dynorphin may disrupt cognition by reducing LTP, neurogenesis, NMDAr-dependent learning, glutamate signaling, and disruption of serotonergic-dependent learning so check these out if you wish to understand more. The impacts of junk food on cognition are likely complex and multivariable, as with all things in biology. Dynorphin may play a key role in explaining some of the impacts that junk food has, on hippocampus-dependent learning.
With all these overlaps of mental health problems, it seems there is core in which consciousness is disrupted through convergent mechanisms. This seems especially true with depression, addiction, trauma, stress, Alzheimer’s disease, and diabetes. Might these problems really represent the same kind of problems (mostly stress and bad feels) from different angles? Perhaps there are more ways to become predisposed to diabetes than stress, perhaps Alzheimer’s involve prions that act as stressors or physiological damagers that trigger a cascade of stress hormones and eventual diabetic-like status (I haven’t looked into that, just to note), and perhaps addiction and diabetes run parallel, even displaying similar narratives. Regardless, this exploration of the research is starting to become very intersectional, which should be expected, as the body is an intersection of many mechanisms.
Lastly, I’d like to thank Mr. Nobody (username) from the discord server for helping to collect sources in our database and discussing some of these ideas. Another special thanks to the two patrons, Abhishaike Mahajan and Charles Wright! Abhi is also the artist who created the cover image for Most Relevant. Please support him on instagram, he is an amazing artist!
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qwerky science 
Actually, well done! Fits gracefully with my experience and limited physiological knowledge. I respectfully suggest checking the relevance of Growth Hormone to the diabetes and Dynorphin interactions…Yours, Tru Luv Flo.
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I noticed most of the studies were done on mice, not humans, so how do you think you can draw conclusions about people from the results?
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That is a good point. This article is a speculation about the potential mechanisms involved in junk food consumption’s impact on cognition. This impairment of cognition seems to occur in humans and animals so the mechanisms might be the same too, but that isn’t proof or anything.
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