In addition to the core symptoms of autism, which include social communication difficulties, restricted interests, and sensory processing difficulties, both children and adults with autism often present with many other ‘autism-related’ symptoms and behaviours. Aggression is one of them.

Aggression in autism can involve severe tantrums, anger, hostility, sudden-onset violent outbursts including self-harm and rage ‘episodes’. Up to 20% of individuals with autism exhibit such violent behaviours. In many cases, aggression involves destruction of property and direct violence towards other people including carers, causing them bodily harm.

Such aggressive behaviours have very negative effects on daily functioning and quality of life of people with autism and their caregivers, and further add to stress and social isolation. Some research suggests that aggression in autism causes carers and teachers greater stress than the core features of autism.

Aggression is associated with more negative outcomes for children with autism and their caregivers, including decreased quality of life, increased stress levels, and reduced availability of educational and social support.

Individuals with autism and aggressive behaviour also have lower educational and employment opportunities, and sometimes get involved with the criminal justice system.

One simple (and largely unknown) cause for aggressive behaviour in autism

When an individual acts aggressively and destructively towards other people, things or themselves – hitting, smashing, tearing, biting, etcetera – the possible reasons and triggers for such behaviours are numerous. This is true for all human behaviours, including aggression towards others.

What we are going to describe in this article is just one of those many reasons that can trigger aggression. However, this one reason is:

1. Largely unknown and almost always missed.
2. In some cases, it could be relatively easy to address.
3. Most importantly, there are many indications that this particular cause of aggression is frequently present in individual with autism.

Introducing… blood (and brain) glucose.

What is glucose

Glucose, also called dextrose, is one of a group of carbohydrates known as simple sugars, or monosaccharides. (Other monosaccharides include fructose, galactose, and ribose). It occurs in nature, where it is found in it is free state in honey, fruits and other parts of plants.

Glucose is also one of the constituent parts in many other foods – more complex carbohydrates such as sucrose (table sugar) or lactose (sugar present in dairy foods) get broken down by gut enzymes into glucose and other parts before they are ready to enter the blood stream. Humans get glucose from sources as diverse as bread, rice, vegetables, fruits and dairy.

Glucose is the major source of energy in the body, and the regulation of glucose metabolism is of great importance to our health and survival.

Glucose in the blood (blood sugar)

Glucose is the major free sugar circulating in the blood, and from the blood it enters our cells. When glucose molecules enter our cells, they get converted into energy.

Blood glucose is derived from two main sources: absorption from the gut, where it is directly obtained from food sources, and release from organ storage — our body constantly ‘stashes away’ glucose inside our various organs, mainly the liver and muscle cells, in order for it to be converted into energy later on. This glucose is stored in the form of glycogen (more on it later).

Once the liver, muscle and other body cells and organs have more glucose that they can use as energy or store for later use, excess glucose is converted into fat.

Levels of glucose in the blood are constantly changing when we eat, or when we use much more (or less) energy than usual, for example while sleeping or exercising. The levels of glucose in the blood and cells are also controlled by a number of hormones, such as insulin, and various complex feedback mechanisms.

If the levels of glucose in the blood get too high (hyperglycemia) or too low (hypoglycemia) for a prolonged period of time, or if the levels simply change too suddenly, this can have negative consequences for health and wellbeing.

Glucose in the brain

Alongside oxygen, glucose is the main energy source for the brain. And the brain requires a lot of energy to run efficiently — despite it accounting for only 2% of a person’s total weight, it consumes almost 25% of the total available glucose.

When glucose levels in the brain, or some parts of the brain, are low, or when glucose is not effectively converted into energy, this can have profoundly negative effects on mood, behaviour and cognitive ability.

The centres in the brain that are used for impulse-control, controlling undesirable behaviours or decision-making, are all highly dependent on glucose. When this source of energy is lacking, particularly in the part of the brain called the prefrontal cortex, a person may find it hard to control their impulsive behaviours or aggressive urges.

Other brain processes that rely most heavily on the smooth supply of glucose to prefrontal cortex are the high-level mental processes such as emotional regulation, decision-making, attention control, planning, and flexible thinking.

“In short, the brain relies on glucose to function. When the flow of glucose to the brain is inadequate—either because glucose is low or because glucose cannot be transported to the brain (i.e., poor glucose tolerance)– cerebral functioning is impaired….There was also ample evidence that low glucose contributes to poor self-control. Controlling attention, regulating emotions, coping with stress, resisting impulsivity…have all been found to be impaired when glucose is low. Low glucose has been linked to…decreased attentiveness…more negative mood states, a higher incidence of emotional disorders…greater susceptibility to mood swings and temper tantrums.” (Gailliot and Baumeister 2007)

Very low levels of glucose in the blood or brain can lead to undesirable behaviours, cognitive impairments, dementia, and even result in a coma. For example, diabetes, a disease of dysfunctional control of glucose levels, is associated with mood swings, impaired brain health, cognitive decline and dementia.

Children with type 1 diabetes are at high risk of developing brain dysfunction and seizures, and having problems with learning, concentration, memory, coordination and motor tasks.

“During hypoglycemic episodes [occurrences of lowered levels of blood sugar] , children with type l diabetes mellitus may show transient intellectual deterioration at significantly higher blood glucose levels than those reported in adults…Mild hypoglycemia was associated with a dramatic deterioration in mental efficiency, as well as an increase in adrenergic symptoms…When evaluated shortly after the beginning of the hypoglycemic nadir…diabetic subjects showed a significant reduction in “mental flexibility.” (Ryan & Becker 1999)

Widespread glucose problems in autism

Various types of metabolic disturbances are highly prevalent in children and adults with autism, who are at a higher risk for obesity and diabetes than the general population. Furthermore, maternal obesity, preeclampsia, diabetes and other metabolic disorders are also associated with an increased risk of autism spectrum disorders in children.

“Compared with those presenting with milder impairments, individuals with severe ASD also show an increased likelihood of obesity alongside various other metabolic disorders including hypertension, diabetes and dyslipidemia. While the reasons for increased obesity rates in ASD are commonly assumed to be due solely to poor eating habits, the lack of physical activity and/or medication, increased weight gain has been recorded during early infancy pointing to possible involvement of intrinsic biological factors.” (Sala et al. 2020)

Both children and adults with autism frequently have lower fasting blood glucose levels compared to a general population. A recent investigation by a team at Bambino Gesù Children’s Hospital in Italy found metabolic abnormalities associated with insulin resistance and reduced glucose metabolism in the brain in a group of 60 ASD patients aged 4-18.

Another recent study that compared glucose metabolism in a group of 17 children with autism found that they had lowered levels of fasting blood glucose compared to typical children. In addition, two of the children with autism had impaired glucose tolerance, and four showed delayed insulin secretion.

“The level of fasting blood glucose in the ASD group was significantly lower than that of the control group (P=0.0055). It might be related to the cognitive dysfunction in children with ASD. Besides, there were three children in the ASD group whose fasting blood glucose was below 4 mmol/L, suggesting insufficient energy supply of these children.” (Zhang et al. 2019)

Several groups of researchers have also suggested that disturbances in the levels of glucose in the brain early in development – either in pregnancy or during early childhood – could play a role in the development of autism. 

Importance of glucose and blood sugar control in human behaviour

Brain glucose and aggressive behaviours

Self-control is the act of overriding an impulse, urge, or a desire to act out in a certain, undesirable way. Self-control helps humans to keep their feelings in check, including feelings of anger and aggressive urges.

Overriding aggressive impulses through self-control requires lots of energy, and that energy is provided in large part by glucose. Unfortunately, this energy is in limited supply and can ‘run out’. Low glucose levels can undermine self-control because people have insufficient energy to overcome unwanted urges, impulses and challenges.

“Numerous studies have found a relationship between low glucose levels and poor self-control…When glucose levels are low, people have more difficulty controlling their attention, regulating their emotions, and overriding their aggressive impulses. Some evidence suggests that low glucose levels might even increase the risk of violent criminal behaviour, including spousal abuse… Our study found that low glucose levels …predicted aggressive impulses, which, in turn, predicted aggressive behavior…Thus, low glucose levels might be one factor that contributes to intimate partner violence.” (Bushman et al. 2014)

Research studies done in humans have provided evidence that low glucose levels in the brain can increase the risk of violent offending and aggression towards others, including close family members.

Irregularities in glucose levels, such as hyperglycemia, hypoglycemia, or sharp fluctuations in glucose levels, resulted in subjects in those studies reporting significant increase in feelings of anger and frustration, and increased hostile and aggressive behaviours.

“It is recognised that many patients often display asocial or aggressive behaviour during low blood glucose levels, and may, for instance, have fierce disputes with their partners. Severe attacks of hypoglycaemia have even been used as a defence against criminal charges, ranging from shoplifting to murder. The implicit assumption is that subjects during a period of severe hypoglycaemia do not act volitionally, and thus cannot be held legally or otherwise responsible for their actions.” (Merbis et al. 1996)

Those studies have also observed that even moderately low levels of blood glucose may result in sharp changes in brain blood flow and metabolism, with the individuals showing a significant stress response and behavioural changes under such circumstances. The findings have also indicated that it is not only the levels of blood glucose that play a role in aggressive behaviours, but also the speed at which those levels change, with aggressive traits seemingly linked to sudden fluctuations in levels.

“Aggressive and violent behaviours are restrained by self-control. Self-control consumes a lot of glucose in the brain, suggesting that low glucose and poor glucose metabolism are linked to aggression and violence. Four studies tested this hypothesis. Study 1 found that participants who consumed a glucose beverage behaved less aggressively than did participants who consumed a placebo beverage. Study 2 found an indirect relationship between diabetes (a disorder marked by low glucose levels and poor glucose metabolism) and aggressiveness through low self-control. Study 3 found that states with high diabetes rates also had high violent crime rates. Study 4 found that countries with high rates of glucose-6-phosphate dehydrogenase deficiency (a metabolic disorder related to low glucose levels) also had higher killings rates, both war related and non-war related…” (DeWall et al. 2011)

Findings of violent mood swings, anger and rage attacks – sometimes called “diabetic rage” – are well known to occur in people with diabetes, which is characterised by fluctuating blood glucose levels.

A minority of people who regularly consume alcohol become irritable, impulsive, aggressive and even in some cases commit violent crimes whilst intoxicated. Drinking large amounts of alcohol is known to reduce glucose metabolism in the prefrontal cortex (self-control centre) and other parts of the brain.

One study that looked at violent offenders in Finnish prisons found that low glycogen levels could predict their future violent offending under alcohol intoxication. (Glycogen is the ‘packaged storage’ form of glucose, the substance our body’s make to store glucose for later use).

The findings of the study point to the possibility that alcohol intoxication could be triggering aggressive and violent behaviours only in those people who already have underlying problems in glucose metabolism. They also suggest that substances that increase glycogen formation, i.e. that raise levels of stored glucose for future energy needs, regular eating habits, and other methods that decrease the risk of low blood sugar could be good strategies for preventing impulsive violent behaviour.

“Aggression is a rewarding behavior that activates pleasure centers of the brain, such as the striatum and the nucleus accumbens. Glucose produces a similar effect, with one crucial exception: in addition to stimulating reward centers, glucose increases neural activation in brain regions that aid self-regulation.” (Pfundmair et al. 2015)

Epilepsy, glucose metabolism and aggression

Links between epilepsy and autism are strongly established. Epilepsy and/or seizure disorders are highly prevalent in autism, with an estimated 10% of people with autism developing epilepsy over a lifetime. Still a higher proportion will suffer some types of seizures. The converse is also true, with children with epilepsy being at much higher risk of developing autism. 

The relationships between epilepsy and glucose metabolism were established almost 100 years ago, when the ketogenic diet was first used for the treatment of epilepsy (more about ketogenic diet below).

Children with type 2 diabetes are known not only to be at higher risk of developing cognitive disfunction, motor coordination, attention, learning and memory problems, but they are also at higher risk of seizures.

“In one study, epileptiform spikes appeared in 47% of the diabetic subjects during the hypoglycemic nadir (47 mg/ dL, 2.6 mmol/L) in comparison with 9% of the nondiabetic subjects, suggesting that chronic hyperglycemia or past episodes of severe hypoglycemia may affect the central nervous system and thereby increase the diabetic child’s risk for convulsions when plasma glucose declines.” (Ryan & Becker 1999)

The link appears to be particularly strong in people with refractory epilepsy – the type that cannot be controlled by antiseizure medications – who often present with abnormal oral glucose tolerance test.

Undiagnosed glucose metabolic disturbances have been suggested as possible reason for some cases of epilepsy being unresponsive to medications.

“All 30 patients with difficult-to-treat epilepsy had at least one point on the OGTT (oral glucose tolerance test) curve below the normal range…During chronic hypoglycemia, the brain adapts to the low circulating levels of glucose…Yet, it may be speculated that daily mild episodes of hypoglycemia repeated over many years or even decades may contribute to neuronal damage…stabilization of glucose levels, that is, avoidance of both highs and lows, may be critical for adequate seizure control.” (Vianna et al. 2006)

Aggression is seen in some people with epilepsy, especially refractory epilepsy. The precise nature of the link between seizures and aggression is not clear but there is strong evidence of the involvement of abnormal glucose metabolism.

“Clinical histories of aggressive behavior of the children generally included reports of outbursts of aggressive attacks during which they would push, kick, bite, or hit other persons and occasionally, hurt themselves. Four aggressive children had…substantial autistic symptoms.” (Juhasz 2001)

Disturbed brain glucose metabolism in those with epilepsy and aggressive behaviour may point to a dysfunction of the regions of the brain that are crucial for self-control (see previous section).

“The analysis demonstrated extensive glucose hypometabolism in the aggressive group bilaterally in the temporal and prefrontal cortex…The findings indicated that the lower the glucose metabolism in the affected temporal and prefrontal cortical regions, the more severe the aggression.” (Juhasz 2001)

Serotonin, cholesterol and other biological factors implicated in aggression – all roads lead to glucose?

Various neurotransmitters play a key role in aggression and violent outbursts, including serotonin, dopamine, and adrenalin.

Serotonin, for example, has an important role in regulation of feelings of anger and aggressive urges. Low levels of serotonin in the central nervous system have even been proposed to predict aggressive behaviours, with serotonin deficiency observed in individuals who engage in impulsive and violent behaviour.

“We postulate that a functional serotonergic deficit may be conducive to poor impulse control, circadian rhythm and glucose metabolism disturbances, and that these disturbances are conducive of violent outbursts.” (Roy et al. 1988)

Glucose metabolism is thought to be an important factor in brain serotonin synthesis and signalling, via its role in cholesterol synthesis. Glucose is the basic building block for brain cholesterol, and reduced supply of glucose leads to reductions in the levels of brain cholesterol. Cholesterol, on the other hand, is a major factor that determines the levels and turnover of serotonin in the brain.

“Low cholesterol and violent behaviour might be related to decreased serotonin transmission…which may lead to a poorer suppression of impulsive behaviour.” (Mascitelli et al. 2010)

“Many studies support a significant relation between low cholesterol levels and poor impulse, aggression and mood control. Evidence exists also for a causal link between low brain serotonin (5-HT) activity and these behaviors.” (Buydens-Branchey et al. 2000)

Incidentally, levels of cholesterol in the blood seem to be significantly perturbed in people with autism – a recent study by a group of Canadian researchers showed that the prevalence of hypocholesterolemia (low cholesterol) in people with autism was more than four times higher than in the general population, although some other studies actually observed increased levels of blood cholesterol in autism.

“We observed four times more hypocholesterolemia in ASD than in the general population. Furthermore, low total cholesterol in ASD was associated with higher rates of ASD-associated intellectual disability and anxiety/depression.” (Benachenhou et al. 2019)

It is not entirely clear in what ways disturbances in blood cholesterol levels are reflective of what is going on in the brain, but some researchers have suggested that “since membrane cholesterol exchanges freely with cholesterol in the surrounding medium, a lowered serum cholesterol concentration may contribute to a decrease in brain serotonin, with poorer suppression of aggressive behaviour.” and that “it is plausible that a lowered serum cholesterol concentration might contribute to a decrease in brain serotonin function.” (Kunugi et al. 1997).

Astrocytes, glucose and brain energy reserves – relevance to hyperactivity and/or aggression

Astrocytes are a specialised cells in the brain. They play a key role in regulating glucose and energy metabolisms in the brain. When glucose enters the brain from the blood some of it is used directly by the neurons as their fuel, and some glucose is taken up by astrocytes and turned into glycogen, to be ‘warehoused’ away for later use (by being first converted into lactate).

During low availability of glucose from the blood, or during increased demand such as prolonged or strenuous exercise, the glycogen stored in astrocytes is released and used as reserve fuel by neurons.

These glycogen stores are the main energy reserve of the brain and play an important role in learning and memory formation. Reduced ability of astrocytes to store or utilise glycogen has negative consequences on learning and memory, has been associated with seizures, Alzheimer’s disease, and type 2 diabetes.

Importantly, creation and utilisation of brain energy reserves is reduced when the astrocytes are in the state of immune stimulation and inflammation, as is the case in autism.

This creation of ‘energy reserves’ and the control of those reserves by astrocytes can be negatively affected by disturbances and fluctuations in the levels of blood sugar in the rest of the body, as well as by pathological states such as inflammation.

It is interesting to note that astrocytes can be stimulated by the sympathetic nervous system to release their energy storage.

Epinephrine (adrenaline) and norepinephrine (noradrenaline) are hormones that the body releases when under extreme stress or perceived danger – that is, when the sympathetic nervous system response is engaged. These hormones, as well as the neurotransmitter dopamine – all of which have been linked to aggressive outbursts – stimulate astrocytes to release their storage of glycogen/glucose and in this way provide fuel to neurons when normal sources of energy are in low supply.

It has been proposed therefore that some acts of aggression, or even hyperactivity, could be a form of self-stimulation. In other words, in situations where person’s brain energy supply is low, aggression and/or hyperactivity, may serve as a way of obtaining energy for the brain.

“Inattention and impulsivity may be related to…decreased neuronal energy availability…At least some forms of ADHD may be viewed as cortical, energy-deficit syndromes secondary to catecholamine-mediated hypofunctionality of astrocyte glucose and glycogen metabolism, which provides activity-dependent energy to cortical neurons.” (Todd 2001)

Recent research also has suggested a link between stress and cytokines (signalling molecules within the immune system). Cytokines may inform the brain of the presence of pathogens in the body, thus triggering a stress-like response, which in turn may increase the person’s ‘readiness’ for conflict and aggression.

“Cytokines, small proteins that support communication between cells of the immune system, can be produced by and influence the function of astrocytes…TNF-alpha and IL-1 can fundamentally perturb the energy metabolism of astrocytes promoting the uptake of glucose without either storing it as glycogen or releasing lactate…This disruption can therefore not only impair short-term demands for energy, but also the long-term requirements for development.” (Russell et al. 2006)

What can be done – possible reasons and solutions for disturbed glucose metabolism

Low or unregulated levels of glucose in the body or in the brain have been linked to various factors, many of which seem to play a role in autism. Those include inflammatory processes in the body and the brain, infections as well as autoimmune phenomena – this article on the links between autoimmune encephalitis and autism, especially regressive autism.

Alternatively, some of the agents that control glucose metabolism might be promising for reducing aggression in autism and related disorders.

Ketogenic and/or low carbohydrate diets

Ketogenic diet provides ketones as fuel sources in the human body, and the ketone bodies cross the blood brain barrier and replace glucose as the main fuel for the brain – even though the brain is dependent on glucose as a primary source of energy, it is capable of utilising ketones when little glucose is available, such as during fasting, starvation or while the person is following ketogenic diet.

“By acting as a supplementary fuel, ketone bodies may free up glucose for its other crucial and exclusive function…glucose-sparing effect of ketone bodies may underlie the effectiveness of ketogenic in epilepsy and major neurodegenerative diseases, which are all characterized by brain glucose hypometabolism.” (Zilberter and Zilberter, 2020)

The Ketogenic diet has been shown to improve many features of autism, including aberrant behaviours and the common comorbidity of seizures in some individuals.

In experimental animal studies it was shown that those animals who were fed high-carbohydrate diet had a marked decrease in their brain glucose utilisation. This was especially evident in animals that were fed a diet high in carbohydrate but low in protein. This combination of nutrients was found to reduce availability and utilisation of glucose in the brain and led to brain dysfunction.

A Modified Atkins diet, which also provides ketones (albeit in lower levels than the Ketogenic diet) has been shown to improve many of the features in autism, including aberrant behaviours, in some individuals.

In the context of diet it should be mentioned that uncooked cornstarch has demonstrated a great efficacy for prevention of low blood sugar. Parental reports indicate beneficial effects from resistant starches in some children with autism. (We previously published a report by a parent whose child with autism experienced lifechanging improvements from uncooked cornstarch drink given at bedtime).

Medical cannabis

Medical cannabis, apart from being a promising treatment for improving some core feature of autism, was shown in one study to be effective at reducing rage attacks in over two thirds of children with autism and aggression. It is interesting to note that one of the major functions of cannabinoid signalling in human body is regulation of blood and brain glucose homeostasis, with cannabinoid receptors being expressed in both the pancreas and the brain, including parts of the brain implicated in glucose-metabolism-linked aggressive behaviours.

Regulation of glucose and lipid metabolism via cannabinoid signalling has been proposed as a target for the management of diabetes, obesity and hyperlipidemia. Incidentally, all of those disorders appear to be significantly more prevalent in people with autism compared to general population.

N-acetyl-cysteine (NAC)

Several studies have found NAC to be an effective treatment for reducing irritability, severe tantrums, self-injurious behaviours and physical aggression in a large proportion of children and young people with autism. Apart from improving calmness, decreasing aggression and agitation, supplementation with NAC also led to greater improvements in verbal communication.

While NAC is a strong antioxidant, in one study on people with multiple sclerosis NAC was observed to improve brain glucose metabolism:

“The results of this study suggest that NAC positively affects cerebral glucose metabolism in MS patients, which is associated with qualitative, patient reported improvements in cognition and attention…NAC might improve cerebral metabolism in areas of the brain known to be associated with cognitive processing, such as the frontal and temporal lobes.” (Monti et al. 2020)

Selective serotonin reuptake inhibitors

SSRI fluvoxamine is one of several agents that has been shown to reduce aggression in adults with autism. While the primary mode of action is most likely linked to direct regulation of serotonin (the mood hormone) signalling by fluvoxamine, the possibility that its positive effects in autism are linked to brain glucose metabolism cannot be discounted.

Selective serotonin reuptake inhibitors are known to improve glucose metabolism in the areas of the brain that are implicated in lack of inhibition and aggressive behaviours.

Dextromethorphan

Dextromethorphan (DXM) is another therapeutic agent that has also been shown to reduce aggression in autism. Although it is commonly assumed that its effects in autism are due to regulation of NMDA receptors in the brain, DXM also has beneficial effects on insulin secretion and glucose regulation.

DMX and other agents that act on NMDA receptors, which are expressed in the pancreas alongside the brain, have been recommended for treatment of type 2 diabetes.

“The NMDA receptor antagonist dextromethorphan (DXM) and its metabolite dextrorphan (DXO) have been recommended for treatment of type 2 diabetes mellitus because of their beneficial effects on insulin secretion.” (Gresch and Duefer, 2020)

Oxytocin

Intranasal oxytocin is one of the most promising therapeutic agents for reducing aggression and improving social behaviours in autism. This anti-aggressive effect of oxytocin is further supported by results from experimental animal studies:

“This study emphasizes the importance of brain oxytocinergic signaling for regulating (aggression). …Oxytocin receptor agonists could clinically be useful for curbing heightened aggression seen in a range of neuropsychiatric disorders like antisocial personality disorder, autism, and addiction.” (Calcagnoli et al. 2013)

While oxytocin is involved in many process in human body and has wide-ranging effects, in recent years there has been increasing evidence of its beneficial in glucose metabolism.

“Oxytocin reduces body weight and fat and improves glucose homeostasis, highlighting its potential as a targeted therapy for metabolic disorders such as obesity and diabetes mellitus.” (Lawson, 2017)

Propranolol

Propranolol is another agent that was found in the studies to reduce aggression in autism. In this context it should be mentioned that propranolol raises the glycogen content in the brain.

Amantadine

In several clinical case reports and small studies amantadine was shown effective for reducing aggressive and irritable behaviours in autism and other neurodevelopmental disorders, as well traumatic brain injury. One of its modes of actions appears to be regulation of brain glucose metabolism and improved availability of glucose in prefrontal cortex – the part of brain that regulates impulse inhibition and self-control.

Other treatment options for normalising glucose metabolism

Other medications, supplements and physical activities that improve availability of glucose to the brain might be worthy of consideration for improving antisocial behaviours and reducing aggression.

One such agent is intranasal insulin, which has shown beneficial effects for reducing stress response induced by socially stressful situations in humans. In animal studies intranasal insulin has also shown promising results for preventing cognitive decline and epilepsy. 

“Intranasally administered insulin enters the brain directly via olfactory neurons enabling the amelioration of CNS glucose metabolism while minimizing systemic hypoglycemia…In six children with 22q13 deletion syndrome, 1-year intranasal insulin treatment led to the significant amelioration of gross and fine motor activities, nonverbal communication, cognitive functions, and autonomy.” (Manco et al. 2021)

Metformin, a drug used to treat diabetes, has been found to correct social deficits and abnormal behaviours in a mouse model of autism. Metformin has also been shown to be beneficial for individuals with Fragile X Syndrome, a genetic disorder with teh highest incidence of autism of all known genetic disorders. Amongst other positive effects noted in the studies, metformin reduced aggressive outbursts in children and adults with Fragile X and autism.

Verapamil and other calcium channel blockers have been suggested as a possible therapeutic agent for normalising glucose metabolism in the brain. It has been shown that those agents are capable of reducing aggressive and hostile behaviours in animals, but data on humans is lacking.

Physical exercise has been suggested as another possible way of regulating glucose metabolism, as it normalises fasting and post-meal insulin levels.

Other possible reasons for aggression in autism

Many other factors – both biological and psychological –  can cause aggressive behaviours in autism. Most are still the subject of research and beyond the scope of this article. However, we can briefly mention a few of them:

• Physical pain and discomfort.
• Sensory processing disturbances — when otherwise normal occurrences and circumstances are wrongly interpreted by the senses as threatening and fearful.
• Social rejection – however there are indications that aggression as a reaction to social rejection can be linked to glucose metabolism, in particular low brain glucose availability resulting in lack of self-control and regulation of impulses, as described in this paper:

Our findings suggest that self-regulation failure may underlie the relationship between social rejection and aggression. Compared to participants who drank a glucose-laden beverage, those who drank a beverage sweetened with a sugar substitute behaved more aggressively in the wake of social rejection…This effect was most pronounced among highly rejection sensitive participants. In other words, aggression was highest at high levels instigation (social rejection), low levels of inhibition (sugar substitute beverage), and high levels of impellance (high rejection sensitivity). (Pfundmair et al. 2015)

Glossary:

Glycemic control

– balancing of blood sugar levels

Hypoglycemia

– lowered levels of glucose in the blood. Hypoglycemia deprives the brain of the constant supply of glucose needed for energy

Relative hypoglycemia

– a drop in blood sugar levels that happens in response to a high carbohydrate food intake and drinks containing caffeine

Hyperglycemia

– increased levels of glucose in the blood

Glycogen

– the ‘packed for storage’ form of glucose, the substance our body’s make to store glucose for later use. Glycogen is stored in various organs, mainly the liver and the muscles, but it is also found in the brain. Disturbances in brain glycogens metabolism have been linked to inflammation, epilepsy, confusion, learning and memory problems, hyperactivity and aggressive and violent behaviours.

Nocturnal hypoglycemia

– lowered blood sugar episodes that occur during sleep
“Nocturnal hypoglycemia seems to have no immediate detrimental effect on cognitive function; however, on the following day, mood and well-being may be adversely affected. Recurrent exposure to nocturnal hypoglycemia may impair cognitive function.” Nocturnal hypoglycemia can be prevented by ingestion of bedtime snacks or a drink of resistant starches (which has been reported to improve sleep in some children with autism!).

Exercise-induced hypoglycemia

– lowering of blood sugar that is caused by physical exhaustion, mostly due to increased utilisation of glucose. It can occur up to 17 h after cessation of strenuous physical activity.

References:

Abraham, S. et al. (2015) ‘Trait anger but not anxiety predicts incident type 2 diabetes: The Multi-Ethnic Study of Atherosclerosis (MESA)’, Psychoneuroendocrinology. Elsevier Ltd, 60, pp. 105–113. doi: 10.1016/j.psyneuen.2015.06.007.

al-Mudallal, A. et al. (1995) ‘Effects of unbalanced diets on cerebral glucose metabolism in the adult rat’, Neurology. Neurology, 45(12), pp. 2261–2265. doi: 10.1212/WNL.45.12.2261.

Alia-Klein, N. et al. (2014) ‘Reactions to media violence: it’s in the brain of the beholder’, PloS one. PLoS One, 9(9). doi: 10.1371/JOURNAL.PONE.0107260.

Anil Kumar, B. et al. (2017) ‘Regional Cerebral Glucose Metabolism and its Association with Phenotype and Cognitive Functioning in Patients with Autism’, Indian journal of psychological medicine. Indian J Psychol Med, 39(3), pp. 262–270. doi: 10.4103/0253-7176.207344.

Ashford, M., Beall, C. and McCrimmon, R. (2012) ‘Hypoglycaemia: exercise for the brain?’, Journal of neuroendocrinology. J Neuroendocrinol, 24(10), pp. 1365–1366. doi: 10.1111/J.1365-2826.2012.02345.X.

Badawy, R. et al. (2013) ‘Cortical excitability changes correlate with fluctuations in glucose levels in patients with epilepsy’, Epilepsy & behavior : E&B. Epilepsy Behav, 27(3), pp. 455–460. doi: 10.1016/J.YEBEH.2013.03.015.

Bak, L. K. et al. (2018) ‘Astrocytic glycogen metabolism in the healthy and diseased brain’, The Journal of Biological Chemistry. American Society for Biochemistry and Molecular Biology, 293(19), p. 7108. doi: 10.1074/JBC.R117.803239.

Bak, L. K. and Walls, A. B. (2018) ‘Astrocytic glycogen metabolism in the healthy and diseased brain’, Journal of Biological Chemistry. Elsevier, 293(19), pp. 7108–7116. doi: 10.1074/JBC.R117.803239.

Barchel, D. et al. (2019) ‘Oral Cannabidiol Use in Children With Autism Spectrum Disorder to Treat Related Symptoms and Co-morbidities’, Frontiers in pharmacology. Front Pharmacol, 9(JAN). doi: 10.3389/FPHAR.2018.01521.

Baruch, N. et al. (2014) ‘An evaluation of the use of olanzapine pamoate depot injection in seriously violent men with schizophrenia in a UK high-security hospital’, Therapeutic Advances in Psychopharmacology, 4(5), pp. 186–192. doi: 10.1177/2045125314531982.

Benachenhou, S. et al. (2019) ‘Implication of hypocholesterolemia in autism spectrum disorder and its associated comorbidities: A retrospective case-control study’, Autism research : official journal of the International Society for Autism Research. Autism Res, 12(12), pp. 1860–1869. doi: 10.1002/AUR.2183.

Bender, C., Calfa, G. and Molina, V. (2016) ‘Astrocyte plasticity induced by emotional stress: A new partner in psychiatric physiopathology?’, Progress in neuro-psychopharmacology & biological psychiatry. Prog Neuropsychopharmacol Biol Psychiatry, 65, pp. 68–77. doi: 10.1016/J.PNPBP.2015.08.005.

Benton, D. (1988) ‘Hypoglycemia and aggression: a review’, The International journal of neuroscience. Int J Neurosci, 41(3–4), pp. 163–168. doi: 10.3109/00207458808990722.

Benton, D. (2007) ‘The impact of diet on anti-social, violent and criminal behaviour’, Neuroscience and Biobehavioral Reviews, pp. 752–774. doi: 10.1016/j.neubiorev.2007.02.002.

Benton, D., Kumari, N. and Brain, P. F. (1982) ‘Mild hypoglycaemia and questionnaire measures of aggression’, Biological Psychology, 14(1–2), pp. 129–135. doi: 10.1016/0301-0511(82)90020-5.

Biag, H. M. B. et al. (2019) ‘Metformin treatment in young children with fragile X syndrome’, Molecular Genetics & Genomic Medicine. John Wiley & Sons, Ltd, 7(11), p. e956. doi: 10.1002/MGG3.956.

Bjørklund, G. et al. (2018) ‘Cerebral hypoperfusion in autism spectrum disorder’, Acta neurobiologiae experimentalis. Acta Neurobiol Exp (Wars), 78(1), pp. 21–29. Available at: https://pubmed.ncbi.nlm.nih.gov/29694338/ (Accessed: 18 July 2021).

Bohringer, A. et al. (2008) ‘Intranasal insulin attenuates the hypothalamic-pituitary-adrenal axis response to psychosocial stress’, Psychoneuroendocrinology. Psychoneuroendocrinology, 33(10), pp. 1394–1400. doi: 10.1016/J.PSYNEUEN.2008.08.002.

Boris, M. et al. (2007) ‘Effect of pioglitazone treatment on behavioral symptoms in autistic children’, Journal of neuroinflammation. J Neuroinflammation, 4. doi: 10.1186/1742-2094-4-3.

Bushman, B. J. et al. (2014) ‘Low glucose relates to greater aggression in married couples’, Proceedings of the National Academy of Sciences of the United States of America. National Academy of Sciences, 111(17), pp. 6254–6257. doi: 10.1073/pnas.1400619111.

Buydens-Branchey, L. et al. (2000) ‘Low HDL cholesterol, aggression and altered central serotonergic activity’, Psychiatry research. Psychiatry Res, 93(2), pp. 93–102. doi: 10.1016/S0165-1781(99)00126-2.

Calcagnoli, F. et al. (2013) ‘Antiaggressive activity of central oxytocin in male rats’, Psychopharmacology. Psychopharmacology (Berl), 229(4), pp. 639–651. doi: 10.1007/S00213-013-3124-7.

Capano, L. et al. (2018) ‘A pilot dose finding study of pioglitazone in autistic children’, Molecular Autism. BioMed Central, 9(1). doi: 10.1186/S13229-018-0241-5.

Chandrasekaran, S. et al. (2015) ‘Aggression is associated with aerobic glycolysis in the honey bee brain’, Genes, brain, and behavior. NIH Public Access, 14(2), p. 158. doi: 10.1111/GBB.12201.

Chen, S. et al. (2021) ‘Association of maternal diabetes with neurodevelopmental disorders: autism spectrum disorders, attention-deficit/hyperactivity disorder and intellectual disability’, International journal of epidemiology. Int J Epidemiol, 50(2), pp. 459–474. doi: 10.1093/IJE/DYAA212.

Coggan, J. et al. (2018) ‘Norepinephrine stimulates glycogenolysis in astrocytes to fuel neurons with lactate’, PLoS computational biology. PLoS Comput Biol, 14(8). doi: 10.1371/JOURNAL.PCBI.1006392.

Cummins, C., Lust, W. and Passonneau, J. (1983) ‘Regulation of glycogenolysis in transformed astrocytes in vitro’, Journal of neurochemistry. J Neurochem, 40(1), pp. 137–144. doi: 10.1111/J.1471-4159.1983.TB12663.X.

Dean, O. M. et al. (2019) ‘Does N-acetylcysteine improve behaviour in children with autism?: A mixed-methods analysis of the effects of N-acetylcysteine’, Journal of Intellectual and Developmental Disability. Routledge, 44(4), pp. 474–480. doi: 10.3109/13668250.2017.1413079.

DeWall, C. N. et al. (2011) ‘Sweetened blood cools hot tempers: Physiological self-control and aggression’, Aggressive Behavior, 37(1), pp. 73–80. doi: 10.1002/AB.20366.

Dienel, G. A. and Cruz, N. F. (2015) ‘Contributions of Glycogen to Astrocytic Energetics during Brain Activation’, Metabolic brain disease. NIH Public Access, 30(1), p. 281. doi: 10.1007/S11011-014-9493-8.

Dienel, G. and Cruz, N. (2016a) ‘Aerobic glycolysis during brain activation: adrenergic regulation and influence of norepinephrine on astrocytic metabolism’, Journal of neurochemistry. J Neurochem, 138(1), pp. 14–52. doi: 10.1111/JNC.13630.

Dienel, G. and Cruz, N. (2016b) ‘Aerobic glycolysis during brain activation: adrenergic regulation and influence of norepinephrine on astrocytic metabolism’, Journal of neurochemistry. J Neurochem, 138(1), pp. 14–52. doi: 10.1111/JNC.13630.

Engelberg, H. (1992) ‘Low serum cholesterol and suicide’, The Lancet. Elsevier, 339(8795), pp. 727–729. doi: 10.1016/0140-6736(92)90609-7.

Estler, C. and Ammon, H. (1966) ‘The influence of the beta-sympathicolytic agent propranolol on glycogenolysis and glycolysis in muscle, brain and liver of white mice’, Biochemical pharmacology. Biochem Pharmacol, 15(12), pp. 2031–2035. doi: 10.1016/0006-2952(66)90231-0.

Gailliot, M. and Baumeister, R. (2007) ‘The physiology of willpower: linking blood glucose to self-control’, Personality and social psychology review : an official journal of the Society for Personality and Social Psychology, Inc. Pers Soc Psychol Rev, 11(4), pp. 303–327. doi: 10.1177/1088868307303030.

Ghaleiha, A. et al. (2015) ‘A pilot double-blind placebo-controlled trial of pioglitazone as adjunctive treatment to risperidone: Effects on aberrant behavior in children with autism’, Psychiatry research. Psychiatry Res, 229(1–2), pp. 181–187. doi: 10.1016/J.PSYCHRES.2015.07.043.

Ghanizadeh, A. and Derakhshan, N. (2012) ‘N-acetylcysteine for treatment of autism, a case report’, Journal of Research in Medical Sciences : The Official Journal of Isfahan University of Medical Sciences. Wolters Kluwer — Medknow Publications, 17(10), p. 985. Available at: /pmc/articles/PMC3698662/ (Accessed: 18 July 2021).

Gresch, A. and Düfer, M. (2020) ‘Dextromethorphan and Dextrorphan Influence Insulin Secretion by Interacting with K ATP and L-type Ca 2+ Channels in Pancreatic β-Cells’, The Journal of pharmacology and experimental therapeutics. J Pharmacol Exp Ther, 375(1), pp. 10–20. doi: 10.1124/JPET.120.265835.

Haagensen, A. M. J. et al. (2014) ‘High fat, low carbohydrate diet limit fear and aggression in göttingen minipigs’, PLoS ONE. Public Library of Science, 9(4). doi: 10.1371/journal.pone.0093821.

Hanigan, M., Heisler, M. and Choi, H. J. (2020) ‘Relationship between county-level crime and diabetes: Mediating effect of physical inactivity’, Preventive Medicine Reports. Elsevier Inc., 20. doi: 10.1016/j.pmedr.2020.101220.

Higashida, H. et al. (2019) ‘Social Interaction Improved by Oxytocin in the Subclass of Autism with Comorbid Intellectual Disabilities’, Diseases (Basel, Switzerland). Diseases, 7(1), p. 24. doi: 10.3390/DISEASES7010024.

Hoirisch-Clapauch, S. and Nardi, A. E. (2019) ‘Autism spectrum disorders: let’s talk about glucose?’, Translational Psychiatry. Nature Publishing Group, 9(1). doi: 10.1038/S41398-019-0370-4.

Holubcikova, J. et al. (2015) ‘The mediating effect of daily nervousness and irritability on the relationship between soft drink consumption and aggressive behaviour among adolescents’, International Journal of Public Health. Birkhauser Verlag AG, 60(6), pp. 699–706. doi: 10.1007/s00038-015-0707-6.

Huang, Y. et al. (2021) ‘Intranasal oxytocin in the treatment of autism spectrum disorders: A multilevel meta-analysis’, Neuroscience and biobehavioral reviews. Neurosci Biobehav Rev, 122, pp. 18–27. doi: 10.1016/J.NEUBIOREV.2020.12.028.

Hwang, J. and Sherwin, R. (2018) ‘Verapamil is a potential therapy for hypoglycaemic brain injury’, Nature reviews. Endocrinology. Nat Rev Endocrinol, 14(8), pp. 443–444. doi: 10.1038/S41574-018-0056-7.

Im, D. (2021) ‘Treatment of Aggression in Adults with Autism Spectrum Disorder: A Review’, Harvard review of psychiatry. Harv Rev Psychiatry, 29(1), pp. 35–80. doi: 10.1097/HRP.0000000000000282.

Juhász, C. et al. (2001) ‘Bilateral medial prefrontal and temporal neocortical hypometabolism in children with epilepsy and aggression’, Epilepsia. Epilepsia, 42(8), pp. 991–1001. doi: 10.1046/J.1528-1157.2001.042008991.X.

King B. et al. (2001) Case series: amantadine open-label treatment of impulsive and aggressive behavior in hospitalized children with developmental disabilities. J Am Acad Child Adolesc Psychiatry. ;40(6):654-657. doi:10.1097/00004583-200106000-00009

Köfalvi, A. et al. (2016) ‘Stimulation of brain glucose uptake by cannabinoid CB2 receptors and its therapeutic potential in Alzheimer’s disease’, Neuropharmacology. Neuropharmacology, 110(Pt A), pp. 519–529. doi: 10.1016/J.NEUROPHARM.2016.03.015.

Kosaka, H. et al. (2012) ‘Long-term oxytocin administration improves social behaviors in a girl with autistic disorder’, BMC psychiatry. BMC Psychiatry, 12. doi: 10.1186/1471-244X-12-110.

Kraus M. et al. (2005) Effects of the dopaminergic agent and NMDA receptor antagonist amantadine on cognitive function, cerebral glucose metabolism and D2 receptor availability in chronic traumatic brain injury: a study using positron emission tomography (PET). Brain Inj. ;19(7):471-479. doi:10.1080/02699050400025059

Kumawat, V. and Kaur, G. (2019) ‘Therapeutic potential of cannabinoid receptor 2 in the treatment of diabetes mellitus and its complications’, European journal of pharmacology. Eur J Pharmacol, 862. doi: 10.1016/J.EJPHAR.2019.172628.

Kupis, L. et al. (2021) ‘Altered patterns of brain dynamics linked with body mass index in youth with autism’, Autism research : official journal of the International Society for Autism Research. Autism Res, 14(5), pp. 873–886. doi: 10.1002/AUR.2488.

Lauretti, E. et al. (2017) ‘Glucose deficit triggers tau pathology and synaptic dysfunction in a tauopathy mouse model’, Translational Psychiatry 2017 7:1. Nature Publishing Group, 7(1), pp. e1020–e1020. doi: 10.1038/tp.2016.296.

Lauretti, E. and Praticò, D. (2015) ‘Glucose deprivation increases tau phosphorylation via P38 mitogen‐activated protein kinase’, Aging Cell. Wiley-Blackwell, 14(6), p. 1067. doi: 10.1111/ACEL.12381.

Lavoie, S. et al. (2011) ‘Altered Glycogen Metabolism in Cultured Astrocytes from Mice with Chronic Glutathione Deficit; Relevance for Neuroenergetics in Schizophrenia’, PLOS ONE. Public Library of Science, 6(7), p. e22875. doi: 10.1371/JOURNAL.PONE.0022875.

Lawson, E. (2017) ‘The effects of oxytocin on eating behaviour and metabolism in humans’, Nature reviews. Endocrinology. Nat Rev Endocrinol, 13(12), pp. 700–709. doi: 10.1038/NRENDO.2017.115.

Lecavalier, L., Leone, S. and Wiltz, J. (2006) ‘The impact of behaviour problems on caregiver stress in young people with autism spectrum disorders’, Journal of Intellectual Disability Research. John Wiley & Sons, Ltd, 50(3), pp. 172–183. doi: 10.1111/J.1365-2788.2005.00732.X.

Lee, C. et al. (2016) ‘Glucose Tightly Controls Morphological and Functional Properties of Astrocytes’, Frontiers in aging neuroscience. Front Aging Neurosci, 8(APR). doi: 10.3389/FNAGI.2016.00082.

Lee, T.-M. et al. (2020) ‘Effectiveness of N-acetylcysteine in autism spectrum disorders: A meta-analysis of randomized controlled trials’:, https://doi.org/10.1177/0004867420952540. SAGE PublicationsSage UK: London, England, 55(2), pp. 196–206. doi: 10.1177/0004867420952540.

Li-Byarlay, H. et al. (2014) ‘Socially responsive effects of brain oxidative metabolism on aggression’, Proceedings of the National Academy of Sciences of the United States of America. National Academy of Sciences, 111(34), p. 12533. doi: 10.1073/PNAS.1412306111.

Li, C., Jones, P. and Persaud, S. (2011) ‘Role of the endocannabinoid system in food intake, energy homeostasis and regulation of the endocrine pancreas’, Pharmacology & therapeutics. Pharmacol Ther, 129(3), pp. 307–320. doi: 10.1016/J.PHARMTHERA.2010.10.006.

Li, Q. et al. (2021) ‘A Ketogenic Diet and the Treatment of Autism Spectrum Disorder’, Frontiers in pediatrics. Front Pediatr, 9. doi: 10.3389/FPED.2021.650624.

Liu, S. et al. (2019) ‘Glycemic Control is Related to Cognitive Dysfunction in Elderly People with Type 2 Diabetes Mellitus in a Rural Chinese Population’, Current Alzheimer Research. Bentham Science Publishers Ltd., 16(10), pp. 950–962. doi: 10.2174/1567205016666191023110712.

Luarte, A. et al. (2017) ‘Astrocytes at the Hub of the Stress Response: Potential Modulation of Neurogenesis by miRNAs in Astrocyte-Derived Exosomes’, Stem Cells International. Hindawi Limited, 2017. doi: 10.1155/2017/1719050.

MacLaren, R. D., Wisniewski, K. and MacLaren, C. (2018) ‘Environmental concentrations of metformin exposure affect aggressive behavior in the Siamese fighting fish, Betta splendens’, PLoS ONE. Public Library of Science, 13(5). doi: 10.1371/JOURNAL.PONE.0197259.

Manco, M. et al. (2021) ‘Cross-sectional investigation of insulin resistance in youths with autism spectrum disorder. Any role for reduced brain glucose metabolism?’, Translational psychiatry. Transl Psychiatry, 11(1). doi: 10.1038/S41398-021-01345-3.

Matsui, T. et al. (2017) ‘Astrocytic glycogen-derived lactate fuels the brain during exhaustive exercise to maintain endurance capacity’, Proceedings of the National Academy of Sciences. National Academy of Sciences, 114(24), pp. 6358–6363. doi: 10.1073/PNAS.1702739114.

McCrimmon, R. et al. (1999) ‘Anger state during acute insulin-induced hypoglycaemia’, Physiology & behavior. Physiol Behav, 67(1), pp. 35–39. doi: 10.1016/S0031-9384(99)00036-0.

McGrane I.R. et al. (2016) Adjunctive Amantadine Treatment for Aggressive Behavior in Children: A Series of Eight Cases. J Child Adolesc Psychopharmacol. ;26(10):935-938. doi:10.1089/cap.2016.0042

Medrano, S., Gruenstein, E. and Dimlich, R. (1992) ‘Histamine stimulates glycogenolysis in human astrocytoma cells by increasing intracellular free calcium’, Brain research. Brain Res, 592(1–2), pp. 202–207. doi: 10.1016/0006-8993(92)91677-7.

Merbis, M. et al. (1996) ‘Hypoglycaemia induces emotional disruption’, Patient education and counseling. Patient Educ Couns, 29(1), pp. 117–122. doi: 10.1016/0738-3991(96)00940-8.

Mergenthaler, P. et al. (2013) ‘Sugar for the brain: the role of glucose in physiological and pathological brain function’, Trends in neurosciences. Trends Neurosci, 36(10), pp. 587–597. doi: 10.1016/J.TINS.2013.07.001.

Miederer, I. et al. (2017) ‘Effects of tetrahydrocannabinol on glucose uptake in the rat brain’, Neuropharmacology. Neuropharmacology, 117, pp. 273–281. doi: 10.1016/J.NEUROPHARM.2017.02.011.

Mohammadi M. et al. (2013) Double-blind, placebo-controlled trial of risperidone plus amantadine in children with autism: a 10-week randomized study. Clin Neuropharmacol. ;36(6):179-184. doi:10.1097/WNF.0b013e3182a9339d

Monti, D. et al. (2020) ‘N-acetyl Cysteine Administration Is Associated With Increased Cerebral Glucose Metabolism in Patients With Multiple Sclerosis: An Exploratory Study’, Frontiers in neurology. Front Neurol, 11. doi: 10.3389/FNEUR.2020.00088.

Moses, L., Katz, N. and Weizman, A. (2014) ‘Metabolic profiles in adults with autism spectrum disorder and intellectual disabilities’, European psychiatry : the journal of the Association of European Psychiatrists. Eur Psychiatry, 29(7), pp. 397–401. doi: 10.1016/J.EURPSY.2013.05.005.

Moura, L. et al. (2019) ‘Chronic insulinopenia/hyperglycemia decreases cannabinoid CB 1 receptor density and impairs glucose uptake in the mouse forebrain’, Brain research bulletin. Brain Res Bull, 147, pp. 101–109. doi: 10.1016/J.BRAINRESBULL.2019.01.024.

New, A. et al. (2004) ‘Fluoxetine increases relative metabolic rate in prefrontal cortex in impulsive aggression’, Psychopharmacology. Psychopharmacology (Berl), 176(3–4), pp. 451–458. doi: 10.1007/S00213-004-1913-8.

Newcomer, J. W. et al. (2002) ‘Abnormalities in glucose regulation during antipsychotic treatment of schizophrenia’, Archives of General Psychiatry. American Medical Association, 59(4), pp. 337–345. doi: 10.1001/archpsyc.59.4.337.

Nomura, S. et al. (2014) ‘Changes in glutamate concentration, glucose metabolism, and cerebral blood flow during focal brain cooling of the epileptogenic cortex in humans’, Epilepsia. John Wiley & Sons, Ltd, 55(5), pp. 770–776. doi: 10.1111/EPI.12600.

Önder, A. et al. (2020) ‘218 The efficiency and safety of N-acetylcysteine augmentation in the autistic children with … Olgu serisi / Case series The efficiency and safety of N-acetylcysteine augmentation in the autistic children with severe irritability and aggression: six cases’, Anatolian Journal of Psychiatry, 21(2), pp. 218–221. doi: 10.5455/apd.53708.

Ozdemir, D., Karabacak, N. and Akkaş, B. (2009) ‘Differences in cerebral blood flow following risperidone treatment in children with autistic disorder’, Turk Psikiyatri Derg, 20(4), pp. 346–356.

Pachmerhiwala, R. et al. (2010) ‘Role of serotonin and/or norepinephrine in the MDMA-induced increase in extracellular glucose and glycogenolysis in the rat brain’, European journal of pharmacology. Eur J Pharmacol, 644(1–3), pp. 67–72. doi: 10.1016/J.EJPHAR.2010.07.004.

Pappas, C. et al. (2019) ‘Blood Glucose Levels May Exacerbate Executive Function Deficits in Older Adults with Cognitive Impairment’, Journal of Alzheimer’s disease : JAD. J Alzheimers Dis, 67(1), pp. 81–89. doi: 10.3233/JAD-180693.

Pedro, J. et al. (2020) ‘Transient gain of function of cannabinoid CB 1 receptors in the control of frontocortical glucose consumption in a rat model of Type-1 diabetes’, Brain research bulletin. Brain Res Bull, 161, pp. 106–115. doi: 10.1016/J.BRAINRESBULL.2020.05.004.

Peng, S. et al. (2020) ‘Low-dose intranasal insulin improves cognitive function and suppresses the development of epilepsy’, Brain research. Brain Res, 1726. doi: 10.1016/J.BRAINRES.2019.146474.

Pfundmair, M. et al. (2015) ‘Sugar or spice: Using I3 metatheory to understand how and why glucose reduces rejection-related aggression’, Aggressive Behavior. Wiley-Liss Inc., 41(6), pp. 537–543. doi: 10.1002/ab.21593.

Protic, D. et al. (2019) ‘Cognitive and behavioral improvement in adults with fragile X syndrome treated with metformin-two cases’, Molecular genetics & genomic medicine. Mol Genet Genomic Med, 7(7). doi: 10.1002/MGG3.745.

Quincozes-Santos, A. et al. (2017) ‘Fluctuations in glucose levels induce glial toxicity with glutamatergic, oxidative and inflammatory implications’, Biochimica et Biophysica Acta (BBA) – Molecular Basis of Disease. Elsevier, 1863(1), pp. 1–14. doi: 10.1016/J.BBADIS.2016.09.013.

Reznikova, T. et al. (2015) ‘The brain structures functional activity and aggression patients’ multiple sclerosis’, Fiziol Cheloveka, 41(1), pp. 35–42.

Rich, L. R., Harris, W. and Brown, A. M. (2019) ‘The Role of Brain Glycogen in Supporting Physiological Function’, Frontiers in Neuroscience. Frontiers, 0, p. 1176. doi: 10.3389/FNINS.2019.01176.

Robb, A. (2010) ‘Managing irritability and aggression in autism spectrum disorders in children and adolescents’, Developmental disabilities research reviews. Dev Disabil Res Rev, 16(3), pp. 258–264. doi: 10.1002/DDRR.118.

Robb, J. L. et al. (2020) ‘The metabolic response to inflammation in astrocytes is regulated by nuclear factor-kappa B signaling’, Glia. John Wiley & Sons, Ltd, 68(11), pp. 2246–2263. doi: 10.1002/GLIA.23835.

Rodrigues Vilela, V. et al. (2014) ‘Hypoglycemia induced by insulin as a triggering factor of cognitive deficit in diabetic children’, TheScientificWorldJournal. ScientificWorldJournal, 2014. doi: 10.1155/2014/616534.

Roy, A., Virkkunen, M. and Linnoila, M. (1988) ‘Monoamines, glucose metabolism, aggression towards self and others’, The International journal of neuroscience. Int J Neurosci, 41(3–4), pp. 261–264. doi: 10.3109/00207458808990732.

Russell, V. A. et al. (2006) ‘Response variability in Attention-Deficit/Hyperactivity Disorder: a neuronal and glial energetics hypothesis’, Behavioral and Brain Functions. BioMed Central, 2, p. 30. doi: 10.1186/1744-9081-2-30.

Sala, R. et al. (2020) ‘Bridging the Gap Between Physical Health and Autism Spectrum Disorder’, Neuropsychiatric Disease and Treatment. Dove Press, 16, pp. 1605–1618. doi: 10.2147/NDT.S251394.

Srivastava, S., Nath, C. and Sinha, J. (1997) ‘Evidence for antiaggressive property of some calcium channel blockers’, Pharmacological research. Pharmacol Res, 35(5), pp. 435–438. doi: 10.1006/PHRS.1997.0149.

Steiner, P. (2019) ‘Brain Fuel Utilization in the Developing Brain’, Annals of Nutrition and Metabolism. Karger Publishers, 75(1), pp. 8–18. doi: 10.1159/000508054.

Šterk, M. et al. (2021) ‘NMDA receptor inhibition increases, synchronizes, and stabilizes the collective pancreatic beta cell activity: Insights through multilayer network analysis’, PLoS computational biology. PLoS Comput Biol, 17(5). doi: 10.1371/JOURNAL.PCBI.1009002.

Taylor, M. and Howard, E. (1971) ‘Impaired glucose homeostasis in adult rats after corticosterone treatment in infancy’, Endocrinology. Endocrinology, 88(5), pp. 1190–1202. doi: 10.1210/ENDO-88-5-1190.

Todd, R. and Botteron, K. (2001) ‘Is attention-deficit/hyperactivity disorder an energy deficiency syndrome?’, Biological psychiatry. Biol Psychiatry, 50(3), pp. 151–158. doi: 10.1016/S0006-3223(01)01173-8.

Tromans, S. et al. (2020) ‘The Prevalence of Diabetes in Autistic Persons: A Systematic Review’, Clinical practice and epidemiology in mental health : CP & EMH. Clin Pract Epidemiol Ment Health, 16(1), pp. 212–225. doi: 10.2174/1745017902016010212.

Tyler, C. et al. (2011) ‘Chronic disease risks in young adults with autism spectrum disorder: forewarned is forearmed’, American journal on intellectual and developmental disabilities. Am J Intellect Dev Disabil, 116(5), pp. 371–380. doi: 10.1352/1944-7558-116.5.371.

Vassou, C. et al. (2020) ‘Hostile personality as a risk factor for hyperglycemia and obesity in adult populations: a systematic review’, Journal of Diabetes and Metabolic Disorders. Springer Science and Business Media Deutschland GmbH, pp. 1659–1669. doi: 10.1007/s40200-020-00551-y.

Vianna, J. et al. (2006) ‘The oral glucose tolerance test is frequently abnormal in patients with uncontrolled epilepsy’, Epilepsy & behavior : E&B. Epilepsy Behav, 9(1), pp. 140–144. doi: 10.1016/J.YEBEH.2006.05.003.

Vilela, V. R. et al. (2014) ‘Hypoglycemia Induced by Insulin as a Triggering Factor of Cognitive Deficit in Diabetic Children’, The Scientific World Journal. Hindawi Limited, 2014. doi: 10.1155/2014/616534.

Virkkunen, M. (1982) ‘Reactive hypoglyceinic tendency among habitually violent offenders: A further study by means of the glucose tolerance test’, Neuropsychobiology, 8(1), pp. 35–40. doi: 10.1159/000117875.

Virkkunen, M. et al. (1994) ‘CSF Biochemistries, Glucose Metabolism, and Diurnal Activity Rhythms in Alcoholic, Violent Offenders, Fire Setters, and Healthy Volunteers’, Archives of General Psychiatry, 51(1), pp. 20–27. doi: 10.1001/archpsyc.1994.03950010020003.

Virkkunen, M. et al. (2009) ‘Low non-oxidative glucose metabolism and violent offending: An 8-year prospective follow-up study’, Psychiatry Research. Elsevier, 168(1), pp. 26–31. doi: 10.1016/J.PSYCHRES.2008.03.026.

Volkow, N. D. et al. (1995) ‘Brain glucose metabolism in violent psychiatric patients: a preliminary study’, Psychiatry Research: Neuroimaging, 61(4), pp. 243–253. doi: 10.1016/0925-4927(95)02671-J.

Wallner, B. and Machatschke, I. (2009) ‘The evolution of violence in men: the function of central cholesterol and serotonin’, Progress in neuro-psychopharmacology & biological psychiatry. Prog Neuropsychopharmacol Biol Psychiatry, 33(3), pp. 391–397. doi: 10.1016/J.PNPBP.2009.02.006.

Walters, R. P. et al. (2016) ‘Frontal lobe regulation of blood glucose levels: support for the limited capacity model in hostile violence-prone men’, Brain Informatics. Springer Berlin Heidelberg, 3(4), pp. 221–231. doi: 10.1007/s40708-016-0034-6.

Watanabe, T. et al. (2015) ‘Clinical and neural effects of six-week administration of oxytocin on core symptoms of autism’, Brain : a journal of neurology. Brain, 138(Pt 11), pp. 3400–3412. doi: 10.1093/BRAIN/AWV249.

White, J. and Rumbold, G. (1988) ‘Behavioural effects of histamine and its antagonists: a review’, Psychopharmacology. Psychopharmacology (Berl), 95(1), pp. 1–14. doi: 10.1007/BF00212757.

Wilder, R. (1921) ‘The effects of ketonemia on the course of epilepsy’, Mayo Clin Proc, 2.

Wink, L. K. et al. (2016) ‘A randomized placebo-controlled pilot study of N -acetylcysteine in youth with autism spectrum disorder’, Molecular Autism 2016 7:1. BioMed Central, 7(1), pp. 1–9. doi: 10.1186/S13229-016-0088-6.

Young, A. et al. (2011) ‘Aberrant NF-kappaB expression in autism spectrum condition: a mechanism for neuroinflammation’, Frontiers in psychiatry. Front Psychiatry, 2(MAY). doi: 10.3389/FPSYT.2011.00027.

Yulug, B. et al. (2016) ‘Topiramate: A Novel Therapeutic Candidate for Diabetes and Aggression? Positron Emission Tomography (PET) Findings’, Central nervous system agents in medicinal chemistry. Cent Nerv Syst Agents Med Chem, 16(3), pp. 227–230. doi: 10.2174/1871524916666160301102055.

Zhang, M. et al. (2019) ‘Altered Peak C-peptide and Fasting Blood Glucose in Children with Autism Spectrum Disorder’, Journal of Diabetes and Clinical Research. Scientific Archives LLC, 1(2). doi: 10.33696/DIABETES.1.008.

Zhang, Y. et al. (2013) ‘Ketosis proportionately spares glucose utilization in brain’, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. J Cereb Blood Flow Metab, 33(8), pp. 1307–1311. doi: 10.1038/JCBFM.2013.87.

Zhao, Y. et al. (2017) ‘Decreased Glycogen Content Might Contribute to Chronic Stress-Induced Atrophy of Hippocampal Astrocyte volume and Depression-like Behavior in Rats’, Scientific Reports 2017 7:1. Nature Publishing Group, 7(1), pp. 1–14. doi: 10.1038/srep43192.

Zilberter, Y. and Zilberter, T. (2020) ‘Glucose-Sparing Action of Ketones Boosts Functions Exclusive to Glucose in the Brain’, eNeuro. eNeuro, 7(6), pp. 1–7. doi: 10.1523/ENEURO.0303-20.2020.