Aggression In Autism – One Simple Cause
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:
- Largely unknown and almost always missed.
- In some cases, it could be relatively easy to address.
- Most importantly, there are many indications that this particular cause of aggression is frequently present in individual with autism.
Introducing… blood (and brain) glucose.
“Thus, a relatively wide body of evidence suggests that low glucose and poor glucose tolerance lead to aggressive, antisocial, and even criminal behavior. Low glucose and poor glucose tolerance are associated with increased aggression.”
(Gailliot & Baumeister, 2007)
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)
“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.”
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.
“Aggression and violence often start when self-control stops. For society to function peacefully, people must control their aggressive impulses. Self-control requires a lot of brain food in the form of glucose. Thus, people who have difficulty metabolizing glucose (breaking it down into an useful form and keeping it at constant levels) are at a greater risk for aggressive and violent behavior.”
(DeWall et al. 2011)
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, 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.
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 (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)
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 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.
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.
“The strongest evidence base (from controlled trials) preliminarily suggests beneficial effects of risperidone, propranolol, fluvoxamine, vigorous aerobic exercise, and dextromethorphan/quinidine for treating aggression in adults with ASD.”
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)
– balancing of blood sugar levels
– lowered levels of glucose in the blood. Hypoglycemia deprives the brain of the constant supply of glucose needed for energy
– a drop in blood sugar levels that happens in response to a high carbohydrate food intake and drinks containing caffeine
– increased levels of glucose in the blood
– 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.
– 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!).
– 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.
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Metabolism is the process through which our bodies convert nutrients from food and drink into energy. We need energy for the basics of life, such as breathing or blood circulation, and so countless metabolic processes take place in our cells and our organs all the...
High rates of depression and suicide in autism Depression is a common and serious problem in autism, and one of the main contributors to poor quality of life. Both children and adults with autism experience high rates of depression and other mood disorders. One...
Autoimmune encephalitis is a class of inflammatory diseases of the brain that can present with a wide spectrum of neurological and psychiatric symptoms. The word autoimmune means that the body, or the person’s immune system, is attacking its own healthy tissues.What...
‘From Bench to Biopharma’ International Conference on Translational Research in Autism – Day 1 Recap
Synchrony symposia, organised by The BRAIN Foundation in partnership with UC Davis MIND Institute and CalTech, is the first and only international conference on translational research in autism that brings together academia, biotech, pharmaceutical companies and...
The Synapse Centre for NeurodevelopmentThe Synapse Centre, based within the ESNEFT (East Suffolk and North Essex NHS Foundation Trust) is a new research centre based in the East of England looking to translate biomedical research into practical therapies for local...
“We must first recognise ASD as a whole body disorder” Autism, or Autism Spectrum Disorder ASD, is traditionally seen as the result of behavioural and neuropsychiatric dysfunction. However there is a strong evidence that various physical, or biomedical, problems can...
The first Brain Foundation annual symposia, Pleasanton, California 8-10 of Nov 2019, aimed to connect researchers with clinicians, donors & stake holders to help translate research efforts into evidence-based treatments for autism and its co-morbidities. It highlighted the need for multidisciplinary collaboration, detailed diagnostics and personalised treatment…
One of the treatment modalities that has shown the greatest promise for reducing symptoms of autism in recent years is transcranial direct current stimulation (tDCS). The most recent study confirmed and expanded on the findings of previous investigations, which strongly indicate that tDCS could have positive effects on cognition, behaviour and physical health, and improve quality of life and autonomy for a large percentage of individuals with autism.
Several studies published in recent months investigated the effects of cannabis-based products for treating autism. Although the studies were open-label and relatively small in scale, the overall results were overwhelmingly positive, with statistically significant improvements in social communication, language, restrictive/repetitive and challenging behaviours.
A small double-blind, placebo-controlled trial shows dramatic effects of suramin as a treatment for autism. Improvements were seen in all three core features of autism: language, social interactions, and restricted or repetitive behaviours across multiple diagnostics in multiple tests in all who received the active treatments, absent in the placebo arm
Children with Congenital Heart Disease, Tuberous Sclerosis Complex, Duchenne Muscular Dystrophy, Ehlers-Danlos Syndrome, Neurofibromatosis Type 1 suffer high rates of autism. Everolimus, an mTOR inhibitor with strong neuro-inflammation attenuating effects, reduces core autism symptoms in some children with TSC, epilepsy and autism…
Numerous medical conditions are significantly more prevalent in children and adults with autism, including allergy and/or immunologic, musculoskeletal, neurologic, psychiatric and gastrointestinal conditions. Early childhood health problems can be used to spot children at high risk of autism…