When we think of common side effects of ADHD medications (especially of the stimulant variety), we often consider things such as cardiovascular risks (increased heart rates and blood pressure), appetite suppression (which may subsequently result in temporary growth impairment), interference with sleep, dampening of creativity and emotions (i.e. taking on a zombie-like state), irritability, moodiness, and the like.
However, it appears that another equally important, but often less-considered side effect of many ADHD medications is a change in blood sugar and glucose metabolism. The first part of this post will investigate some of the research out there on the effects of common ADHD medications on brain glucose metabolism. The second half will zero in on some of the general metabolic differences between the ADHD brain and the non-ADHD brain, and will also investigate possible effects of age, gender and co-existing disorders:
- A drop in blood sugar following methylphenidate treatment: A case study involving a diabetic woman who underwent a surgical operation for a brain tumor. While we cannot make any logical conclusions about the population based on one individual of unique needs, the fact that a pronounced drop in blood glucose (over 25%) following methylphenidate treatment is at least worth noting. It is unclear as to whether the effects were due merely to the methylphenidate (common forms of this drug include Ritalin, Metadate and Concerta), or rather to a drug-drug interaction.
- Methylphenidate reduces required brain glucose amounts to perform cognitive tasks: A study done at the National Institute of Drug abuse found that the administration of methylphenidate reduces the amount of glucose (the brain's desired energy source) needed to perform a thinking task. It is believed that this lower energy requirement is mainly due to less "wasted" energy from a constantly wandering and side-tracked mind, such as one seen in individuals with ADHD.
Interestingly, this same study also found that during non-cognitive tasks, the differences in brain energy requirements did not change with or without the drug. This may at least call into question the merits of ADHD stimulant medication usage if higher order cognitive tasks are not required. Furthermore, if the brain is already focused, the utilization of methylphenidate may even be overkill. The authors concluded that this may be a primary reason why adverse effects in concentration and focus can be seen when methylphenidate is administered to "normal" functioning brains. - Methylphenidate's influence on brain metabolism may be regio-specific: Another study done by the same author as in study #2 found that the effects of methylphenidate on brain glucose metabolism may depend on individual subregions of the brain. For example, this study found that for the basal ganglia region of the brain (this brain region essentially governs how fast a particular individual's brain "idles"), the relative activity of this brain region was typically reduced following methylphenidate treatment, compared to activities in other brain areas. This may be a bit counter-intuitive, since basal ganglia activity is typically lower in individuals with ADHD and higher in individuals with obsessive compulsive or anxiety-ridden behaviors.
However, other brain regions such as the frontal and temporal regions of the brain (which are responsible for filtering out unimportant external stimuli and inhibiting impulsive behaviors, and, perhaps not surprisingly, often show lower levels of activity in the ADHD brain), experienced a boost in metabolic activity following methylphenidate treatment. It is believed that these responses are modulated through categories of receptors for the brain chemical dopamine (called Dopamine D2 receptors, which help control levels of this important neuro-signaling agent, which is often deficient in key regions of the ADHD brain).
In this blogger's opinion, this dual action of inhibiting impulsivity (which can potentially dampen creativity) and shutting down some of the basal ganglia activity may actually be a reason why "zombie-like" behaviors are sometimes seen in children medicated or overmedicated with stimulants for ADHD. - The "Energy Deficient" Hypothesis of ADHD: While still in the hypothetical stage, there is a fair amount of evidence suggesting that ADHD may be due, in a large part, to a lack of energy to specific neurons in key brain regions such as the prefrontal cortex (part of the "frontal" regions of the brain discussed in the past point). This ADHD as an energy-deficiency hypothesis carries that astrocytes (star-shaped cells that provide energy and nutrition for growth and repair of neuronal cells) may be starved of some of their important nutritional needs for glucose and related nutrients. As a result, they are unable to effectively "feed" the neurons in these key brain regions associated with governing attentional and impulsive behaviors in the brain. Should this hypothesis hold true, it would stand to reason that regulating and improving glucose levels either via either medication-manipulated, or alternative dietary methods may help offset some of the energy deficient imbalance in ADHD. Some natural supplemental options to boost glucose levels in the ADHD brain may include ginseng and carnitine.
- Reduced brain metabolism in teenagers with ADHD: The results of this study on metabolic differences in teenage ADHD brains agree with many of the findings discussed in point #3 above. This study investigated the effects of an auditory-based attentional task on rates of brain glucose metabolism in adolescents with ADHD. It found that there was minimal differences between glucose metabolic patterns in the brains as a whole when comparing the ADHD and non-ADHD individuals.
However, it is also worth mentioning that in other related studies on brain metabolism in teens with ADHD, it was found that metabolic deficits were seen at significantly lower levels throughout the brain as a whole. Interestingly, according to the second study mentioned, these differences in brain metabolism were only seen in the girls with ADHD and not the boys, which suggests possible gender-specific differences in the etiology of the disorder.
However, upon investigating for the more hyperactive forms of the disorder in the first study (remember that ADHD behaves as a spectrum, in which some individuals have the predominantly inattentive symptoms, while others exhibit the hyperactive and impulsive symptoms more readily, these different predominant features are typically grouped together as unique subtypes of ADHD), it was found that the hyperactive component of ADHD corresponded to a significantly reduced level of glucose metabolism in the whole brain. This brings up the question as to whether these metabolic differences exhibit any sort of subtype-dependent effects with regards to ADHD.
Also, as in point number 3 above, metabolic deficits were apparent in more specific brain regions such as the left frontal lobe regions of the brain. Even more remarkably, there appeared to be somewhat of a sliding scale with regards to the relationship between reduced glucose metabolism and increased symptom severity in this particular "hot spot" (the left frontal lobe) region of the ADHD brain.
The following sidenote is a personal comment by the blogger regarding some of the methods of the previous study. As mentioned above, the test for this adolescent ADHD study involved an auditory based attention task. However, as discussed in earlier posts on this blog, we have seen that auditory processing disorders sometimes accompany ADHD.
Furthermore, due to a high degree of symptom overlap, a comorbid auditory processing disorder can often be missed in an ADHD child or adolescent. Because of this, we should not rule out the possibility that comorbid auditory processing issues may interfere with the results of studies such as this one.
We can see that auditory processing takes place in multiple regions throughout the brain, many of which do not have significant overlap with the "ADHD brain regions". One would expect the brain of an individual with an auditory processing disorder to work harder to achieve the same results as that of a non-auditory disordered individual. Thus, a confounding processing disorder could, in theory result in an increased demand for energy utilization to the portions of the brain responsible for stimulatory processing, which could leave less available energy for the frontal lobe regions of the brain responsible for modulating hyperactive and impulsive ADHD behavior. These assertions remain hypothetical at the moment, but this blogger feels that the presence of undetected comorbid disorders can easily skew the results of these metabolic studies on the ADHD brain. - Age-Dependent Decline in Brain Glucose Metabolism in Adults with ADHD: Apparently, metabolic differences in ADHD brains are not limited just to children, adolescents, and young adults with the disorder. Some of the findings of this following study may seem inherently counterintuitive at first. While ADHD symptoms often decline as an individual with the disorder ages, we would expect that an accompanying level of improvement in glucose metabolism in ADHD-specific brain regions would hold true. However, according to this study on brain glucose metabolism in older ADHD adults, it appears that the opposite is actually the case.
The authors hold that the decrease in glucose metabolism may actually be markers of a more efficient process of brain metabolism (i.e. these older ADHD brains may somehow conform to an efficient energy-conservation state allowing them to function more optimally, thereby decreasing the prevalence of ADHD symptoms), although this finding is somewhat suspect in this blogger's personal opinion.
As an interesting side note, the decrease in brain glucose metabolism in adults is apparently gender-specific, according to the study. This parallels the findings from some of the adolescent ADHD brain metabolic studies. The notable metabolic decreases were observed in women with the disorder to a much larger degree in men. The authors of the study suggested this may be due to hormonal influences, such as changes in post-menopausal women.
Given the anecdotal evidence supporting the association between ADHD and higher onsets of neurodegenerative diseases later in life, this blogger finds the results of this study to be of particular interest. There may even be some claims that genetics may be partly to blame for the overlap between ADHD and neuro-degenerative diseases. For example, a gene referred to as DAT1 (short for dopamine transporter gene 1, located on the 5th human chromosome) may be connected to both ADHD and parkinsonism (a secondary or alternate form of Parkinson's disease). DAT1 also helps regulate dopamine function, (although via a different method than the dopamine receptors mentioned in point #3), by coding for an enzyme that helps transport or shuttle dopamine into and out of neuronal cells. We have discussed these dopamine transporter genes in earlier posts.
We have covered a number of works on the metabolic differences of glucose in the ADHD brain, and how they differ from the brains of non-ADHD individuals. There is the distinct possibility that stimulant medications used to treat ADHD, such as methylphenidate (Ritalin, Concerta, Metadate, Daytrana) can significantly alter brain glucose requirements. It appears that significant differences in brain glucose utilization patterns and efficiency may affect the entire brain, but certain ADHD "hot spot" regions of the brain may be particularly hard-hit. It is unclear whether this is due to preferential metabolic differences of the ADHD brain (compared to the "normal" brain), or whether it is due to an all-out brain energy shortage.
It is also worth noting that significant gender-specific factors may also affect this process, with ADHD girls in particular showing the greatest metabolic deficits. It also appears that these effects are also being observed across the lifespan of the ADHD individual. Finally, there is at least a hypothetical possibility that sensory processing difficulties or other comorbid disorders commonly seen alongside ADHD may also play a role in these metabolic differences of ADHD brains.
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