In the previous articles, we discussed the main ingredients of the human brain and how they work together in broad strokes. This was due to both the complexity of the topic and the fact that we do not know better yet. Despite great advances in neuroscience during the last century, it is safe to say we are still only scratching the surface, and it is important to keep this in mind when we start discussing the effects of drugs and diets on brain function.
This article attempts to explain how external molecules interact with our brain physiology in such profound ways as to change how we process information, the decisions we make, and the feelings inside us. If the explanations seem vague or the examples too circumspect, it is because they are. The best we can say as of now is that drugs and diets change brain neurochemistry. Their mechanisms and the full extent of its effects, however, remain largely obscure.
Coffee, the most widely consumed psychoactive drug in the world, serves well to illustrate one of the common ways whereby exogenous molecules can alter brain function. Caffeine, a natural substance that is abundant in coffee, tea, sodas and chocolate, can be absorbed into the brain where it blocks adenosine receptors. Under normal circumstances these receptors are activated by adenosine, causing feelings of fatigue and sleepiness. The molecular similarities between adenosine and caffeine are enough for the latter to bind to adenosine receptors but not enough to activate them. This means that, when consumed in large doses, caffeine can block access of adenosine to its receptors, which in turn prevents the feelings of drowsiness associated with them.
Molecular configuration of caffeine and adenosine. The red squares highlight the similar double ring structure that enables caffeine to bind to adenosine receptors.
The effects of caffeine become slightly more complex when we consider the relation between adenosine, dopamine receptors and sleep deprivation. As we have discussed in the last article, sleep deprivation and its symptoms are associated with a reduction in dopamine receptors, which curtails dopamine’s ability to stimulate and keep us awake as it usually does. While we are still not sure of how these receptors disappear, there is tantalising evidence that adenosine receptors play a role. If this is true, then ingested caffeine should block the effects of adenosine receptors on the dopamine system, which would explain how coffee prevents the symptoms of sleep deprivation.
The complexity of the interplay between caffeine and brain chemistry grows exponentially when we start to think about more indirect or long-term effects that caffeine seems to have in learning, memory, and cognition, as well as in disorders such as dementia, Parkinson’s, epilepsy, depression, schizophrenia, chronic pain, and migraines. We will discuss these interesting aspects in the future, but for now let us leave coffee on the side and take a look at synthetic drugs.
Pharmaceutical drugs differ from natural ones due to their increased potency arising from laboratory refinement, being slightly better understood from a biochemical standpoint, their controlled doses and formats, and having a clear health purpose. The history of aspirin, the pain killer that dominated the industry for over half a century, is a good example of this.
Plants and trees containing the main active substance of aspirin – acetylsalicylic acid –, such as the willow, have been used since ancient times to treat pain and fever. In the beginning of the 19th century organic chemists managed to isolate the active compound of willow bark, but their processes were too complex and inefficient. These achievements, however, paved the way for the synthesis of the substance and, by 1899, the German company Bayes was selling the drug under the name of aspirin around the world.
It was not until the 70s – two decades after the decline in popularity of aspirin - that John Vane and other researchers finally discovered the mechanism through which the drug worked. In their work, which was recognised with the Nobel Prize in 1982, they showed that aspirin works by shutting down the synthesis of Prostaglandins, a local hormone that conveys pain information to the brain, and which can also regulate the brain’s thermostat (thus explaining its anti-fever effects).
Prostaglandin is a local hormone that is synthesized in the advent of tissue damage, where it activates neurons that convey pain information to the brain. Source: Purves et al. (2001)
This indirect mechanism of aspirin, acting on the metabolism of neuronal messengers instead of binding to specific receptors like caffeine does, is shared by several other modern psychoactive drugs. Antidepressants such as iMAO and SSRI (like Prozac) affect serotonergic activity, not by binding to its receptors, but by altering the metabolism of naturally occurring serotonin (in this case, inhibiting its destruction). This approach is necessary because most neurotransmitters cannot cross the blood-brain barrier.
As psychiatric (and “natural”) drugs act blindly on broad neurotransmitter systems – which we have seen have a myriad of functions –, they inevitably carry lots of side effects besides the therapeutic ones. Look at Ritalin, the SSRI equivalent for dopamine that is commonly prescribed to treat ADHD symptoms. On the one hand, it potentiates the cognitive effects of dopamine that reduce external overstimulation, but on the other it also enhances the sleep/waking effects of dopamine, leading to frequent insomnia. Ironically, this sleep disruption might counterbalance the gains obtained during the day by the drug. For our purposes, it illustrates the inherent difficulty of modulating brain chemistry to our advantage.
SSRIs increases serotonergic activity by blocking its return to the home neuron where it is generally recycled or destroyed. CNS Stimulants have a similar effect for dopamine.
More than a culinary metaphor: The link between diet, neurotransmitters availability, and brain function
All brain processes require ingredients that, in one way or the other, depend on external input. This can happen through a generic caloric intake that provides energy for the body to produce its own ingredients, or by adapting external compounds that the body cannot synthesise into vital molecules. Such is the case of serotonin.
Serotonin is derived from tryptophan, which can only be found in food. After learning this, researchers started experimenting with tryptophan diets and other complex methods to alter internal levels of tryptophan, finding that they could lower people’s moods and increase aggressive behaviours, as would be expected when lowering levels of serotonin.
Even though dopamine synthesis does not rely on any external compound, the dopaminergic system is still susceptible to dietary factors. Like in serotonin, some of these effects are mediated by chemical precursors - as with the plant Mucuna Pruriens that contains L-DOPA - but other effects can be much less intuitive. A 2014 experiment with rats showed that chronic Omega-3 deprivation leads to changes in dopaminergic activity in association with a myriad of behaviour and cognitive impairments (anxiety, memory, cognitive flexibility). Even more interestingly, these effects were greatly exacerbated in offspring raised under the same diet, suggesting an intergenerational effect of diet in dopaminergic function.
Research suggests that changes in diet can have the greatest impact in the brain function of subsequent generations. Source: O’Connor & Cryan (2014)
If understanding the role of individual molecules is already difficult, studying what happens with entire diets seems insurmountable. Despite the challenge, researchers have been making great strides. Two examples of this include the better understanding of the effects of ketogenic diet in cortical activity associated with epilepsy, and a few epidemiological studies linking Mediterranean diet and lower depression. The ability to extract information from such a complex interplay of ingredients, metabolic factors, individual characteristics and neural systems is already astonishing, yet only indicative of what is to come.
Swiftly the brain becomes an enchanted loom, where millions of flashing shuttles weave a dissolving pattern — always a meaningful pattern — though never an abiding one. - Charles Sherrington
Credit
Ricardo Oliveira is a neuroscientist passionate about research and science divulgation, based in Portugal.
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On an April 2024 episode of The Diary of a CEO with Steven Bartlett, Gary discussed a host of interesting biohacking and healthspan ideas, including his daily routine.
