This post was written by the original Peak Nootropics blog team and has been recreated for reference purposes:
If you’re already using or considering using nootropic supplements, then chances are you’re already fairly educated about supplement use and cognitive enhancement. However, one important thing to remember is that if you’re using substances to increase intelligence, the best way to do so is to utilize each of these compounds to suit your own chemistry.
It will be vital to ensure that you use each nootropic safely and efficiently in order to get the maximum return from your personal enhancement routine. Educating yourself about the basics of how these substances work such as how they interact with each other and the best way to use them should be your first step. After you have achieved this, you can begin “tweaking the control panel,” so to speak.
The simplest way to maximize the efficiency of your supplementation schedule and cut down on negative side effects is by adding to your knowledge base. This article will cover the interactions of neurotransmitters and their systems. Understanding these systems and how the brain works may help you understand your own personal chemistry.
HOW DO NEUROTRANSMITTERS WORK & INTERACT WITHIN THE BRAIN?
One important thing to keep in mind when attempting any major biological, physiological or psychological change is the function of homeostasis on the applicable biological system. The human brain seeks a constant state of homeostasis, which is the tendency of a system to self-regulate its internal conditions in order to create a balance.
When using supplements, drugs and nootropics, the brain strives for the correct balance. There are a series of complex systems that take place within the brain, ranging from every neuron firing to each neurotransmitter system working to create an action. These neurotransmitters work to activate signals within the brain that regulate every single activity of our lives. The delicate balance of these systems can sometimes be put off kilter, either naturally or through the use of drugs or supplements.
THE GABA & GLUTAMATE RELATIONSHIP
GABA and Glutamate are the two most abundant neurotransmitters within the brain, and they work in balance with each other. GABA is inhibitory, and Glutamate is excitatory. Glutamate stimulates our senses and enhances learning and memory. In fact, Glutamate receptor activation is the primary method of action of both the racetam and ampakine nootropic families. GABA on the other hand calms and relaxes the brain on a psychological and physiological level.
Too much glutamatergic activity can be a negative thing. For example, an overabundance of Glutamate within brain synapses can contribute to excitotoxicity, which is a high accumulation of Glutamate that leads to neuronal cell death. Excitotoxicity is one of the leading theories behind many neurodegenerative diseases. In essence, Glutamate receptor activity can be positive for cognitive function, but if levels of activity get too high, it could lead to brain damage through excitotoxicity.
GABA works alongside Glutamate to help reduce the levels of excitability. High levels of Glutamate can lead to advanced levels of excitability and increased brain function, but over-activity is known to cause brain damage. GABA is a calming neurotransmitter that is synthesized from Glutamate. GABAergic activity calms the brain and can help to decrease stress and anxiety, boost mood and reduce insomnia. When levels of Glutamate are high, the brain strives for homeostasis by increasing GABAergic activity. In this way, the brain regulates between excitable and inhibitory states. Too much Glutamatergic activity may lead to oxidative stress and even seizures, whereas high levels of GABAergic activity may lead to fatigue and cognitive impairment.
There are many drugs that regulate GABA and Glutamate. Ampakine nootropics may help to increase the level of Glutamate receptor activity, which may lead to increased learning and memory function. Most Ampakines aren’t believed to increase the level of Glutamate within the brain, but rather, activate the receptors. On the other hand, food additives such as Aspartame and Monosodium Glutamate directly increase or mimic the levels of Glutamate which may lead to excitotoxicity.
Drugs like benzodiazepines and Phenibut mimic GABA and activate GABA receptors. Over-using GABAergic drugs and supplements may lead to down-regulation of GABA receptors. Down-regulation will cause the brain to release and activate less GABA naturally. This is the main reason why using GABAergic drugs regularly can be very dangerous. Down-regulation of the GABAergic system may increase the levels of Glutamate, which in turn would lead to excitotoxicity. Due to this, there is a link between the use of benzodiazepines and Alzheimer’s disease.
Before you begin using any type of nootropic supplement, you should understand the link between GABA and Glutamate. Stay away from neurotoxins like MSG and Aspartame that are known to increase Glutamate. Also, taking certain brain antioxidants such as ALCAR may help to reduce free radicals associated with excitotoxicity.
Ampakines have not been shown to be neurotoxic. However, one should consider the risks when using Ampakines like Sunifiram as there could be dangers with these newer types of nootropics. They are less studied and long term use has not been established. Racetams with some glutamatergic activity are a safer bet than direct ampakines.
You should steer clear of down-regulating GABA receptors. You can help yourself avoid this potential issue by avoiding regular consumption of alcohol, Phenibut and benzodiazepines. The GABA-a subtype receptors are extremely hard to upregulate once they have been down-regulated. Benzodiazepines are the worst for doing this and some people experience brain damage and long-term withdrawals, consisting of persistent anxiety and insomnia even years of discontinued use. There is even a link between Alzheimer’s disease and regular benzodiazepine use.
THE DOPAMINE & SEROTONIN RELATIONSHIP
Dopamine and Serotonin are two complex monoamine neurotransmitters with opposing interactions. Both of these monoamine neurotransmitters can help regulate mood, memory, learning, emotions and social interaction. A dysfunction or any off-balance in either system can contribute to variety of impairments and disorders including cognitive impairment.
Dopamine is the “reward” neurotransmitter. It is excitatory and has a large role in memory, learning, focus, motivation and social behaviours. Dopamine is the primary neurotransmitter thought to regulate our goals and desires. Low Dopamine can lead to depression and memory loss in some people. These low levels can even make us feel a lack of purpose or enjoyment due to the missing reward aspect.
It is also theorized that people with low Dopamine or dopaminergic activity may be more likely to become addicted to stimulant drugs like cocaine or highly dangerous and daring acts such as gambling and sexual promiscuity. These people are likely seeking the “high” associated with Dopamine and endorphin release that is missing from their natural chemistry.
Although Dopamine sounds great, high levels of Dopamine or a dysfunction of regulation can have extremely negative consequences. Disorders such as Borderline Personality Disorder, Parkinson’s disease, Schizophrenia, ADHD and Psychosis have all been linked to Dopamine dysfunction. Apart from these disorders, high Dopamine has also been linked to aggressive and impulsive behaviour.
People with low Dopamine levels can benefit from many type of Dopaminergic drugs. Modafinil works as a wakefulness enhancer nootropic by increasing extracellular levels of Dopamine. Doctors usually prescribe Modafinil as an alternative to dangerous stimulants to combat daytime fatigue, narcolepsy and sometimes even as an off-label option for bipolar-depression and ADHD.
Other drugs and stimulants like Adderall, which work with the Dopamine and the related Norepinephrine system, are usually prescribed for ADHD. Amphetamine drugs are more dangerous and affect Dopamine as well as the closely related neurotransmitter, Norepinephrine. These drugs, while they may improve mood, focus and productivity, can also lead to addiction and psychosis from down-regulation or hyperactivity in the Dopamine system. They can also have negative benefits on physical health due to effects on the central nervous system (mostly related to Norepinephrine).
In some cases, other safer Dopamine drugs such as MAO-B inhibitors and NDRI’s may be prescribed for mood and anxiety disorders. People with low Dopamine activity or dysfunction may be able to improve mood, cognition and quality of life through the usage of these safer and less addictive drugs.
Serotonin, like Dopamine, also regulates cognitive function, mood, social behaviours, sleep cycles and appetite. Unlike Dopamine, Serotonin is inhibitory. Higher levels of Serotonin have been linked to stable moods, increased satisfaction and submissive behaviour. Because of these factors, Serotonin has become a target for most modern-day antidepressant drugs.
Serotonin has less of an impact on focus and motivation and more of a connection with memory and learning than Dopamine does. It is less of a nootropic neurotransmitter and more of a mood regulator than Dopamine. Although it has been a target for many antidepressant medications like SSRI’s, it generally has a stabilization effect. These drugs and supplements can also have a range of side effects.
Having healthy levels of Serotonin is generally good. However, high activity can have its downsides. Higher serotonergic activity has been linked to “emotional blunting”. This is perhaps the most common complaint received from patients who are prescribed SSRI’s. Emotional blunting is described as a reduction in emotional responses, including the ability to feel sadness, anger, irritability, sexual pleasure and desire. High levels of serotonergic activity can have serious sexual side effects in both males and females. It may also create a reduction in the ability to achieve goals or take risks due to a reduced desire for rewards.
All of this brings us to an interesting point about Dopamine and Serotonin. These two systems are striving for homeostasis, and raising the activity in one may affect the other. In fact, these systems have almost opposite effects. Dopamine controls risk/reward mechanisms, wakefulness, focus, motivation, sexual desire and appetite. Meanwhile, Serotonin controls mood stability, social submission, sleep cycles, hunger, contentment and learning.
Having higher or lower levels of either neurotransmitter activity can lead to variety of disorders or issues, depending on a person’s physiology. That is why some people experience negative reactions to certain drugs. It is important to understand this closely knit web that controls our quality of life. You are advised to be extremely careful when using drugs that modulate these systems because they may have the opposite effect rather than those that are intended. Supplement precursors such as 5HTP, L-Tryptophan, L-Dopa and L-Tyrosine are actually much safer if you have low levels of a certain neurotransmitter.
Acetylcholine and the Glutamate receptors are the primary targets of Nootropics such as Piracetam and the other racetams because they are believed to have fewer side effects and addictive potential than Dopaminergic targets. This section will discuss the actions Acetylcholine.
Although the Acetylcholine content in the brain is much less than the other neurotransmitters, it has a variety of important functions. These functions include learning and memory, muscle contraction and sensory perception. Just like the other systems, Acetylcholine, or the cholinergic system, is essential for our daily survival.
Activation of Acetylcholine receptors have been linked to increased learning and memory, reading skills, verbal fluency and test scores. Acetylcholine is synthesized from natural choline and is prominent in the brain and throughout our bodies. One can also raise Acetylcholine through supplements. It controls many nerve functions that operate muscle contractions. Cognitive function is also another believed action of this nootropic neurotransmitter. In fact, cholinergic drugs have been the topic of study for many potential treatments in cognitive impairments and diseases.
Like the other neurotransmitters, Acetylcholine also strives for homeostasis. This neurotransmitter is both excitatory and inhibitory, depending on its particular application.
Acetylcholine has a series of complex interactions with the other neurotransmitter systems. It has been suggested in rat studies that certain Acetylcholine receptor activation may cause Dopamine, Norepinephrine and Glutamate release in certain parts of the brain. The Norepinephrine release observed from Acetylcholine activation also appears to induce partial GABA release as a response to the release.
There is some evidence that Acetylcholine release may be mediated through Serotonin activation but not the other way around. It is possible that Acetylcholine receptor activation may not release Serotonin and actually lower the level in parts of the brain. This theory might explain why some people experience higher irritability and depression through elevated Acetylcholine production and receptor activation.
There are some claims that suggest racetams and cholinergics might have side effects such as irritability, depression and brain fog. This could be a result of indirectly increasing the Dopamine and Norepinephrine release in certain parts of the brain through Acetylcholine receptor activation. This release may in turn, reduce serotoninergic activity thus producing these side effects.
Some racetam users complain about experiencing brain fog and headaches when using racetams, and this may also relate to parts of the complex cholinergic activity. More study is needed to see why some people experience these effects and others do not because a combination of homeostasis of certain neurotransmitters and differing brain chemistry is likely a major factor.