Probably the most well-known type of nootropics are the cholinergic supplements, especially the racetam family. Cholinergics aren’t the only class of mechanism of action for nootropics by a long shot. Most always, nootropics affect the functioning of one or more neurotransmitter systems or specific subreceptors. AMPAkines are in some cases some of the most potent of all the different  classes of nootropic supplements. Ampakines derive their name from AMPA, a subreceptor of glutamate, the primary excitatory neurotransmitter. Ampakines  have a stimulating effect due to their activity related to the Glutamate AMPA subreceptors in the brain.

Ampakines are benzamide compounds which modulate the AMPA receptors. Aniracteam, piracetam, sunifiram, unifiram, IDRA-21, CX516, CX546 and BDP are just some of the chemical compounds classed as Ampakine. Generally ampakines are considered nootropic and as a result possess some cognitive enhancing potential related to their effect on neurotransmission, memory, learning and long

MECHANISM OF ACTION: AMPAKINES

AMPAkines, as we mentioned, specifically modulate AMPA receptors in the hippocampus. It is the hippocampus that is responsible for storing short term memory as well as processing, encoding, pattern completion, and pattern separation. The hippocampus is formed of densely-packed neurons containing glutamate, which is also the most prevalent neurotransmitter in the body and brain.  AMPA receptors enable rapid excitatory transmissions from one neuron to the next. Neurotransmission is based on an “all or nothing” principle and only occurs if a sufficient electrical charge is present. This happens at the intersection between dendrites (the “branches” at the end of a nerve) known as the synapse. The synapse is the junction between two neurons and any inward or outward movement of ions takes place across these channels within the cell membrane. AMPA subreceptors specifically interact with glutamate. .

What ampakines do is to prolong the time the ion channels are open. This increases the glutamergic excitatory effect. Any neurotransmitter will be either inhibitory or excitatory. Inhibitory neurotransmitters (like GABA and its subreceptors) inhibit the firing of neurons, whereas the excitatory neurotransmitters (like AMPA or glutamate) excite the neurons causing them to fire off.

Cells in your brain containing AMPA receptors show potentiated calcium signaling which results in increased single-channel conductance of electrical signals and, as a result, reduced receptor deactivation. This is the process known as long-term-potentiation which is vital to the growth of new interconnections in the neural net. Ampakines seem to specifically and significantly affect the pyramidal neurons in the hippocampus (where short term memories are formed) and cerebral cortex.

This translates into an increase in glutamergic neurotransmission which in turn can result in more favorable conditions related to learning, memory, focus as well as neuroplasticity and long-term-potentiation, which are fundamental to cognition. Plasticity is the ability to be molded, so neuroplasticity is vital when critical thinking and other executive or creative tasks are being exercised.

Some anecdotal evidence suggests users claiming an improved attention span, improved concentration, better comprehension, memory boost and even improvement in reasoning skills and confidence levels. This is no accident either. In addition to improved focus and memory, ampakines are theorized to have a possible beneficial affect related to some psychological disorders from ADD and ADHD to schizophrenia.

Ampakines aren’t as common as the more well known and widely available cholinergic supplements like piracetam or noopept. Technically, however several racetams (and noopept, which behaves like a racetam in many ways) have some weak to moderate ampakine activity in addition to their primary mechanism of action as cholinergics.

Ampakines, as the new kids on the block, aren’t as widely studied and researched as the classic nootropics. For the moment though, like other nootropics, they seem well-tolerated with few side effects.

In addition to their activity on the AMPA receptors, ampakines also act on the NMDA receptors. Both NMDA and AMPA receptors rely on the glutamergic system for proper functioning. Currently, researchers are looking for safe and effective ways to specifically modulate both of these receptor system. It is theorized that specific modulation of AMPA and NMDA may lead to a breakthrough in the prevention and treatment of certain types of age related cognitive diseases like Alzheimer’s and mild forms of dementia.

Since ampakines act on the systems related to glutamate, the primary excitatory neurotransmitter, they should be used as directed to safeguard against excitotoxicity. Excitotoxicity can result in brain cell death due to a dangerous overfiring of neurons. When the brain has too much glutamate produced, excess firing can lead to potentially dangerous excitotoxicity. When the neurons over-fire they can literally burn themselves out.

Excess glutamate is a common cause of this. In fact, the preservative MSG (that is often banned in many Chinese restaurants) is known as mono-sodium glutamate and can lead to excitotoxicity itself. Long term exposure to high levels of glutamate may result in cell death, so over use of ampakines is not suggested. Luckily, there are other supplements that specifically reduce the danger of excitotoxic neuronal death. In fact, most of the primary racetams (oxiracetam, aniracetam and piracetam) which are already considered weak or “hybrid” ampakines have some potential to reduce the potential for glutamergic excitotoxicity.

EXPERIMENTAL AMPAKINES
A certain group of ampakines are currently being researched and produced by the company Cortex Pharmaceuticals, based in Irvine, California. The researchers at Cortex Pharmaceuticals are working on treatments for Alzheimers and ADD and ADHD. The research has covered most of the last decade and currently both animal and human trials have taken place.

CX-516, is one of the first experimental ampakine prescription drugs from Cortex. Ampalex, Ampalex showed excellent results in animal trials, but in humans the drug was shown to have a very low potency and short half-life (duration of effects).

CX-717 is the next from Cortex Pharmaceuticals. It was shown to be stronger by a long shot than the other possible ampakine prescription drugs. In addition, it shows potential application in both Alzheimer’s and ADD/ADHD treatment. According to internal studies by Cortex, CX-717 is effective for treatment in these conditions. The FDA still has the drug on hold currently due to potential concerns related to tissue toxicology based on tests on animal subjects so there will be more time involved before it’s available as a pharmaceutical therapy.

Eli Lilly is working on a new ampakine based prescription drug, LY-404187. It has been shown to be an effective BDNF (brain derived neurotrophic factor) protein stimulator. BDNF has an important role in the formation of new neurons and synaptic connections which, once again, is vital to long term potentiation and the formation of new memories and long-term memory creation. So far, Eli Lilly’s experimental medication has shown potential as a therapy for improving cognitive decline as well as being a potential treatment for schizophrenia, Parkinson’s and ADD and/or ADHD.

Many of the new nootropics like CX-516 (Ampalex), CX-614, CX-546, CX-717 and LY-404187 are in the Ampakine class. These are currently being researched as potential treatments for mental decline and other brain disorders from ADD to schizophrenia.

TYPES OF AMPAKINES

There are multiple types of ampakines. Many of these ampakines already in use have a long history of being used as nootropics, while others are new and still considered experimental, research compounds. Two of the more well known of the ampakines are sunifiram and unifiram. Sunifiram is theorized to be some 1,000 times as potent as piracetam and is taken in doses around 5mg. Aniracetam and pramiracetam are classed as racetams which means their primary mechanism of action will be as cholinergics, but they are also classed as weak or mild ampakines.

Many of the experimental ampakines are still very expensive which may make them cost prohibitive for the average nootropic user. As these drugs become more common the price may eventually drop. For now though, some ampakine supplements are being used to treat Parkinson’s, Alzheimers or even depression.

One of the secrets to the effectiveness of ampakines across the board are stimulating the AMPA and NMDA receptors. Improving the interconnections in the neural net allowing the brain to communicate. More connections means improved neuronal transmission and faster signaling. As well as improving neuroplasticity and facilitating long term potentiation to ensure memories are stored long term.

One of the primary concerns with ampakines, as we’ve mentioned is the potential for excitotoxic danger is used improperly. As with any nootropic supplement, it’s important to take them as directed and use them at the minimum effective dosage. In the case of certain experimental, research nootropics that work on AMPA, if there is a potential for excitotoxicity, adding aniracetam, or piracetam or other nootropics that help prevent excitotoxicity may be advised.