Ampakines - An Overview
Ampakines are a class of nootropic drugs that modulate the brain’s AMPA receptors and may have a positive effect on:22Zheng Y, et al. <a href=”https://www.ncbi.nlm.nih.gov/pubmed/22171951″
- Memory and learning
Ampakines may prove to be a novel new treatment for various conditions such as Alzheimer’s, Parkinson’s, treatment-resistant depression, ADHD, schizophrenia, and others.
There are several ampakines currently in development and undergoing clinical trials that may hit the market soon.
Ampakines can increase the size and duration of excitatory synaptic responses and induce the expression of neurotrophic factors as well.23Arai A, et al. <a href=”https://www.ncbi.nlm.nih.gov/pubmed/7911064″
This indicates that ampakines can have a large effect on increasing certain kinds of brain activity and improving brain plasticity.
What Does Ampakines Do?
There is currently clinical evidence that ampakines can have a nootropic effect on cognition.
One preliminary study on rats shows ampakines enhanced their ability to focus and pay attention. On the other hand, it did show a decrease in object recognition memory.1Zheng Y, et al. <a href=”https://www.ncbi.nlm.nih.gov/pubmed/22171951″
Anther rats study reduced two measures of exploratory activity in aged rats but increased the speed of performance in a radial maze. The drug also caused substantially improved retention of spatial information.2C. Mike Davis, et al. <a href=”https://link.springer.com/article/10.1007/s002130050386″
There is evidence that ampakines are effective in enhancing synaptic responses, most likely by slowing deactivation. This could be the source of its cognitive enhancement.3Arai AC, et al. <a href=”https://www.ncbi.nlm.nih.gov/pubmed/10999951″
Learning and Memory
It seems that ampakines can selectively improve at least some aspects of memory.
4Ingvar M, et al. <a href=”https://www.ncbi.nlm.nih.gov/pubmed/9270067″
The ampakine BDP-12 can enhance synaptic responses even at lower levels.
This means that less activation is required to trigger a reaction, leading to quicker information transmission.6Arai A, et al. <a href=”https://www.ncbi.nlm.nih.gov/pubmed/8768713″
One study found that these drugs enhance AMPA-type glutamate receptors by selectively increasing hippocampal spatial cell firing.
This action can improve both acquisition performance and memory retention in middle-aged rats to levels equivalent to those found in young adult animals.
In other words, it effectively turned back the clock on the brains of older rats.7Granger R, et al. <a href=”https://www.ncbi.nlm.nih.gov/pubmed/8867027″
The ampakine BDP-12 can reduce the amount of training needed for the formation of long-term memory in rats.8Larson J, et al. <a href=”https://www.ncbi.nlm.nih.gov/pubmed/8613739″
BD12 was also shown to enhance AMPA-type glutamate receptors to selectively increase hippocampal spatial cell firing, which improves both acquisition performance and memory retention in middle-aged rats.9Granger, R, Deadwyler, S, Davis, M, et al. <a href=”https://escholarship.org/content/qt9b38c3s0/qt9b38c3s0.pdf?t=pgcgu0″
Another study found that ampakines improved memory in three behavioral tasks.
Researchers concluded that ampakines could cross the blood-brain barrier and facilitate glutamatergic transmission in a way that enhances the encoding of memory across tasks.10U Staubli, G Rogers, G Lynch. <a href=”https://www.ncbi.nlm.nih.gov/pmc/articles/PMC43032/”
Although most of the memory studies on ampakines have focused on animal trials, one study looked at elderly adults.
The researchers found that the subjects who took ampakines scored twice as well on memory tests, closer to the memory capacity of young subjects.11Lynch G, et al. <a href=”https://www.ncbi.nlm.nih.gov/pubmed/9184112″
Schizophrenia is a hypoglutamanergic condition, meaning sufferers may experience lower rates of glutamate transmission.
So, upregulating this process could be a potential avenue to correct this deficit.12Sokolov BP. <a href=”https://www.ncbi.nlm.nih.gov/pubmed/9832144?dopt=Abstract”
The experimental ampakine BDP-29/CX564 greatly attenuated methamphetamine-induced hyperactivity, which was used as a model of psychosis.13John Larson, et al. <a href=”https://www.sciencedirect.com/science/article/pii/S0006899396010499″
Ampakines enhanced the action of typical and atypical antipsychotics like haloperidol and clozapine synergistically. This result suggests that ampakines may be useful as an adjunct therapy with traditional drugs.14Johnson SA, et al. <a href=”https://www.ncbi.nlm.nih.gov/pubmed/10087029″
Similar results were also obtained in a study with 1-BCP.15Vanover KE. <a href=”https://www.ncbi.nlm.nih.gov/pubmed/9286612″
In a human clinical study, the ampakine CX516 was added to clozapine in 4-week, placebo-controlled trial.
CX516 was tolerated well and was associated with moderate to large improvements in attention and memory compared with the placebo.
These preliminary results suggest that CX516 and similar compounds hold promise for the treatment of schizophrenia.16Goff DC, et al. <a href=”https://www.ncbi.nlm.nih.gov/pubmed/11593073″
One trial looked at ampakines on animal testing models commonly used to identify clinically useful antidepressants.
The preliminary findings indicate that biarylpropylsulfonamide-type ampakines, exemplified by LY392098, may represent a novel class of antidepressants.17Li X, et al. <a href=”https://www.ncbi.nlm.nih.gov/pubmed/11406194″
Another rat study also suggests that ampakines may have antidepressant activity.
The authors of this study noted that the rats that took the ampakines displayed less depressive behavior, even more so than the rats on traditional antidepressants.18Knapp RJ, et al. <a href=”https://www.ncbi.nlm.nih.gov/pubmed/11959085″
Although there are no human trials on ampakines and depression currently, it seems to be a promising avenue for future research, and we look forward to seeing more studies.
Like the racetams from which they were derived, ampakines seem to have a neuroprotective quality.
One study saw a significant improvement in rats with methamphetamine-induced lesions when they were given ampakines CX546 or CX614.
Results were evident within 15 minutes of behavioral testing, indicating that ampakines may be particularly fast-acting neuroprotectives.19U.S Hess, et al. <a href=”https://www.sciencedirect.com/science/article/abs/pii/S0306452203004238″
How Ampakines Works In The Brain
Ampakines and Aniracetam
Aniracetam is one of the most popular racetams for nootropics enthusiasts, with proven effects for memory and mood.
In 1990 researchers discovered they could selectively activate AMPA receptors via the ampakine aniracetam.20I Ito S Tanabe A Kohda H Sugiyama. <a href=”https://physoc.onlinelibrary.wiley.com/doi/abs/10.1113/jphysiol.1990.sp018081″
Aniracetam wasn’t designed specifically for the AMPA receptors, but this discovery provided a plausible explanation for a nootropic action for the first time.
However, aniracetam, despite its efficacy in some experimental settings, did not appear to have much clinical utility, in part because it is metabolized rapidly and requires relatively large doses.
So, using aniracetam as a point of departure, researchers began developing a separate family of drugs termed Ampakines. These drugs are the most widely studied group of AMPA receptor modulators, and they have been systematically tested for their effects on synaptic transmission, synaptic plasticity, activity in neuronal circuits, gene expression, and neuronal survival.
These efforts led to the discovery of IDRA-21, the alkyl-benzothiadiazide D1, S18986-1, and the pyridothiadiazines.
They also uncovered new compounds with distinct structural components such as PEPA and the biarylpropylsulfonamides, which are presently among the most potent AMPA receptor modulators
Ampakines can be orders of magnitude more potent than Aniracetam.21Arai AC, et al. <a href=”https://www.ncbi.nlm.nih.gov/pubmed/10999951″
The development of ampakines was largely guided by measuring their effectiveness in enhancing synaptic transmission rather than by their ability to block desensitization of AMPA receptor currents
Ampakines Potential Side Effects
So far, initial trials saw no negative influence on heart rate, blood pressure or mood.
However, there is also evidence that ampakines might cause headaches, somnolence, and nausea.
There is also the possibility that shifting cortical neural plasticity in favor of long-term potentiation (long term memory) could lead to impairments in spatial memory and perhaps motor function.
We strive to bring you the most up to date, research-based information about Ampakines and other nootropics.
Something we missed? Do you use Ampakines? Share your thoughts and experiences in the comments below.
About the author:
Erik Levi is a co-founder of HolisticNootropics.com and a certified holistic nutritional therapy practitioner.
As an NTP Erik takes a nutrition first approach to health. He has worked with many different people to help them use nutrition to optimize their quality of life.
Erik believes that mental health is a physiological process and cognitive enhancement is not something that can be achieved by just taking some pills with good Amazon reviews.
Instead, true cognitive enhancement comes with the right balance of nutrients, movement, and gratitude. Erik continues to stay up to date with the most current nootropic and holistic health research and promises to deliver the best solutions possible.
You can check out his personal health blog/podcast/YouTube Channel all under the name Holistic A-Hole.