## Edit 2013-10-08 ## – We have been informed that Natural Stacks have developed a CILTEP formula in partnership with Abelard Lindsay. A potent combination of standardised artichoke and forskolin, b6 and ALCAR. Check the product out here – your purchase supports Smarter Nootropics.
My time here at The Garden has been characterized by a polarization of behaviour. When I say that, I mean that my daily activities are sprinkled across a spectrum that includes low-skill, but physically demanding manual labor, and high-functioning , technological troubleshooting.
A typical day may consist of:
Learning Ruby on Rails using Michael Hartl’s excellent (free) online tutorial
Designing web graphics using Adobe CS6
Digging 36 inch post-holes with hand tools
Writing a blog post on trending nootropic supplement stacks
You get the idea. In any case, I take in a lot of information every day. I’m also relatively active in a way that mandates mindfulness. When you’re using a 15lb pneumatically operated nail gun to install siding on a shed, the last thing you want to do is fall off your ladder and accidentally break an ankle or send a nail through your skull.
So I do what I can to keep my brain running at high level of performance. Other than the Fasting experiment, my most recent experiment in mental acuity has involved the highly theoretical CILTEP Stack. This combination of alleged “nootropics” is popular on the internet for it’s cognitive enhancing capabilities. I decided to try it for a month and see what happened.
(This is a long, research-dense read, skip to the bottom to read my experience)
What is CILTEP?
CILTEP stands for chemically-induced long-term potentiation. Long-term potentiation is a state of enhanced connection between neurons. Here’s what Trinity College Institute of Neuroscience in Dublin said in an abstract:
“Of the several animal models used in identifying the changes which accompany plasticity in synaptic connections, long-term potentiation (LTP) has received most attention, and although it is not yet clear whether the changes that underlie maintenance of LTP also underlie memory consolidation, significant advances have been made in understanding cell signaling events that contribute to this form of synaptic plasticity.”
A CILTEP stack (theoretically) induces LTP through two primary methods of action:
There are methods of (theoretically) enhancing CILTEP efficacy that I have tested which I’ll go into towards the end of this post.
1. PDE Inhibition
Many drugs act as PDE Inhibitors. Caffeine is known as a non-selective PDE Inhibitor. The recommended PDE inhibitor for purposes of CILTEP Stack is Luteolin: a flavonoid that is naturally occurring in many substances, however artichoke extract is the source we’ll discuss today.
Another popular PDE Inhibitor used by nootropic enthusiasts is Vinpocetine which selectively targets PDE1.
What are PDEs?
PDE stands for phosphodiesterase. There are eleven different families of PDE but Luteolin is only proven to inhibit 1-5.
PDE is an enzyme that breaks down secondary messengers in the brain such as cyclic Adenosine Monophosphate (cAMP) and cyclic Guanosine Monophosphate (CGMP). PDE Inhibitors have been shown to increase object memory in rats,
Evidence for PDE Inhibitors as Nootropic
All the research I’ve done yielded quite positive results in favor of PDE Inhibitors.
If you Google Scholar the terms “PDE”, “Inhibitor”, “Cognitive”, you’ll receive more than 8,000 results. Here are some of the headlines:
Selective PDE inhibitors rolipram and sildenafil improve object retrieval performance in adult cynomolgus macaques
Persistent improvement in synaptic and cognitive functions in an Alzheimer mouse model after rolipram treatment
The novel selective PDE9 inhibitor BAY 73-6691 improves learning and memory in rodents
Phosphodiesterase inhibitors enhance object memory independent of cerebral blood flow and glucose utilization in rats.
A 2008 review was strongly in favor of selective PDE inhibitors being developed for cognitive enhancement purposes. However, this particular review suggests PDE2 and PDE9 inhibitors as the best bet for positive effects on mental performance.
(Some of these drugs have been shown to “block allergen-induced contraction of passively sensitized human airways in vitro by a dual mechanism involving a direct relaxant effect on smooth muscle and inhibition of histamine…”)
A 2006 report suggests that selective inhibitors can be developed to address specific problems. Specifically, the Journal of Pharmacology says PDE4 inhibition could prevent inflammatory airway disease.
A 1988 study published by the European Archives of Psychiatry and Clinical Neuroscience suggests that PDE inhibitors have anti-depressant applications.
As far as I am aware, there is little research that suggests PDE’s are not at least somewhat effective at enhancing cognitive function.
2. cAMP Levels Improvement
The second part of the CILTEP stack involves increasing cAMP levels in order to amplify the effects of the PDE Inhibitor. Consider, if PDE breaks down cAMP, and PDE inhibition is desirable, then it isn’t a stretch to say that cAMP is the real cognitive enhancer at work here.
But it’s not that simple. We don’t know exactly how these different PDE inhibitors behave. It could be the cAMPs that improve brain function or it could be something else.
The only natural cAMP-promoter I’ve been able to find is Forskolin.
My research regarding cAMP’s role in brain activity has yielded mixed results.
Evidence Against cAMP
Yale University’s Amy Arnsten conducted a study in 2007 that concluded that cAMP-inhibition can positively affect working memory. In their own words “cAMP Suppresses PFC Neuronal Firing during Memory Tasks”
The Arnsten website specifically targets cAMP’s: ”Molecules that inhibit calcium and/or cAMP signaling strengthen network connectivity”
(The same website discusses Dopamine 1: “Optimal levels of DA enhance spatial working memory by reducing PFC neuronal firing to nonpreferred inputs”
I’d like to have someone take a second look at her data and give their feedback.
The EurekAlerta report includes the following disclaimer at the bottom of the page:
“Arnsten and Yale have a license agreement with Shire Pharmaceuticals for the development of guanfacine for treatment of patients with ADHD. Yale has submitted a patent application on the use of HCN blockers for the treatment of PFC [pre-frontal cortex, the executive brain] cognitive deficits based on the data reported in the Cell paper.”
The disclaimer also mentions that the study was sponsored by Shire Pharmaceuticals, the National Institutes on Aging, the National Institute of Mental Health, and The Kavli Institute of Neuroscience at Yale.
The Kavli Institute at Yale is supported by the Kavli Foundation which was founded by Mr. Fred Kavli who, despite being alive since 1927, has not a single blemish on his available reputation.
In all seriousness I won’t speculate as to the Kavli Institutes biases. But I don’t have to about Shire pharmaceuticals. Maybe it’s just me, but I can’t trust research results from a study that was conducted on a pharmaceutical company’s dime. Especially if there is evidence that directly contradicts the findings of the paper.
If I am missing something, someone please correct me in the comments section.
Many people would say “There is no such thing as an honest pharmaceutical company.”
I may or may not agree with that sentiment.
Evidence for cAMP
A 1999 report published by The Brain Research bulletin said this regarding cAMPs role in memory and learning:
an unbiased screen for Pavlovian conditioning mutants in Drosophila, initiated in the laboratory of Seymour Benzer at the California Institute of Technology in the mid-1970s, also revealed evidence for the involvement of cAMP signaling in learning and memory. In fact, three out of the four learning and memory mutations found to date in genetic screens Drosophila code for members of the cAMP-signaling pathway. For example, the ﬁrst mutant to be discovered by Benzer and colleagues
named dunce , lacks a phosphodiesterase that degrades
cAMP . Importantly, these ﬁndings have recently been extended into vertebrates, where electrophysiological and behavioral studies have conﬁrmed the critical importance of cAMP
signaling to learning and memory”
That particular is often cited as evidence of cAMP’s effect on cognitive processes. Personally, I don’t think it’s enough to go on. So I went in search of more research. Here’s what I found:
Forskolin can be used in conjunction with PDE4 inhibitor Rolipram to deter growth in colon cancer cells. Significant medically, but irrelevant to our purposes.
Sleep deprivation impairs cAMP signaling in hippocampus. This is important because the hippocampus is commonly associated with memory and noone is more forgetful than the sleep deprived (and the amnesiacs). The study explicitly states: “These findings demonstrate that brief sleep deprivation disrupts hippocampal function by interfering with cAMP signaling through increased PDE4 activity.”
Forskolin-inducible cAMP pathway negatively regulates T-cell proliferation by uncoupling the interleukin-2 receptor complex. In other words, there are possible forskolin-related risks to those with autoimmune disorders.
Caveats to cAMP Induction: The missing piece to the CILTEP stack
In 1955 a team from Brandeis University published a paper in the Journal of Neurophysiology that said:
Chemically induced long-term potentiation (cLTP) could potentially work by directly stimulating the biochemical machinery that underlies synaptic plasticity, bypassing the need for synaptic activation. Previous reports suggested that agents that raise cAMP concentration might have this capability
However, the same paper also notes that stable LTP wasn’t possible until they added PTX (a GABAa inhibitor)
Research also showed that the effects are “NMDA receptor dependent” and that ”stable LTP was entirely blocked by NMDA receptor antagonist”
So in order for the forskolin/artichoke extract stack to be effective, there should be some mechanism to pre-activate the NMDA receptors. Inhibited NMDA receptors significantly decrease magnitude of LTP.
According to wikipedia, known NMDA receptor activators include:
There have also been reports that Dopamine 1 receptor activation can improve the efficacy of the CILTEP stack.
My Experience with CILTEP
I had a unique experience with CILTEP because I chose to adopt a modified stack. Here was my daily intake:
25mg of Forskolin (after calculation for dilution)
600mg of Artichoke Extract
750mg of Flaxseed Oil- Omega-3s and Omega 6 is known for it’s brain health attributes
~200mg caffeine from black coffee
The effects were subtle, but perceptible. My appetite was affected slightly, as was my productivity throughout the day. Overall, I’d recommend testing the stack to anyone in a position that requires alertness and excellent memory.
There are certainly side-effects, although I did not personally experience them. Reports of upset stomach seem common.
Have you had any experience with nootropics or CILTEP stacks? I’m looking into conducting more controlled experiments. Any suggestions? Comments on the validity of the research? Post it all in the comments!