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One thought really terrifies me about self-experimentation with nootropics.
I worry that a nootropic will backfire and leave me worse off than if I'd done nothing at all. What if a purported nootropic turns to hinder rather than help cognitive ability? And what if the negative effect is permanent?
I read a story a few months ago about a clinical trial in France that killed one person and left other patients with irreversible brain damage. This definitely rekindled these fears about the potential for harm of nootropics.
Nootropics are (by definition) supposed to be free of harm. But many aren't sufficiently tested in humans making the entire project trialling nootropics a big gamble.
Burning The Candle At Both Ends
The flame that burns Twice as bright burns half as long.
― Lao Tzu, Tao Te Ching
There are purported nootropics that are akin to burning the candle at both ends.
Such nootropics might enhance cognitive performance in the near-term. But over the long run, they exhaust neurons and promote excitotoxicity.
The brain has built-in mechanisms to prevent excessive neural activity.
Excitotoxicity is a process where neurons are killed by excessive stimulation, usually by glutamate.
NMDA and kainic acid are representative excitotoxins that activate glutamate receptors in the absence of glutamate. This leads to unchecked calcium ion entry into cells, activating enzymes that damage the cell.
In this post, I will discuss two nootropics that I would avoid due to their potential for harm.
Sunifiram
Sunifiram is one such nootropic that has waned in popularity precisely because of its potential for harm.
Sunifiram is an ampakine that packs a serious punch. Pharmacologically, sunifiram has the following effects:
- Activation of the glycine site of NMDA receptors, boosting glutamatergic signaling
- Increased AMPA receptor phosphorylation also boosting glutamatergic signaling
So what’s the problem? Sunifiram results in "too much of a good thing."
NMDA and AMPA receptors are two of the three canonical receptors that bind glutamate. Too much activity at these receptors can result in excitotoxicity.
When NMDA and AMPA are triggered, calcium ions enters the cell. Under normal conditions, this calcium ions are just second messengers that participate in essential signal transduction pathways.
But overstimulation of NMDA and AMPA by sunifiram induces excess calcium influx. Since Ca++ has two positive charges, the cell’s interior (cytoplasm) begins to lose it's usual -70 mV resting potential. Electrochemical gradients become disrupted. Neurons need a negative cytoplasmic charge so that they can depolarize (“fire”) in the first place.
Eventually, sufficiently damaged neurons are killed by programmed cell death.
OK that got dark quickly. Let's take a break and look at at picture of a pretty girl.
Lessons Learned
There’s nothing necessarily dangerous about a moderate boost in glutamate activity.
Learning and memory actually depend on a modest boost in glutamate-related signaling. Modafinil is another drug that augments extracellular glutamate and is actually net-neuroprotective.
But Sunifiram’s unchecked twofold activation of NMDA and AMPA receptors is potentially dangerous.
Activating these glutamate receptors circumvents the brain’s built-in mechanisms for protecting against excessive neuronal firing. Neuronal firing rate is under homeostatic control for a reason!
Like sunifiram, domoic acid is neurotoxin that activates AMPA receptors. Amnesic shellfish poisoning results in profound memory impairment.
Further Reading
- Sunifiram brain damage?
- Sunifiram Excitoxicity Dangers
Cerebrolysin
Cerebrolysin a is a mixture of peptides extracted from porcine (pig) brain. It's marketed by the pharmaceutical company EVER pharma in Europe as a treatment for dementia.
The rationale for Cerebrolysin is that pigs also have neurotrophic factors that are homologous (similar in amino acid sequence) to human neurotrophic factors. I’m talking about proteins like brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF). These proteins show a lot of promise in promoting neuroregeneration, though some studies have been mixed.
So what's the problem with Cerebrolysin?
Misfolded Proteins
The problem is aberrant, self-propagating proteins. Misfolded prion proteins can interact with normal prion proteins. This interaction induces a conformational change such that formerly normal prion proteins become misfolded.
Under normal circumstances, there’s nothing wrong with a few defective proteins. The ubiquitin-proteasome system is constantly “cleaning up” abnormal proteins to keep the cell running smoothly.
The problem here is that misfolded prion proteins are self-propagating. A single misfolded prion protein introduced into the body can result in a cascade where a majority of normal prion proteins are converted to the dark side. This is the pathophysiology of the fatal and incurable Creutzfeldt-Jakob Disease (CJD).
CJD is called a "spongiform encephalopathy" because it causes holes in the brain, giving nervous tissue a characteristic "spongey" appearance.
Your parents may have been lying to you when they said cannabis causes holes in your brain, but there's no question that this happens with prion diseases.
Circling Back: Why Cerebrolysin is Dangerous
Why are prion’s relevant to Cerebrolysin? You can probably guess where I'm headed with this narrative.
The bovine version of Creutzfeldt-Jakob Disease is called mad cow disease. Hence non-human animals are also susceptible to prions. Mad cow and prion diseases in general are also zoonotic, meaning that they can spread between animals and people.
Remember how Cerebrolysin was manufactured by homogenizing porcine brain? Porcine may also be able to carry prions.
Cerebrolysin is particularly dangerous for three reasons:
- It’s manufactured from proteins derived from porcine brain, which could be contaminated with misfolded prion proteins.
- Cerebrolysin was developed prior to the discovery of prion proteins. Therefore there is no way that EVER pharm (the company that manufactures Cerebrolysin) could have anticipated this prion disease concern.
- Cerebrolysin is typically injected intravenously or intramuscularly. This route of administration is ideal for transmitting prion diseases. If you ate a prion, it would in most cases be hydrolyzed into amino acids in the stomach. Despite this, getting prion diseases from eating mad cow beef has been reported. But intravenously delivering prions bypasses all the body’s defense mechanisms against infectious proteins.
Last Words
I hope I didn’t scare you! As always, it’s best to do your own research before hopping on any bandwagons.
To recapitulate:
- I’d avoid Sunifiram because it synergistically activates both NMDA and AMPA-type glutamate receptors, which could promote excitotoxicity.
- Cerebrolysin is a bad deal all around because of the possibility of inadvertently infecting yourself with misfolded prion proteins.