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Sunday, July 9, 2017

How to Downregulate the Norepinephrine Transporter! (Supplements to Decrease NET Expression / mRNA)

Norepinephrine is a vital catecholamine and monoamine that regulates blood pressure [1] (typically increasing it) and the nervous system activities [2] [3]. Norepinephrine also is a HUGE topic for scientists, researchers and the pharmaceutical industry [4]. When it comes to discussing Depression, its discussed almost as much as Dopamine and less than Serotonin - but its actually more important than both - in some ways [5]. Because norepinephrine is critical to alertness [6], Cognition [7], common-sense [8] and self-preserving behaviors [9] - it is an important molecule in regards to mental stability and especially social behavior [10]

Though high levels of norepinephrine are found in essential hypertension (high blood pressure) [11], low levels of norepinephrine are found in orthostatic hypotension [12] and sometimes with postural tachycardic syndrome (POS/POTS) [13]

Therefore, Norepinephrine is an incredibly important natural substance within the body that is well worth the amount of talk and investment that has been surrounding it. 

When discussing norepinephrine LEVELS in the Brain though, there is an important protein that gets the most attention - the Norepinephrine Transporter (or NET) [14]. NET is so important that an entirely different class of antidepressants have been created to target it called ''norepinephrine-selective antidepressants'' or ''Norepinephrine-Transporter-Inhibitors'' [15]. By inhibiting the transporter, norepinephrine can no longer be recycled or removed from the brains synapses [16]. This leads to an effective accumulation of norepinephrine in the Brain. What's more, is many of these antidepressants actually DOWNREGULATE, or decrease the number/amount of, norepinephrine transporters - when used long-term (1 month +). So in order to get the FULL-EFFECT of these noradrenergic antidepressants, months of use is often required [17]

The reason you are here though, is to be able to understand how average people can downregulate the transporter in much the same fashion, in order to get all the benefits of enhanced norepinephrine activity.

To be able to do that, we have to understand some of the regulatory mechanisms the body has with regard to expression of norepinephrine transporters. 

  • Substance P or Neurokinin-1 (tachykinin-1) can activate the Neurokinin-1-receptor (NK1R) to then activate Protein Kinase C - which in effect ends up downregulating the amount of norepinephrine transporters in the Brain & Body [18]
  • TAAR1 Activators; such as Amphetamine, have been proven  to downregulate the norepinephrine transporter in Humans [19], through a mechanism that involves TAAR1 and second messengers; such as cAMP and cGMP [20] [21] [22].
  • Thus, cyclic adenosine monophosphate & Protein Kinase C activation seem crucial to downregulate the norepinephrine transporter (NET) which is also called the noradrenaline transporter (NAT).
Working with this logic we can come up with two major conclusions.

1.) You could take the dirty route and use Amphetamine to downregulate norepinephrine transporters (not recommended).
2.) You can work with the other mechanisms described which is more consistent with forum reports of long-term use resulting in Insomnia, stimulation, work-a-holism and euphoria.

...Long-term use of what? Right? 

Forskolin as a cAMP enhancer, which is already proven to upregulate HUMAN dopamine D2 receptors [23] and can certainly enhance norepinephrine activities [24], though no PET studies currently exist to say for sure that forskolin supplements would downregulate the norepinephrine transporter, it is implied in studies such as this one.

If in doing so, cAMP enhancement decreases the norepinephrine transporter (and I'm 99.9% sure it does) - then adding a PDE-inhibitor such as Butea Superba Extract would amplify that effect!

Then, I would go ahead and start supplementing with these two.

So then - where do we go from here?

My best assumption is of course, to look into the research of the Substance P/Neurokinin-1-Receptor. The only problem I have with that strategy, is that directly activating the Substance P receptor by substance P or any ligand, would probably result in increased pain sensitivity [25]. In people with Chronic Pain, this would likely be an automatic deal breaker.

Also, Substance P and its cousin-receptors (NK2R's etc) are implicated in Asthma as well [26] - so its a long shot, but if you aren't asthma prone and don't have chronic pain, it might be worth trying?

Problem is, other than Substance P itself, or the drug / ligand GR-73632, there isn't much proven to activate the receptor. So you'd have to contact a chemical supply company, and that just isn't feasible for most people.


One study did indicate that Androgens and DHT in particular, could reduce NET expression in the frontal cortex and several other brain areas [27], however there has been no confirmation in human studies (PET studies) to guarantee this as a method. Though, many anecdotal reports seem to jibe with the conclusion that androgens can increase norepinephrine levels, and blood tests seem to confirm this.

If you are looking for a valid hormonal method to increase norepinephrine and decrease norepinephrine transporters, you could...


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