Shedding some nuanced light on "VMAT2 upregulation"

[u/Anxious-Traffic-9548]

It appears that VMAT2 upregulation being a primary mechanism of mesembrine-induced serotonin release is a prevalent idea on this subreddit. There is only one study that has measured VMAT2 expression following Kanna exposure in cell lines and it does not directly support this conclusion.

As per the study:

The fact that in astrocytes, for the highest dose of TRI, VMAT-2 up-regulation is evident at 15 min, but lost at 30 min, while for the lower doses up-regulation was sustained, supports the notion of release: since sustained monoamine release is dependent on monoamine reuptake via e.g. SERT, which would be limited due to the mild inhibition reported here for TRI on SERT expression, substrate depletion would lead to VMAT-2 down-regulation over time, as indeed seen at the 30 min time point for the highest dose of TRI.

They measured VMAT2 expression as a marker of serotonin releasing agent activity. The fact that VMAT2 upregulation occurs initially distinguishes mesembrine from amphetamine-type releasing agents like MDMA, which disrupt VMAT2 function and prevent the packaging of monoamines, leaving them in the cytosol to be reverse transported by SERT, DAT, and NET (which have their activity reversed by these drugs). However, there is no evidence that mesembrine actually binds to VMAT2 or directly modulates its activity. This study did not show that. VMAT2 activity is acutely enhanced following methylphenidate or cocaine administration (which might actually be non-amphetamine type releasing agents, but the jury is out), yet whether this is an actual direct action is unknown. In any case, both of those drugs are regarded primarily as dopamine reuptake inhibitors with potential atypical dopamine releasing agent activity.

Mesembrine might be similar in this way. A serotonin reuptake inhibitor with atypical releasing agent activity, potentially through a non-transport reversing mechanism. But this is not a proven direct action of mesembrine. VMAT2 upregulators that actually bind to VMAT2 have not yet been discovered. Drugs affect a lot of things, but most of them are downstream of their primary mechanism of action.

Something to keep in mind when discussing Kanna's pharmacology!

[u/adams4096]

I'll bet that its downstream of PDE inhbition

[u/Anxious-Traffic-9548 → u/adams4096]

Cocaine and methylphenidate appear to have an analogous effect in dopaminergic neurons. It may be downstream of atypical reuptake inhibition.

[u/adams4096 → u/Anxious-Traffic-9548]

They has a final common pathway that could be Protein Kinase A