Pharmacodynamic interactions of Sceletium/Kanna with antidepressants, particularly SSRIs?

[Alchemica]

Anyone have real-world evidence that Kanna is significantly contraindicated with combined SSRI/SNRI use etc? It's become common-place to have a (often hard to see, small-print) warning on many products containing Kanna that they shouldn't be combined with MAOIs (understandably), but also with SSRIs/SNRIs. Are there significant, actual risks in the later combination?

I'm curious if anyone has actually experienced signs of potential (serotonin syndrome, or otherwise) toxicity, or is aware of any cases of negative reactions, from these combinations, as if it's use continues at the current rate, the combination of prescription antidepressants with Kanna could growingly become a very real potential combination, very widely encountered, even inadvertently, in society.

 

Kanna has become more of a 'functional food', finding it's way into everything from Australian Pre-Workout powders, to overseas having broad use in things like functional beverages, chocolates, quick dissolve breath mints, adaptogenic functional food blends etc

I posed the following question to a Psychiatrist:

 

Quote

 

Do you know how real-world relevant the risk of serotonin syndrome is when SSRIs are combined with other substances impacting the serotonin transporter, likely allosterically but also as a potential serotonin releasing agent? The example I'm wondering about is with Kanna/Sceletium and combined SSRI use. I've vaguely (?) heard of adventurous psychs in South Africa trying to augment SSRIs with Sceletium but it has generally become common-place in some communities to put a blanket warning that the combination is contraindicated.

 

Aside from pharmacokinetic interactions, in the real world, pharmacodynamically, is combining something that potentially allosterically modulates SERT to inhibit reuptake, or also potentially releases serotonin (VMAT-2 mediated?) with SSRIs an actual significant risk for precipitating serotonin toxicity? Do you ever hear of say escitalopram with it's allosteric SERT binding, combined with other SSRIs causing cases of serotonin syndrome? I would have thought that SERT was already inhibited to a near maximal occupancy by therapeutic doses of SSRIs and as such, adding another substrate for the transporter is unlikely to pose much added risk, instead they'd probably more just competitively displace each other from SERT unproblematically eg in the same way MDMA+SSRI seems to simply inhibit the pharmacological effect of MDMA via competition of the SSRI for SERT binding?

 

I'm just curious as with Kanna becoming such a common ingredient to the point of functional food status in a way, if there is a legitimate risk of SSRIs having a dangerous interaction with Kanna, or if it's more just a text-book over-reaction, just in case, mentality?

It might also be that half-life for mesembrine seems quite short, not that I've seen a human t1/2 reported yet, subjective effects maybe lasting around 5hrs (?), so even if there is potential serotonin toxicity building, mesembrine may clear relatively quickly from the body and the symptoms come to their own resolution. Still, it's incredibly potent SERT binding for mesembrine, 1.4nM or something, so it's worth having an idea about how real the risks are.

 

If it means anything, I've briefly explored the combo (with cyproheptadine on hand) and maximal dose sertraline + potent doses of high-mesembrine Kanna (said to be more the serotonin releasing aspect) were not overly remarkable, in that the acute mood elevation/empathogenic/more euphoric aspects, the generally sought after aspects, were greatly attenuated by combination but there was potential signs of maybe slight overheating, sweating etc. No drastic signs of anything too toxic but then my brain is a freak of nature that seems to handle combos that no brain technically should

 

Their response was: In general I think "potential" adverse interactions can be over-called due to pharmaceutical medicolegal risk (eg. SSRIs and opiates contributing to Serotonin Syndrome- see that combo often but not SS). I suspect Individual pharmacogenomics are more pertinent than interaction profiles (provided it's not a major one like MAOIs) but precision psychiatry is still rudimentary. I agree that the agents would probably compete, with the higher Ki agent more likely to "win out". The danger would be if max dose of 1 agent doesn't cause max occupancy and the additional agent causes increased binding to a dangerous level. Generally don't see serotonin syndrome with SSRI/SSRI combos, but it's generally not effective or good medicine.

 

 

Any input you can offer is greatly appreciated.

 

[Alchemica]

To add to this:

From: Serotonin Syndrome: Mechanisms, Diagnosis, High-Risk Interactions and Management

Diagnosis relies on identifying the characteristic triad of symptoms in the context of serotonergic agent exposure: Altered mental status, Autonomic instability, Neuromuscular hyperreactivity

 

Serotonin syndrome reflects excess serotonergic neurotransmission, primarily through overstimulation of postsynaptic 5-HT₂A and 5-HT₁A receptors in the brain and spinal cord. The risk of toxicity increases exponentially when drugs with different mechanisms are combined, as this creates a synergistic effect on the serotonin system

• 5-HT2A receptors: Mediate life-threatening effects (severe hypertonicity and hyperthermia); activated at higher serotonin concentrations
• 5-HT1A receptors: Higher affinity for 5-HT; contribute to milder symptoms (anxiety, hyperactivity) at lower concentrations

 

They suggest to consider these three questions when evaluating any drug combination:

 

1. Are multiple mechanisms being targeted? (eg MAO inhibition + reuptake inhibition = synergistic danger)

2. What is the potency at the serotonergic target? (High-affinity SERT binding vs. weak affinity)

3. Are pharmacokinetic factors amplifying exposure? (CYP inhibition causing accumulation)

 

And that the level of risk can be stratified via considering the pharmacological properties of the combination, pdf attached:

Serotonin syndrome risk stratification via pharmacological mechanism.pdf

 

I was always under the impression that the MDMA + SSRI case was not too bad in that any extensive MDMA-induced serotonin release was largely attenuated (and also the effects significantly blunted) by the presence of a SSRI, by competing for the transporter and preventing MDMA's reversed transporter-mediated serotonin efflux but they list it in the above paper as High risk, with significant association with severe toxicity: "Extremely dangerous when combined with prescription serotonergic medications"

 

Back to the mesembrine, if we consider that high mesembrine-extracts are considered to act primarily as monoamine releasing agents [1] with a secondary action of reuptake inhibition, that makes it sound like the real-world risks aren't to be totally dismissed...

 

1. Are multiple mechanisms being targeted? (dual - serotonin release + reuptake inhibition)

2. What is the potency at the serotonergic target? (High-affinity SERT binding vs. weak affinity) High affinity binding for mesembrine to SERT 1.4nM

3. Are pharmacokinetic factors amplifying exposure? (CYP inhibition causing accumulation) Unsure, not well studied

 

[1] https://doi.org/10.1016/j.jep.2015.11.034