Hello everyone,

I'm researching the neurochemical dynamics between the monoamine oxidase inhibiting harmala alkaloids present in Banisteriopsis caapi (the MAOI component in ayahuasca) and gabapentinoids, specifically pregabalin (Lyrica) and gabapentin (Neurontin). My interest is in understanding any potential pharmacological interactions or contraindications, particularly from a safety perspective.

According to Dr Benjamin Malcolm's 2023 UConn School of Pharmacy presentation on ayahuasca drug interactions, gabapentinoids such as pregabalin and gabapentin are generally considered low-risk when combined with ayahuasca. This categorisation is based on their lack of binding to monoamine reuptake pumps or release of monoamines (such as 5HT, NE, and DA), which are crucial factors in the risk profile for serotonergic drugs combined with MAOIs. However, given pregabalin's mechanism as an α2δ subunit ligand of voltage-gated calcium channels and its sedative properties that share some similarities with benzodiazepines, I wonder if there might still be nuanced interactions worth exploring, even in the absence of direct serotonergic activity.

Specifically, I'm interested in theoretical safety risks regarding potential CNS depressant effects or subtle alterations in neurochemical stability during the ayahuasca experience. While Dr. Malcolm's presentation suggests a lack of life-threatening interactions, the question remains whether pregabalin might modulate the subjective or physiological response to ayahuasca or present secondary risks in any capacity.

I would greatly appreciate your insights if anyone has encountered additional research, pharmacological theories, or public case studies exploring this interaction. I'd also welcome any perspectives on the pharmacodynamic implications of combining these substances.

Thanks in advance for your input!

Source: Ayahuasca Drug Interactions (Malcolm, 2023) - University of Connecticut School of Pharmacy

Hey!

I just found this paper from a couple days ago.

https://molpharm.aspetjournals.org/content/early/2024/08/26/molpharm.124.000947.long

The scientists postulate that ketamine, norketamine and 6-hydroxynorketamine act as a positive allosteric modulator (PAM) of all opioid receptors at nanomolar concentrations. At micromolar concentrations it acts as a full agonist.

As a PAM ketamine (and metabolites) enhance endogenous opioid signalling through endorphins, in contrast to morphine - which activates all opioid receptors, regardless of endogenous peptide signalling. This, according to the authors, might be one reason for it's differential efficacies in MDD.

This, to them, seems to unify some conflicting data as to whether the opioid system takes part in the antidepressant actions. Moreover, they go a step closer to elucidating the rapid but short-lasting antidepressant effect of ketamine -> half-lives of major metabolites.

I'm really not deep into ketamine pharmacology, but I've heard about conflicts in the past regarding whether naltrexone/naloxone inhibit antidepressant actions and to which extent the opioid system takes part in therapeutic efficacy.

Would be great to hear what you guys think, especially those of you that are deeper in the topic!

Hey!

I haven't seen much on the reversible MAO-B inhibitor (and anticonvulsant) safinamide here. Why is that?

In this letter to the editor (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10983021/) they mention the following:

"Despite the promise of MAO‐B inhibitors in treating brain diseases, a limitation of drugs like selegiline (L‐deprenyl) is their effects are not long‐lasting. In APP/PS1 mice, selegiline showed a therapeutic effect lasting approximately one week, but this effect diminished with long‐term administration of about four weeks. Notably, prolonged use of selegiline triggered a compensatory mechanism involving diamine oxidase (DAO)‐dependent GABA synthesis, a pathway alternative to MAO‐B that degrades putrescine into GABA. As an irreversible MAO‐B inhibitor, selegiline forms a covalent bond with MAO‐B, eventually destroying it and subsequently activating the compensatory mechanism (i.e. DAO‐dependent GABA synthesis). On the other hand, reversible MAO‐B inhibitors such as safinamide (Xadago) and the newly developed KDS2010 (Tisolagiline) have less compensatory effects because they compete with the substrate and consequently leave MAO‐B intact. This contrast strongly suggests the use of reversible, but not irreversible, MAO‐B inhibitors as a long‐term treatment to reduce MAO‐B‐dependent GABA synthesis in pathological conditions."

I had found this info in a proper paper as well, but I can't seem to find it anymore - PubMed really has a bad search function imho.

While not fully elucidated in humans, I believe, tonic GABA increase (through astrocytes) seems to be related with MDD as well (in mice afaik):

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408154/

https://www.mdpi.com/2073-4409/13/4/318

So there might be merit to avoiding compensatory DAO activation in MDD?

From what I could see "Safinamide is vastly more selective for MAO-B than MAO-A (1,000 times more selective in humans), when compared with rasagiline (203 times) or selegiline (127 times)." (https://www.dovepress.com/safinamide-in-the-management-of-patients-with-parkinsonrsquos-disease--peer-reviewed-fulltext-article-TCRM).

And "Single oral administration of safinamide at 600 μg/kg (36 mg for a 60-kg subject) inhibited 91% of platelet MAO-B activity in a few hours, and a steady-state plasma concentration of safinamide could be achieved with only five days of repeated daily administration" (https://www.sciencedirect.com/science/article/pii/S0022510X2030349X).

From what I could see, safinamide has low to mid nanomolar affinity to MAO-B and sigma 1, while having mid micromolar affinities to voltage gated calcium and sodium channels (like lamotrigine/lamictal) and tendentially NDRI properties. At 100 mg/day it seems to affect the ion channels, while at 50 mg/day it does not, though inhibiting MAO-B to a similar extent. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10479837/)

This sounds to me like a very interesting combination of properties and I'm wondering why it's not discussed more - as augmentation of existing AD drugs or as a standalone therapy.

I believe I read it on here somewhere, but there's data suggesting high doses of moclobemide (900-1200 mg) being more efficacious than common doses (300-600 mg). This could be explained by that one PET trial (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4772270/) showing only around 75% occupancy at common doses and 85% at high doses (comparable to occupancy of irreversibles) or maybe even of moclobemide losing its selectivity at those doses and also partially inhibiting MAO-B (analogous to selegiline losing its selectivity at high doses used for MDD)?

Wouldn't a common dose of moclobemide + 50 mg (or lower even?) of safinamide then have a similar effect? Has anybody looked into this? To me this sounds like a safer (regarding dietary restrictions) alternative to common unselective irreversible MAOIs.

Looking forward to your thoughts!

So i've been doing some research on meth

to see why it's FDA approved despite the bad rep and why so controversial so anyway here goes nothing.

This study, once you read it, will reveal some interesting facts.

My question is if that single 17.9mg for a 70kg human dose that would equivalate the 0.5mg/kg/h on rats for 24h according to the study still holds true if :

the dose is taken IV or basically in a highly bioavailable method in one shot, considering the striatal dopamine would increase drastically and have a spike (which typically we try to avoid to avoid its addictive nature, that's why we created Vyvanse^(tm))

Or is that drastic fact in fact NOT a determining factor in the pharmacoproteomics of neurotoxicity.

Also it seems that only young rats (uninjured) benefit from significant cognitive benefits (learning as assessed by the Morris water maze) 45 days after 2 mg/kg for 15 days (post-natal day 20–34) and not adult rats (post-natal day 70–84).

What does this mean and how could we extrapolate the benefit to adult rats ? Raising the dosage ? What are the most plausible hypotheses for this and overall for this highly dose dependent neuroprotection/neurotoxicity ratio.

Thank you for any input.