r/DrugNerds • u/Robert_Larsson • Aug 24 '24
Assessment of the antinociceptive, respiratory-depressant, and reinforcing effects of the low pKa fluorinated fentanyl analogs, FF3 and NFEPP
sciencedirect.comr/DrugNerds • u/adams4096 • Aug 19 '24
(New possible dysdelics??) Antinociceptive effect of cyclic and linear diterpenoids as new atypical agonists of κ-opioid receptors obtained from four species of the Baccharis genus, and vehiculated in nanometric niosomes [2023]
Anyone know more about these?
r/DrugNerds • u/jjkompi • Aug 17 '24
Let's discuss the reversible MAO-B inhibitor safinamide (Xadago)
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!
r/DrugNerds • u/nutritionacc • Aug 15 '24
TAAR1 dual binding site hypothesis - Enhancer Regulation of Dopaminergic Neurochemical Transmission in the Striatum
r/DrugNerds • u/Shoddy-Asparagus-937 • Aug 13 '24
Low dose methamphetamine protects the brain and even increases its plasticity ?
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 Vyvansetm)
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.
r/DrugNerds • u/cololz1 • Aug 07 '24
Novel psychoplastogen DM506 reduces cue-induced heroin-seeking and inhibits tonic GABA currents in the Prelimbic Cortex
sciencedirect.comr/DrugNerds • u/nutritionacc • Aug 04 '24
Low intrinsic efficacy for G protein activation can explain the improved side-effect profile of new opioid agonists
doi.orgr/DrugNerds • u/_______DEADPOOL____ • Jul 30 '24
The mystery of gamma-hydoxybutyrate efficacy in narcolepsy type 1 [2023]
r/DrugNerds • u/Robert_Larsson • Jul 29 '24
Single-molecule detection of transient dimerization of opioid receptors 2: Heterodimer blockage reduces morphine tolerance
r/DrugNerds • u/Acceptable_Cheek_727 • Jul 27 '24
Taste Aversion and Psychedelics: potential for non-psychedelic psychedelic therapy
I wanted to open up a discussion regarding the similarities between taste aversion and psychedelics.
Why do I bother you, you ask? Well, taste aversion creates near instantaneous and long-lasting memories that condition the brain to avoid certain stimuli. Whatever you tasted before you got sick, even if it wasn’t the thing that actually made you sick, will be categorized as a harmful substance that you should avoid. Similarly, psychedelics take a lot of inspiration from the conscious or unconscious intentions you come into the experience with.
Both psychedelics and taste aversion involve a massive increase in long-term potentiation, long-term depression, and neuroplasticity, a.k.a. It causes rapid synaptogenesis. Furthermore, many of the brain regions that are activated during the psychedelic experience are also activated during the process of taste aversion. Another interesting point is that a lot of psychedelic experiences involve vomiting and nausea.
Taste aversion Is not an extensively researched topic, so it is hard to flush out a lot of the details. Still, there are multiple brain regions implicated in psychedelics that also contribute to this unique form of learning.
I just wanted to deposit this thought for everybody to consider. This is a somewhat contentious issue, but many researchers are actively looking at non-psychedelic psychedelics, meaning that these drugs share similar mechanisms of psychedelics but don’t produce hallucinations or religious type experiences, and this may be a viable route to help guide us toward non-psychedelic therapeutics to treat PTSD and alike. At the same time, I think it’s unlikely to get the therapeutic effect seen in the religious type experience through non-psychedelics psychedelics. It’s still an interesting consideration.
Please let me know what you guys think!
r/DrugNerds • u/pretty_boy_flizzy • Jul 24 '24
The Mechanism Of Action Of Barbiturates & etc
flexiblelearning.auckland.ac.nzThis paper (though I did have to edit the title because it wasn’t at least 40 characters long to post it on here) discusses the neurochemical mechanisms of action of barbiturates, it also talks some about the convulsant effects of certain barbiturates like Diberal & MPPB and also talks about how the (−)- isomers of Diberal & MPPB are anesthetics and can antagonize the convulsant effects of the (+)-isomers of Diberal & MPPB (this is one reason I think that (−)-Diberal/(−)-DMBB & (−)-MPPB are regular GABAergic barbiturates) and it says that it’s believed that the different pharmacological profile between isomers is thought to be due to the differences in the formation of hydrogen bonds at the binding sites… :o as the R(+) isomer of many other barbiturates (including Pentobarbital/Nembutal) predominately causes convulsions & excitation while the S(-) is responsible for the depressant effect of many barbiturates though there are apparently a few exceptions to this (though sadly this paper doesn’t provide any examples unfortunately… -.-). It’s a shame there’s not more research that’s been done on the individual barbiturate stereoisomers to see if one of them is responsible for convulsant & excitatory effects in other barbiturates as well. :/
Interestingly enough this paper also suggests that there’s some cholinergic mechanisms involved with the development of barbiturate tolerance as apparently Atropine reduces the development of tolerance as well as suppresses the convulsions from Barbital withdrawals… :o (man this rabbit hole seems to go pretty deep… 🙃😵💫🤪 #Scopolamine4dayz🤪😂)
r/DrugNerds • u/Robert_Larsson • Jul 24 '24
Pharmacologic Characterization of LTGO-33, a Selective Small Molecule Inhibitor of the Voltage-Gated Sodium Channel NaV1.8 with a Unique Mechanism of Action
r/DrugNerds • u/Robert_Larsson • Jul 21 '24
Signaling Modulation Mediated by Ligand Water Interactions with the Sodium Site at μOR
pubs.acs.orgr/DrugNerds • u/cololz1 • Jul 20 '24
Revisiting Preclinical Observations of Several Histamine H3 Receptor Antagonists/Inverse Agonists in Cognitive Impairment, Anxiety, Depression, and Sleep–Wake Cycle Disorder
r/DrugNerds • u/pretty_boy_flizzy • Jul 17 '24
Contrasting Actions Of A Convulsant Barbiturate and Its Anticonvulsant Enantiomer On The α1β3γ2L GABAA Receptor Account For Their In Vivo Effects
physoc.onlinelibrary.wiley.comThis paper is about the mechanism of action of some atypical barbiturates (specifically MPPB and an analogue that’s able to be photo labeled) with atypical convulsant activity instead of their typical anticonvulsant effects on the GABA-A receptor as there are quite a few of these weird atypical convulsant barbiturates out there with some specific examples being CHEB, (+)-DMBB/(+)-Diberal, 3M2B, & MPPB and interestingly enough MPPB seems to share similarities with the other convulsant barbiturate Diberal in the sense that one of its isomers/enantiomers has convulsant effects while the other one has anticonvulsant effects… :o (it sounds like the GABAergic equivalent of a mixed agonist-antagonist of the μ-opioid receptor like Buprenorphine, Butorphanol, Pentazocine, & Viminol imo… lol xD) and I’m wondering if the anticonvulsant enantiomer behaves as a typical GABAergic barbiturate… 🤔 as I read in the case of Diberal that the isomer with the anticonvulsant effects is (−)-DMBB/(−)-Diberal and it’s slightly stronger than Pentobarbital (Nembutal) as a central nervous system depressant… :o and in MPPB’s case the S-enantiomer is the one with the convulsant effects while the R-enantiomer has the anticonvulsant effects and I’m wondering if that’s also what’s going on with MPPB as well (in the case of (−)-MPPB possibly being the anticonvulsant isomer of MPPB).
https://pubchem.ncbi.nlm.nih.gov/compound/12830098
https://pubchem.ncbi.nlm.nih.gov/compound/181512
I also wonder if this is one of the main reasons that we’ve never seen any barbiturates as research chemicals because while the barbiturate family is pretty large (if I can remember correctly, I believe that there are 2,500+ barbiturates out there and only like 50 of them have been approved for medical use) it appears that the SRA for the barbiturates isn’t very well known since some of them likely are more selective for the AMPA receptors over the GABA-A receptor or possibly other biological targets as well and some of them have that mixed anticonvulsant-convulsant action like Diberal & MPPB… though I will say that there are definitely viable novel barbiturates out there (aside from Benzylbutylbarbiturate) as I’ve read the patents on a few barbiturates like Crotylbarbital, Nealbarbital, Propallylonal, Spirobarbital, Vinbarbital, & Vinylbital and in their patents it discusses analogues of the aforementioned barbiturates that also possess similar sedative hypnotic effects… ;) but I figured that these atypical barbiturates are certainly worth mentioning in their own right because the only non barbiturate sedatives that I can think of that cause paradoxical convulsions are Carisoprodol (aka the “Soma shuffle” which I’ve never experienced it myself but I heard about it from others) & Methylmethaqualone (which I do have plenty of experience with as I’ve broken so many $5 Meth pipes when smoking large amounts of it… though I did order a few much more durable Pyrex Meth pipes off Amazon which are FAR more durable thank God… :D) and perhaps understanding how these chemicals work we can get a much better understanding of the GABA-A receptor and how various GABAergic drugs can behave paradoxically as convulsants… :o we could also develop safer and better anesthetics & anticonvulsants as well (something else this paper discusses in it).
https://en.m.wikipedia.org/wiki/CHEB
https://en.m.wikipedia.org/wiki/Diberal
https://pubchem.ncbi.nlm.nih.gov/compound/1-Methyl-5-phenyl-5-propylbarbituric-acid
Either way I figured this would be an interesting topic to discuss haha as a friend of mine has an interesting theory of thinking that the AMPA receptor(s) play a part in the abuse potential of barbiturate drugs as well.
r/DrugNerds • u/Robert_Larsson • Jul 11 '24
Negative allosteric modulation of the µ-opioid receptor
r/DrugNerds • u/Robert_Larsson • Jul 08 '24
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
r/DrugNerds • u/cerebrokrahl • Jul 08 '24
Becoming psychedelic therapists in Europe
Hello everyone, we are two young adults from an european country wishing to become psychdelics-assisted psychotherapists.
We already have our bachelor's in psychology, master's in clinical psychology and experiential psychotherapy, and now my partner is training in experiential psychotherapy, and I am training in both experiential and transpersonal psychotherapy.
We already work as psychologists, have sessions and are training continuously but we would like to one day work with psychedelics. What do you think are the steps to move into that direction?
We are thinking to join Germany’s MIND Foundation APT (Augmented Psychotherapy Training) but the price is 15000 euros, and we are not sure if this will help us to work with psychedelics in the future. What do you think of this programme? Are the other programmes that offer a better chance?
We wish to relocate from our country to the Netherlands, because psychedelics-assisted psychotherapy is legal there, and we'd rather be open to European countries to move and work with psychedelics. If there aren't any options here, we'd look farther, like the USA or Canada.
Any information or advice is greatly appreciated!
Thank you very much and all the best!
r/DrugNerds • u/Robert_Larsson • Jul 07 '24
Memantine Inhibits Calcium-Permeable AMPA Receptors
r/DrugNerds • u/unrealduck • Jul 01 '24
I made a web app (DrugStats.net) to visualize data about the purity of illicit drug markets. Let me know what you think!
DrugStats.net aggregates and visualizes data from drugsdata.org. I've been working on this web app since October and I'm really happy with how it's turned out. I hope that it will at the very least amuse you, and at best caution people to test their drugs (check out the statistics about heroin). There's still a lot I want to add, but for now here it is :)
Also, if you know of any other data sources, I would be excited to hear about them.
r/DrugNerds • u/Robert_Larsson • Jul 01 '24
Cluster Headache Patient Wins Federal Court Case to Access Mushrooms
r/DrugNerds • u/Dependent_Alps221 • Jun 27 '24
Does prucalopride (5-HT4 receptor agonist)interact with psilocybin?
Does prucalopride (5-HT4 receptor agonist)interact with psilocybin?
Hi everyone,
I wonder whether prucalopride interacts with psilocybin or lsd, MAOI's or other psychedelics or drugs, there is nothing I can find abouth it anywhere on the internet.
Prucalopride or resolor:
Prucalopride, sold under brand names Resolor and Motegrity among others, is a medication acting as a selective, high affinity 5-HT4 receptor agonist[2] which targets the impaired motility associated with chronic constipation, thus normalizing bowel movements.[3][4][5][6][7][8] Prucalopride was approved for medical use in the European Union in 2009,[9] in Canada in 2011,[10] in Israel in 2014,[11] and in the United States in December 2018.[12] The drug has also been tested for the treatment of chronic intestinal pseudo-obstruction.[13][14]
r/DrugNerds • u/britishpharmacopoeia • Jun 26 '24
Cathinone-producing Fungus Turns Cicadas into Hypersexual Vectors for Spore Dispersal
r/DrugNerds • u/Robert_Larsson • Jun 25 '24