Rules (click)

Im seeing different data on this,

this page says it's effects are down to "dietary uridine-5'-monophosphate supplementation increases potassium-evoked dopamine release and pro-motes neurite outgrowth in aged rats" https://pubmed.ncbi.nlm.nih.gov/16055952/

But i've read elsewhere that it's a GABA-A agonist.

This study on rats says "Uridine decreases morphine-induced behavioral sensitization by decreasing dorsal striatal dopamine release possibly via agonistic effects at GABAA receptors" https://www.sciencedirect.com/science/article/abs/pii/S0924977X14001783

perhaps it's both?

I take gabapentin for sleep. I've read a study about how gabapentin prevents the formation of new synapses. I am also on Wellbutrin which works at the synaptic level? Would these two contradict each other?

And are these studies about gabapentin and synaptic formation accurate?

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https://med.stanford.edu/news/all-news/2009/10/study-pinpoints-key-mechanism-in-brain-development-raising-questions-about-use-of-antiseizure-drug.html

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I've read here that " In Buspirones case, agonism of the 5-HT1a receptor causes a decrease in serotonin in certain areas of the brain and increases dopamine and norepinephrine while also causing a secondary increase in oxytocin" https://www.reddit.com/r/DrugNerds/comments/gyvhmp/silexan_lavender_oil_mechanism_of_action/ftd0ynr/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6354602/

Is this the case with all 5-HT1a agonists ?

Looking for answer as title says. I know, that if I want to shorten activity of amphetamine I have to eat something acidic in order to make my urine low pH. Low pH prevents reabsorbing already “used” amphetamine in bladder back in bloodstream eventually.

But what is the “crossing point “ where it doesn’t cause any changes and where it does. Ie ingesting 1000mg of vitamin C kills the activity. Eating baking soda increases its activity.

I am asking bc for example energy drinks are full of acids, coffee as well, but caffeine isn’t.

Below article I found says what to avoid, but I need to get vitamin C for my damaged immunity

https://nw-adhd.com/wp-content/uploads/2017/01/ADHD-Medication-Information-Sheet.pdf

reposting this from r/drugs in hopes that i can get some better answers! a few months ago, my friend told me that tylenol + ibuprofen was better for pain than opioids, which i immediately dismissed as bullshit. today i got bored and did some research, and it seems like it might actually be true? or at least in some specific cases.

i’m no scientist, just bored & on adderall, so i wanted to ask this sub for their thoughts, and see if anyone smarter than me could come up with a better answer. here’s a handful of studies that i looked at – there are definitely more, but i’m getting bored and i already used all my brain cells on finals yesterday.

NSAIDs are stronger pain medications than opioids - A Summary of Evidence

compares a handful of studies on the effectiveness of different drugs, including opioid + non-opioid. a combination of acetaminophen + ibuprofen was the most effective at reducing pain.

Evidence for the efficacy of pain medications

published by the same guy as the above summary, similar conclusions. he suggests that the only reason opioids are considered effective is the mental effects – reduced anxiety, depression, etc.

Effect of Opioid vs Nonopioid Medications on Pain-Related Function in Patients With Chronic Back Pain or Hip or Knee Osteoarthritis Pain

compares opioids to either acetaminophen or ibuprofen, and found that they were equally effective in treating pain over 12 months.

Effect of a Single Dose of Oral Opioid and Nonopioid Analgesics on Acute Extremity Pain in the Emergency Department

compares a single dose of 4 medications (3 with opioids, 1 without), and found they were equally effective in treating pain over 2 hours.

so i guess my specific questions are:

1. why are weaker opioids so frequently prescribed for mild/moderate pain, such as after surgery, if there are non-opioid alternatives that seem to be equally or more effective?
2. is it entirely due to overprescription, or is there a real clinical reason for it?
3. at what point would opioids become a better option than acetaminophen + NSAIDs? since obviously you're not just getting a tylenol after a massive car crash, for example.

thanks in advance :))

I am looking at this through the eyes of mental health.

Guanfacine and Clonidine seem to be the only drugs whom are direct agonists of the alpha-2 adrenergic receptor that are prescribed within the boundaries of Psychiatry. Note: I already take Clonidine.

My question is: what other mental health drugs (or perhaps supplements) might directly or indirectly target this receptor?

Do drugs that target NET ultimately have indirect effects on this receptor? I would assume that’s how it’s stimulated naturally (by norepinephrine)?

Would Strattera or Desipramine provide the effect I’m looking for?

One article I read concludes the Desipramine’s anti-depressant affects are due to the stimulation of this receptor: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727683/

Another article I read suggests long-term use Desipramine decreases the sensitivity of this receptor: https://pubmed.ncbi.nlm.nih.gov/6274268/

Decreased sensitivity is opposite of what I want, correct? A similar study was done on Amitriptyline, but their hypothesis was that this decrease in sensitivity is what induces the anti-depressant effects, which doesn’t make sense to me (and seems to go against other research on this receptor).

Can someone explain what this “decrease in sensitivity” means for neurotransmission?

How do clinical trials deal with the fact that the subjects of a given clinical trial might have a bunch of nutrient deficiencies? Suppose that you don't correct those deficiencies; in that case, won't the data suggest that what you're testing isn't effective when in fact maybe it would be effective if the deficiencies were corrected first?

I was thinking about this question because I saw a piece about LAC, which is a substance that seems to have major potential:

https://link.springer.com/article/10.1007/s44192-023-00056-z

Mitochondrial metabolism can contribute to nuclear histone acetylation among other epigenetic mechanisms. A central aspect of this signaling pathway is acetyl-L-carnitine (LAC), a pivotal mitochondrial metabolite best known for its role in fatty acid oxidation. Work from our and other groups suggested LAC as a novel epigenetic modulator of brain plasticity and a therapeutic target for clinical phenotypes of depression linked to childhood trauma. Aberrant mitochondrial metabolism of LAC has also been implicated in the pathophysiology of Alzheimer’s disease. Furthermore, mitochondrial dysfunction is linked to other processes implicated in the pathophysiology of both major depressive disorders and Alzheimer’s disease, such as oxidative stress, inflammation, and insulin resistance. In addition to the rapid epigenetic modulation of glutamatergic function, preclinical studies showed that boosting mitochondrial metabolism of LAC protects against oxidative stress, rapidly ameliorates insulin resistance, and reduces neuroinflammation by decreasing proinflammatory pathways such as NFkB in hippocampal and cortical neurons. These basic and translational neuroscience findings point to this mitochondrial signaling pathway as a potential target to identify novel mechanisms of brain plasticity and potential unique targets for therapeutic intervention targeted to specific clinical phenotypes.

This article describes research in our and other laboratories on mitochondrial metabolism of acetyl-L-carnitine (LAC) that has led to the discovery of novel epigenetic mechanisms for the rapid regulation of brain plasticity in multiple rodent models and then has prompted us to uncover a role for this proposed mitochondrial signaling pathway of epigenetic function as a therapeutic target for clinical phenotypes of depression linked to childhood trauma, and implications for Alzheimer’s disease (Fig. 1). Multiple preclinical and clinical studies showed that epigenetic mechanisms are involved in the pathophysiology and treatment of stress-related depressive and cognitive disorders; the reversible properties of epigenetic modifications posit them as emerging potential targets for next-generation therapeutic interventions [1,2,3,4,5]. The goal is to recognize those biological changes that underlie aberrant epigenetic programming of brain plasticity, and to recognize mitochondrial signaling pathways, metabolic factors, transcriptomic profiles and structural changes that indicate flexible adaptability or the lack thereof. A key concept for understanding this interface is the model of allostasis (adaptation) and allostatic load (pathophysiology) [6] that we review below examining this model in relation to new insights from the recent work on the link between mitochondrial metabolism and epigenetic function to promote healthy behaviors and cognitive function.

...

In summary, there appears to be a common denominator in the trajectories of stress-related disorders that we propose involves an epigenetic embedding of early life experiences through the mitochondrial metabolite LAC acting as part of a critical network system with other important mediators of brain plasticity and function, and that, when supplemented, rapidly alters gene expression profiles to ameliorate behaviors and cognitive function in animal models deficient in LAC because of stress-induced causes. While it is not possible to “roll back the clock”, deeper understanding of the biological pathways and mechanisms through which adverse childhood experiences produce a lifelong vulnerability to altered mitochondrial metabolism and the related pathways can provide a path for compensatory plasticity toward more positive health directions. Of note, a growing number of studies support mitochondrial metabolism of LAC as a common culprit underlying psychiatric and neurodegenerative diseases such as MDD and AD as well as obesity, making it important to further understand mechanisms for the development of aberrant mitochondrial metabolism of LAC. A key concept for understanding this interface is that while health-damaging behaviors (e.g.: poor diet, excessive alcohol consumption, sleep deprivation and circadian disruption) contribute to allostatic load and the many consequences of such behaviors on triggering and exacerbating these illnesses, it is increasingly recognized that health-promoting behaviors that protect mitochondrial metabolism and energy regulation are an essential component of successful allostasis.

My own experience happens to be that this LAC stuff was an absolute "dud" for me (it did nothing) when I first tried it...and that it was a huge "winner" for me (huge and rapid impact) once I had corrected one/more nutritional issues.

I don't think (unless I'm misreading things) that the clinical trials regarding LAC have been particularly impressive. And yet, given my own experience (where I needed to correct nutrient deficiencies before LAC could do anything), I wonder whether the clinical trials were flawed in that nutrient deficiencies weren't dealt with before the LAC was given to people.

I suppose that having a large sample of people ought to make it so that the people with nutrient deficiencies are balanced out by others who don't have any nutrient deficiencies; maybe using a large enough sample eliminates the problem.

In my case, it seems like vitamin B12 and vitamin B6 and folate and iron...that one or more of those nutrients were deficient in my body. One can imagine that if LAC's mechanism of action has to do with mitochondria then it stands to reason then deficiencies in those nutrients that I just mentioned (all of which relate to the mitochondria) might have to be corrected in order to "lay the foundation" for the LAC to have an impact.

People with nutrient deficiencies very often will have issues with gastrointestinal absorption of things, so malabsorption is another reason why it's crucial to deal with nutrient deficiencies before giving people LAC.

In the book, Supernatural, Graham Hancock suggests that tryptamine is the essence of all the beneficial and ineffable effects of classic tryptamines and LSD and ibogaine. His thoughts prompted me to describe LSD as a form of DMT, indeed DMT is a component of the LSD molecule, not just tryptamine. However, I now see that DMT is a component of all ergolines, many of which are toxic,* indeed, it is a component of the base ergoline structure, lysergic acid. This seems to detract from Hancock’s thoughts.

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As the reader is already well aware, DMT, the active ingredient of ayahuasca, is a prominent member of a family of hallucinogenic and non-hallucinogenic molecules, known collectively as the tryptamines. These are the very molecules highlighted by Terence McKenna earlier in this chapter for their possible role in making “information stored in the neural-genetic material . . . available to consciousness.”

We saw in Chapter Eleven that one of the best known tryptamines is the neurotransmitter serotonin, 5-hydroxytryptamine, which is itself entirely non-psychedelic. Another well-known – and definitely psychedelic! – tryptamine is psilocybin. Ibogaine, the African psychedelic that put me on my back for 48 hours, has a tryptamine core, and so too does the most famous psychedelic in the world, lysergic acid diethylamide (LSD),[30] discovered by Albert Hoffman in Switzerland in 1943 and elevated to cult status by the hippie movement in the 1960s. Peculiarly appropriately, one of the key amino acids with which DNA does its mysterious work of constructing and replicating life is tryptophan,[31] the parent molecule from which all the tryptamines, including DMT, are derived.[32]

According to a report published in London on August 8, 2004 in The Mail on Sunday, Crick had privately admitted to colleagues that he was under the influence of LSD in 1953 at the moment when he “perceived the double helix shape” and unraveled the structure of DNA.[33]

While he was using LSD, as he supposed, to free himself from rigid preconceptions, is it possible that the drug’s tryptamine core brought Crick inadvertently into that hypothetical hall of records in our DNA to which ayahuasca gives us access, where “clever entities” long ago hid away the secrets of the universe?

30. See Rick Strassman MD, DMT: The Spirit Molecule: A Doctor’s Revolutionary Research into the Biology of Near-Death and Mystical Experiences, Park Street Press, Rochester, Vermont, 2001, pp. 34–6.

31. Francis Crick, Life Itself: Its Origin and Nature, Futura Macdonald, London, 1982, pp. 171–3.

32. Strassman, DMT, p. 34.

33. Daily Mail, London, August 8, 2004, pp. 44–5.

Supernatural. Graham Hancock. 2005, 2007. 13. ‘Ancient Teachers in Our DNA?’ ... ‘Francis Crick, LSD, and the double helix’

​

*Clavines are thought to contribute substantially to convulsive ergotism, while the ergopeptines are known to produce similar symptoms and also to cause gangrenous ergotism [31,101]. (4.2 Toxicity, p. 908)

31. Schardl CL, Panaccione DG, Tudzynski P (2006) Ergot alkaloids-biology and molecular biology. Alkaloids Chem Biol 63:45–86

101. Eadie MJ (2003) Convulsive ergotism: epidemics of the serotonin syndrome? Lancet Neurol 2:429–434

Ergot Alkaloids: Chemistry, Biosynthesis, Bioactivity, and Methods of Analysis. Arroyo-Manzanares, N., Gámiz-Gracia, L., García-Campaña, A.M., Diana Di Mavungu, J., De Saeger, S. (2017). In: Mérillon, JM., Ramawat, K. (eds) Fungal Metabolites. Reference Series in Phytochemistry. Springer, Cham. DOI: 10.1007/978-3-319-25001-4_1

My mother has Alzheimer's, and I get an occasional bout of high blood pressure from TRT so Sildenafil and/or tadalafil is of interest to me.

Would taking tadalafil be as effective as sildenafil for Alzheimer as indicated in this paper?

https://content.iospress.com/articles/journal-of-alzheimers-disease/jad231391

There's an experience where one will take a drug or vitamin and will experience an extremely powerful beneficial effect at first that then fades. I suppose that one possible explanation (for vitamins like niacin too, not just drugs) is that receptors react powerfully at first but then become desensitized. But what other mechanisms might account for "tachyphylaxis" when it comes to drugs and vitamins? And how much is known about how prominent each hypothesized mechanism actually is in reality?

In the case of vitamins, I wonder if it could be the case that people will get a big reaction from (e.g.) niacin at first because they have a pool of one or more substances in their body that are required to convert niacin to its "active form"; that pool has built up over time, but once niacin is introduced that pool gets depleted and so there's an initial powerful reaction that then fades as the pool runs out and as the body becomes unable to convert niacin into the "active form". That's just an idea, of course. If one finds that taking the "active form" of vitamins brings back the amazing reaction then that might lend some evidence (not sure, but maybe it would lend some evidence) to this idea about the pool becoming depleted.

My sense (perhaps incorrect) is that researchers don't know much about "tachyphylaxis". My sense (again, maybe wrong) is that drugs and vitamins "fizzling out" is a mysterious phenomenon about which little is known.

I saw the following paper:

https://jpet.aspetjournals.org/content/381/1/22.abstract

Attenuation of drug response with repeated administration is referred to as tachyphylaxis or tolerance, though the distinction between these two is obscured through both their usage in the literature and imprecise definitions in common pharmacology texts. In this perspective, I propose that these terms be distinguished by the mechanisms underlying the attenuation of drug response. Specifically, tachyphylaxis should be reserved for attenuation that occurs in response to cellular depletion, whereas tolerance should be used to describe attenuation that arises from cellular adaptations. A framework for understanding behavioral tolerance, physiologic tolerance, and dispositional tolerance as distinct phenomena is also discussed. Using this framework, a classification of drugs exhibiting attenuation of drug response with repeated administration is presented.

SIGNIFICANCE STATEMENT Distinction between tachyphylaxis and tolerance is unclear in the literature. Nonetheless, a mechanistic basis for distinguishing these important terms has practical implications for managing or preventing attenuation of drug response with repeated administration.

i want to figure out when a drug would be at its highest levels in humans, if you know the equivalent in mice

for example, in this study the aspirin effects was highest 2 hours after taking it

"we carried out a time-dependent study using 2 µM aspirin and found that aspirin was capable of upregulating TH mRNA significantly starting from 30 min of incubation with maximum stimulation observed at 2 h followed by a decrease in subsequent hours of incubation"

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6401361/

To determine whether aspirin, a commonly-used drug, could be used to stimulate TH, MN9D dopaminergic neuronal cells were treated with different concentrations of aspirin for 2 h under serum-free conditions. It is evident from RT-PCR (Fig. 1A) and real-time PCR (Fig. 1B) that aspirin dose-dependently stimulated the mRNA expression of TH in MN9D cells. Although aspirin was not effective in inducing the expression of TH mRNA at a concentration of 0.25 µM, significant increase in TH mRNA was seen at 0.5 µM aspirin with the highest increase observed at 2 µM aspirin (Fig. 1A–B). However, fold induction of TH mRNA decreased at higher concentrations of aspirin and we did not find any induction at 10 µM aspirin

Boric acid has been reported as a cut in cocaine, but there are no instances of it in Drugsdata.org. Do they test for it? Is there a way to confirm if they test for it? If their analysis only comes up with, say, 3 compounds, none of which are similar to boric acid in mass, that would rule out the presence of boric acid with certainty, correct? Thank you.

For instance a mild kratom withdrawal lasts 3-5 days in the acute stage, and severe heroin withdrawal also lasts for around the same duration despite the intensity and level of dependence between these 2 being significantly different to each other.

Forgive my oversimplification, I'm not too knowledgeable on this area, but does mu opioid receptor upregulation following secession of use only start after a perioid of time, and is that process very quick once it does start? I can't find any relevent data on the exact reason for this phenomenon.

Anyone who has a good answer for this I would appreciate your answer. Thanks.

Unrelated study: https://pubmed.ncbi.nlm.nih.gov/7841858/

A long-standing question in neuropsychopharmacology was why serotonin wasn't psychedelic if it acts upon 5-HT2A receptors, while LSD, DMT, and Psilocin are psychedelic. A paper from 2022 suggests that serotonergic psychedelics activate intracellular 5-HT2A receptors to induce their effects, whereas the activation of membrane 5-HT2A receptors doesn't achieve the same effect. Psychedelics are more fat-soluble than serotonin, so unlike serotonin, they diffuse freely across the cell membrane to gain access to intracellular 5-HT2A receptors. This makes sense - DMT and Psilocin both have 2 extra methyl groups (which increase fat solubility), compared to serotonin, and DMT also lacks the hydrophilic hydroxyl group that serotonin has.

While that is a sound hypothesis, this does not explain why Lisuride is non-psychedelic. Lisuride activates 5-HT2A, but is nonpsychedelic - however, its chemical structure suggests it should be fat-soluble enough to diffuse across the cell membrane and activate intracellular 5-HT2A receptors.

According to the online chemical prediction tool, SwissADME, Lisuride is almost as lipophilic as LSD - Lisuride has a Consensus Log Po/w of 2.52, while LSD has a Consensus Log Po/w of 2.76. They're also structurally similar, so this tool aside, it is likely Lisuride also mimics LSD's high lipophilicity.

Going back to the 2022 paper - if the only reason serotonin itself is not psychedelic is because it cannot cross the cell membrane to activate intracellular 5-HT2A, then why is Lisuride not psychedelic? Lisuride is both highly lipophilic and a 5-HT2A agonist - which is unlike serotonin, but very much like LSD, DMT, Psilocin.

I've heard before that Seroquel's anticholinergic effects were dose dependent starting at around 100 mg yet accoring to the chart in the link listed below it's a strong anticholinergic even at doses as low as 6.25 mg/day. Wondering what you guys think of this and why there is very conflicting information regarding the anticholinergic burden of low dose Seroquel?

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6941288/#:\~:text=According%20to%20Table%202%2C%20the,score%20of%201%20was%20aripiprazole.

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This is not an emergency post or current thing I’m going thru… just a thought I had this evening. So hallucinogens like shrooms and marijuana etc. contain chemicals (THC, psilocybin) that effect neurotransmitters / synapses in the brain and nervous system which result in having a trip or other sensations.

My question is are there other plants or natural substances that essentially do the exact OPPOSITE: up-regulate or down-regulate whatever neurotransmitters or like bind/block receptors for aforementioned substances. For example, I believe I heard CBD can reverse effects of THC but I could be wrong. Wondering if any other known plants / substances that can do this?

Sorry if that was wordy, hard to articulate.

Example (for sake of rules):

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3797438/

**Edit: I should have specified natural only (not a Rx drug)

I know that clonidine and guanfacine have distinct mechanisms of action, but I'm unsure about the extent to which it's ever the case that a patient will find that guanfacine doesn't work and that clonidine does. Why would clonidine work in a situation where guanfacine didn't?

I saw the below:

https://www.mdpi.com/1422-0067/22/8/4122

Guanfacine is a selective agonist of the α2A adrenoceptor [11,12,13,14]. The α2A adrenoceptor is mainly expressed in the dendritic spines of frontal glutamatergic pyramidal neurones [13]. Based on the findings, the major mechanisms of action of guanfacine are proposed as two hypotheses [7,14,15]. The first hypothesis is that guanfacine activates frontal pyramidal neurones associated with working memory due to blockades of the hyperpolarisation-activated cyclic nucleotide-gated channel (HCN) [16], induced by the activation of the postsynaptic α2A adrenoceptor in superficial layers (HCN hypothesis) [14]. The second hypothesis is that guanfacine suppresses the hyper-function of pyramidal neurones of ADHD due to an enhanced inhibitory postsynaptic α2A adrenoceptor (excitatory postsynaptic current hypothesis) [7,15]. These two hypotheses emphasise the importance of the intra-frontal glutamatergic system. Both hypotheses were supported by a number of experiments. In particular, both guanfacine and clonidine improve attention/cognition performance and the regulation of impulsivity in rat ADHD models [17], but do not improve behaviour in the α2A adrenoceptor knockout model [18]. The behavioural effects of both guanfacine and clonidine were attenuated by α2A adrenoceptor antagonists but were unaffected by antagonists of α2B or α2C adrenoceptors [17]. These preclinical findings suggest that the modulation of noradrenergic transmission via the activation of the α2A adrenoceptor probably plays fundamental roles in the pathophysiology of ADHD.

THCv and THC tolerance

I've noticed that THCv seems to be a cb1r antagonist/inverse agonist. I wad wondering if there would be a reverse tolerance to THC while using THCv. Considering this is an antagonist, it should cause an upregulation of cb1 receptors correct. So, this leads me to thinking about using THCv to rapidly reduce THC tolerance. I cannot however, find anything about it, so I'm coming to this subreddit.

Menthol is a monoterpene that’s widely used as a natural flavoring agent and natural product. Menthol also acts as a weak KOR agonist as well as seeming to have GABAergic activity and apparently acting as an inhibitor of 5-HT3 receptors.

I’ve been hyperfixated on this subject since I found that out and realized there’s little to no research on menthol use, and was hoping someone here might be able to help?

Obviously the menthol concentration in any commercial product intended to be consumed is way too low for you to notice any psychoactive effects, but perhaps a high dose of a concentrated / pure menthol solution would have a different effect?

These pure menthol crystals are actively for sale on Amazon and you can buy as much as a pound at a time if you desire to do so. This pure liquid menthol crystal product is also for sale and offers an extremely concentrated extract dosed at 770mg/ml.

The bioavailability of pure menthol seems to be quite low, so I suspect orally ingesting a dose this high would be very irritating to the stomach and GI tract.

However, it is readily bioavailable when inhaled. My current theory is that one could possibly vaporize these pure menthol crystals in a puffco or similar and inhale the vapor to dose effectively.

I’ve spoken to one individual very briefly who claimed to actively abuse menthol, and said it’s similar to a low dose salvia plain leaf experience, except extremely dissociative, and supposedly lasts like an hour once inhaled.

However, I have also come across a few reports online claiming they dosed and felt nothing but slight stimulation, similar to caffeine or nicotine.

EDIT: Turns out there’s actually 8 different stereoisomers of menthol:

(+)-Menthol, (−)-Menthol, (+)-Isomenthol, (−)-Isomenthol, (+)-Neomenthol, (−)-Neomenthol, (+)-Neoisomenthol, (−)-Neoisomenthol

The racemate of dextromenthol and levomenthol is whats commonly sold as pure menthol crystal, but I’ve found a few chemical supply companies that actually carry some of these stereoisomers in their purest form.

Could there be differing psychoactive effects between these? This topic has very very little research, so I’d love for someone with more knowledge to comment on this

It has been long known that Escitalopram (S-Citalopram), the left-handed isomer of Citalopram, is the one fully responsible for its serotonin reuptake inhibition. It was even discovered that the right-handed isomer, R-Citalopram, antagonizes S-Citalopram binding to SERT and reduces clinical efficacy in animal models.

In humans, Escitalopram seems to result in more rapid antidepressant effects, presumably due to less antagonism of SERT binding by absent R-Citalopram, and thus a faster rise in synaptic serotonin & presynaptic 5-HT1A autoreceptor desensitization.

If all R-Citalopram does is antagonize the beneficial mechanism of action of S-Citalopram, why is racemic Citalopram even prescribed at all?

You may be surprised to read this given that flumazenil is a BZ receptor antagonist at all subtypes aside from a5 containing GABA-A (where it is a partial antagonist). Indeed, some medical guidebooks warn against using it for anything but acute overdose due to a theoretical potential for precipitating withdrawal and seizure. However, there exists a whole host of evidence demonstrating that flumazenil attenuates withdrawal in benzo-dependent patients while producing negative symptoms in controls.

How could this be the case given its antagonist action? I have seen receptor conformation changes cited in some studies but wanted to ask nonetheless in case someone else understands this better.

Hi r/AskDrugNerds community!

Hi, I have been fascinated by the recent advancements in protein structure prediction, especially with DeepMind's AlphaFold. For those in drug-related fields, how do you perceive the current and potential future applications of AlphaFold in understanding drug-related systems?Additionally, in your expert view, can you envision any possibilities arising from integrating AlphaFold technology into drug-related research? Whether it's drug discovery, enzyme engineering, or any other domain, your insights would be highly appreciated.Eagerly anticipating your thoughts and experiences!

https://deepmind.google/technologies/alphafold/

There seems to be a debate whether mephedrone in laboratory doses is neurotoxic or not. However, suppose we are dealing with a hypothetical case of a heavy mephedrone user, for whom potential neurotoxicity poses a higher risk factor. We know that it is generally advised to take supplements like ALA, ALCAR or vitamin C to diminish the risk of MDMA's neurotoxicity, especially for heavy users [1] [2]. Given that the mechanism which induces damage to serotogenic neurons is relatively similar for mephedrone, would it be a sound piece of advice to take the same supplements that one would take were one to use MDMA? Has anyone tried to scientifically test this, or at least provide a very solid anecdotal account?

I'm somewhat knowledgeable on DXM's pharmacology and together with my own experiences, I am wondering if it possible that DXM and its metabolite DXO could change what receptors they are blocking over time in waves?

Whenever I do DXM in heavy doses I feel as if one minute I'm feeling lots of serotonin and then a few minutes later it gets slighty/very dysphoric and speedy and I'm wondering if this could be caused by DXM going from antagonizing SERT to antagonizing NET making it more speedy and dysphoric?

Another thing I noticed is how come on wikipedia DXM doesnt have much affinity for histamine 1 even though its known to cause heavy outbreaks in most individuals?

https://pubmed.ncbi.nlm.nih.gov/26826604/ (wikipedias source for DXM/dxo binding affinities)

Thank you

This is a largely simplified question for what I assume is a set of complex mechanisms but spare the details as I just want a general answer.

What I mean by this is as the plasma concentrations increase towards the peak, does the rate of increase and direction of change coincide with the subjective positive emotional effects of the drug? Does the same apply vice versa when the plasma levels begin to decrease and is this responsible for the euphoria/dysphoria experienced during the course of the drug and its effects?

For instance when insufflating the drug rather than orally ingesting the drug, there is a consensus that the experience is more extreme at each end of the subjective effect profile meaning a greater feeling of wellbeing as the drug approaches peak concentrations quickly vs the slower, less intense and more sustained feeling of wellbeing when taken orally.

I'm aware that ethanol likely follows this general rule due to research I have seen indicating it only maintains it's positive effects on the ascending limb of it's blood concentration, so does this also apply to amphetamine, and perhaps by extension many other drugs?

(Study is largely unrelated as I could not find a study answering or eluding to my exact question) - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3666194/

I came across this when I was doing some searching. As the information isn't detailed, I simply acknowledged it as interesting and moved on.

1. The 2,3-dihydro-diethylamide of lysergic acid induces LSD-like autonomic and mental changes in man but is less potent than LSD.

2. The effects of 2,3-DH-LSD appear more slowly than those of LSD-25.

A comparison of 2,3-dihydro-lysergic acid diethylamide with LSD-25. Gorodetzky, C.W., Isbell, H. Psychopharmacologia 6, 229–233 (1964). DOI: 10.1007/BF00404013

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I just learned that the medication, hydergine, (created by Hofmann) is a combination of three dihydrogenated ergot alkaloids (dihydroergocristine, dihydroergocornine, and alpha- & beta-dihydroergocryptine). I know that hydergine has been viewed as a nootropic. I remember one person on Bluelight said that if LSD was Hofmann's problem child, hydergine is his wonder child. So, is there any reason to believe that dihydrogenated LSD is an enhanced version of LSD?

On a loosely related noted, I recently found out about dehydrobufotenine. Interestingly, this chemical is structurally similar to LSD.* A form of DMT with an LSD-like effect, that certainly qualifies as enhanced! It is reportedly psychedelic, from anonymous reports,** however, someone said that there's no way it's psychedelic.†

​

*http://herbpedia.wikidot.com/dehydrobufotenine

**See second paragraph of ‘Psychoactivity’ in above article.

†Not a chance in hell this is active as a psychedelic. Look at the damn structure; yes it's a constrained tryptamine analog, but that itself doesn't mean it's gonna bind the same.

Even if you've got all the right "parts" there, they're in the wrong places to activate the receptor. You need that amine to be sticking further out from the indolic nitrogen and oxygen than that.

u/Argenteus_CG, https://www.reddit.com/r/researchchemicals/s/q47Z8XEwUm

See the part in bold:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10618096/

The main mechanism of trimetazidine is modulating mitochondrial energy production [117]. Mitochondria mainly utilize oxidation of glucose or fatty acids to produce ATP [118]. While fatty acid oxidation produces more ATP per gram, it requires more oxygen and can be slower than glucose oxidation in producing ATP, which increases risks such as hypoxia and oxidative stress to the cell [119]. Specifically, fatty acid oxidation may not keep up with required rapid ATP generation during periods of extended continuous and rapid neuronal firing, making it less suitable than glucose oxidation for brain metabolism [119]. Fortunately, inhibiting fatty acid oxidation can shift the metabolic processes to rely more on efficient glucose oxidation [118, 120]. Trimetazidine is a selective inhibitor of 3-ketoacyl-CoA thiolase, a key enzyme in fatty acid oxidation [121]. By selectively inhibiting β-oxidation of free fatty acids, trimetazidine promotes glucose oxidation and decreases oxygen consumption [121]. Trimetazidine also increases pyruvate dehydrogenase activity to decrease lactate accumulation [117]. These processes ultimately result in trimetazidine reducing intracellular calcium ion accumulation, reactive oxygen species and neutrophil infiltration to increase cellular membrane stabilization [113, 122–127].

A couple questions come to mind.

First, why do mitochondria in the brain even do fatty-acid oxidation at all if it's a bad thing? What advantage does this process have that makes it even a thing at all when it comes to the brain?

Second, what exactly causes some people's brains to do fatty-acid oxidation such that the harm (from this process) becomes significant? Not sure exactly how a person's brain ends up doing so much fatty-acid oxidation such that significant damage arises.

Third, people take fatty-acid supplements in order to improve brain health, correct? But how does the fact that fatty-acid supplements help the brain square with the fact that fatty-acid oxidation is harmful? One might imagine that sending fatty acids to your brain would be harmful given that fatty-acid oxidation is harmful; of course, fatty acids presumably do many good things in the brain even if fatty-acid oxidation is a bad thing.

Question related to this: https://www.jci.org/articles/view/168783

Graphical abstract: https://dm5migu4zj3pb.cloudfront.net/manuscripts/168000/168783/medium/JCI168783.ga.jpg

The study above posits that adolescent idiopathic scoliosis (AIS) could be the result of variants in SLC6A9 gene, resulting in reduced glycine uptake, leading to increased glycine levels (hyperglycinemia), and overstimulation of NMDA receptors. The researchers treat this with medical grade sodium benzoate, as this is a glycine neutralizer, and find this to be quite successful.

I've also done some further research and it appears that other therapies like benzodiazipines are also used to treat hyperglycinemia via upregulating GABA. Regardles,s the study linked originally seems quite promising to me especially with their replication of AIS in zebrafish by inducing variants of SLC6A9.

My question: How could excessive glycine levels be downgregulated via other therapies, like mineral/vitamin supplementation, considering that the use of sodium benzonate for this condition is still in the research phase? My guess would be something like NAC and magnesium.

Consider niacin. Suppose that two facts are observable:

• the niacin takes action very quickly (within a couple minutes)

• the niacin has to be taken regularly (every few hours)

To what extent can one use those two observations to narrow down the list of possible mechanisms that the niacin might be acting through?

See here some ideas on how niacin might operate:

https://www.mdpi.com/1422-0067/20/18/4559

Niacin or vitamin B3 has been shown to have a novel neuroprotective role in animal models of Parkinson’s disease (PD), stroke, traumatic brain injury, and multiple sclerosis [1,2,3]. Niacin has been studied clinically for over fifty years in the treatment of dyslipidemia [4], Crohn’s disease [5] and inflammatory bowel disease [6]. These studies have shown that niacin treatment improved vascular permeability, reduced apoptosis in epithelial cells, and most importantly suppressed the pro-inflammatory gene expression of macrophages (M1). Niacin triggers and boosts anti-inflammatory immune responses in humans and animal models of PD [7]. Specifically, niacin treatment had an anti-inflammatory polarization effect from pro-inflammatory macrophages (M1) to anti-inflammatory macrophages (M2) in PD subjects [8]. Neuroinflammation is one of the hallmarks of PD pathophysiology and although inflammation may be beneficial initially, prolonged and uncontrolled inflammation exacerbates brain damage [9]. Niacin may reduce neuroinflammation through the G-protein-coupled receptor, GPR109A, which has been noted to be up-regulated in PD patients [10].

GPR109A is ubiquitously expressed in a variety of cells including monocytes, leukocytes, neutrophils and macrophages [11]. This receptor is present in the brain and all other organs of humans and remains dormant until the onset of inflammation [12,13]. Interestingly, GPR109A was shown to be anti-inflammatory in colonic and retinal inflammation [14,15]. An up-regulation of GPR109A in the substantia nigra (SN) of PD patients has also been observed in postmortem PD subjects, making it an attractive target for niacin therapy [10].

In vivo and in vitro studies showed a robust activation of microglia that has been found in both, 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)- and 6-hydroxydopamine (6-OHDA)-induced PD animal models [16,17]. Due to lineage proximity to microglia, macrophages have attracted increasing attention in relation to the onset and progression of PD. The interaction between microglia and macrophages, and their role in the progression of PD has gained recognition in the potential pathophysiology of PD [18]. In this study, we have utilized macrophages due to their higher expression of GPR109A [11] as compared to other similar available cell lines, such as human microglial cells. Moreover, macrophages are known to cross the leaky blood–brain barrier in PD to interact with microglia and stimulate the secretion of inflammatory cytokines to cause brain damage through neuroinflammation [9]. Uncontrolled release of inflammatory cytokines such as TNF-α, IL-1β, and IL-6 are key components contributing to neurodegenerative disease progression by inducing neuroinflammation [19,20,21].

Until now, it is unknown what specific role GPR109A plays in PD pathology or how niacin could possibly work to alleviate PD symptoms. In this study, we utilize lipopolysaccharide (LPS) as a mitogenic stimulant derived from Gram-negative bacteria [22,23], which induces the production of pro-inflammatory cytokines [24,25], as is similarly observed in PD subjects. Even though quality of life for PD subjects taking niacin supplements has been improved, the underlying molecular mechanism(s) has never been explored. Here, we focus on the molecular mechanism of niacin’s anti-inflammatory role in an in vitro study based on the observations shown in PD subjects [10]. Our aim was to elucidate the mechanism of niacin by examining its effects on macrophage cells treated with LPS. This study can provide useful information to understand the potential underlying mechanism of niacin on human PD subjects.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7824468/

The brain–gut axis, bidirectional neural connections from the CNS to the ENS, is evolving to incorporate the gut microbiome. Investigation of the microbiome–gut–brain axis has led researchers to propose a GI origin pathogenesis for PD and other neurodegenerative disorders [44,45,46]. A recent microbiome-wide association study by Wallen et al. found three clusters of co-occurring microorganisms in PD with an overabundance of a polymicrobial cluster of opportunistic pathogens, reduced levels of SCFA-producing bacteria, and/or elevated levels of carbohydrate metabolizers commonly known as probiotics [47]. In a study of 24 PD patients compared to 14 healthy controls, proportions of endotoxin-producing bacteria, Actinobacteria and Proteobacteria, were increased, whereas populations of SCFA-producing bacteria, Bacteroides, Prevotella, and Ruminoccoccus, were decreased, as shown in Table 1 [41]. The presence of SCFA-producing bacteria ferments resistant non-starch polysaccharides, non-digestible oligosaccharides, and dietary fibers to produce SCFAs. SCFAs such as acetate, butyrate, propionate, formic acid, and isobutyric acid decrease intestinal inflammation and downstream pathology in various diseases [11,14,48].

...

The intestinal barrier comprises a single layer of epithelial cells tightly stitched together by a special group of tight junction proteins such as claudins, occludens, tricellulin, and cadherins, shown in Figure 1. These tight junction proteins play an important role in maintaining gut permeability and homeostasis [49]. The luminal surface of the intestinal barrier is the largest body surface in close contact with external pathogens and the gut microbiome. Therefore, optimal functioning of these tight junction proteins is critical to the protection of the enteric nervous system, vasculature, and other crucial structural elements on the tissue side.

Gut microbiome and their bacterial byproducts can activate immune cells to regulate the expression of pro-inflammatory cytokines, such as TNF-α, IL-1β, and IL-6, which, in turn, act on tight junctions to increase barrier permeability [50]. These pro-inflammatory cytokines also initiate the recruitment of neutrophils, monocytes, and components from circulation to sites of inflammatory insult, thus prolonging the inflammatory response. Bacterial lipopolysaccharide (LPS) is a well-known endotoxin that is a potent trigger for TNF-α production [51]. GPR109A, a luminal G-protein coupled receptor on the intestinal epithelial surface, is a promising target for the modulation of intestinal permeability and potential reversal of leaky gut.

https://www.sciencedirect.com/science/article/abs/pii/S0278584622000756

Blood–brain barrier (BBB) is a critical gateway that regulates the passage of molecules and cells between the blood and the brain (Abbott et al., 2010). BBB is primarily comprised of microvascular endothelial cells with tight junctions (TJs) including transmembrane proteins (claudin and occludin) and cytoplasmic proteins (zonula occludens; ZO). The transmembrane proteins, occludins and claudins, interact on adjacent endothelial cells to form a physical barrier against paracellular diffusion (Hirase et al., 1997; Fanning et al., 1999; Furuse et al., 1999). The ZO family (ZO-1 and ZO-2) anchors the transmembrane proteins to the cytoskeleton (Anderson et al., 1995; Haskins et al., 1998; Huber et al., 2001).

The integrity of the BBB is essential for central nervous system homeostasis. Disruption to BBB can contribute to the pathogenesis of various neurological disorders including epilepsy, depression, and schizophrenia (Marchi et al., 2007; Rigau et al., 2007; Menard et al., 2017; Greene et al., 2018b; Kealy et al., 2020). Indeed, psychiatric patients showed higher cerebrospinal fluid/serum albumin ratio, a standard biomarker for altered BBB function and integrity as compared to controls (Reiber, 1994). In a rodent model of psychosis-like post-traumatic syndrome, animals exhibited increased BBB permeability (Abdel-Rahman et al., 2002). The onset and the duration of schizophrenia are associated with disrupted mRNA and protein levels of TJs proteins. Aberrant and discontinuous expression of claudin-5 was observed in the postmortem brains of schizophrenic patients as compared to age-matched controls. Moreover, the loss in claudin-5 is linked to the reduction in the acoustic pre-pulse inhibition, a schizophrenia-related behavioral abnormality (Greene et al., 2018b). BBB disruption could be a modifying factor in the development of schizophrenia, thus targeting and regulating proteins involved in BBB function could be a potential therapeutic strategy for this disorder.

Niacin (vitamin B3 or nicotinic acid) is the most effective medication in current clinical use for increasing high-density lipoprotein cholesterol and it substantially lowers triglycerides and low-density lipoprotein cholesterol (Ito, 2004). Niacin is a high-affinity agonist of GPR109A (also known as niacin receptor 1; NIACR1, hydroxycarboxylic acid receptor 2; HCAR2), which is a G protein-coupled high-affinity niacin receptor (Soga et al., 2003; Tunaru et al., 2003; Wise et al., 2003). GPR109A and its agonists are known for their anti-inflammatory roles in a variety of in vivo and in vitro experimental conditions (Kwon et al., 2011; Digby et al., 2012; Si et al., 2014; Graff et al., 2016; Salem and Wadie, 2017). Niacin is a precursor to several neurotransmitters in the brain, which may have an impact on mood. Moreover, niacin is a neuroprotective and neurorestorative agent that promotes angiogenesis and arteriogenesis after stroke and improves neurobehavioral recovery following central nervous system diseases such as stroke, Alzheimer's disease, and multiple sclerosis (Fukushima, 2005; Chen and Chopp, 2010; Feingold et al., 2014; Chen, 2019). However, the literature reports conflicting data on the relation between niacin and psychosis (Gasperi et al., 2019). An epidemiologic study conducted on 140 subjects (73 controls and 67 patients with schizophrenia) has revealed that affected individuals showed markedly lower dietary intakes of specific nutrients, including niacin (Kim et al., 2017). Niacin deficiency is well known to manifest with several psychiatric symptoms (Jagielska et al., 2007; Amanullah and Seeber, 2010; Wang and Liang, 2012). Also, historical evidence has been accumulated that niacin augmentation can be used for treatment of schizophrenia. Xu and Jiang (2015) highlighted the subgroups of schizophrenia that responded to niacin augmentation and reviewed some mechanisms by which niacin deficiency could lead to schizophrenic symptoms. On the contrary, a one-year case-control study performed on 101 controls and 128 cases of schizophrenia found a direct relationship between the disease and nicotinamide levels (Cao et al., 2018). Moreover, Loebl and Raskin (2013) reported the incidence of manic-like psychotic episode with niacin treatment, an effect that could be attributed to the increase in the production of serotonin and dopamine in a sensitive patient.

Although BBB–associated TJs disruption is a hallmark feature of major psychiatric disorders (Greene et al., 2020), not enough data is available on the effect of niacin on disrupted BBB in neuropsychiatric disorder. Therefore, the present study was constructed to evaluate the effect niacin on ketamine–induced psychosis and BBB disruption. Meanwhile, mepenzolate bromide (MPN), a GPR109A receptor blocker, was used to investigate the role of this receptor on the observed niacin's effect.

Suppose that the niacin is acting by repairing "leaky gut" or "leaky BBB"; you wouldn't then expect there to be a need to regularly take more niacin in order to restore the niacin's positive effect, would you? I would imagine (though I might be wrong) that it's not like you have to take more niacin every few hours because your gut is starting to get too permeable again or because your BBB is starting to get too permeable again...it seems implausible that you'd have to be constantly "beating back" the issue of a too-permeable gut or a too-permeable BBB.

And you could also ask whether a candidate mechanism X makes sense given the speed with which the niacin takes action; if the niacin takes action within a couple minutes, is that enough time for the niacin to enter the brain and bathe the brain and produce an "anti-inflammatory polarization effect from pro-inflammatory macrophages (M1) to anti-inflammatory macrophages (M2)"? You could ask for each mechanism whether that mechanism can happen within a couple minutes. If a mechanism would take hours to occur, then that mechanism could be ruled out.

I wonder whether it would make sense to propose that the niacin is working via the aforementioned "anti-inflammatory polarization effect" if the niacin needs to be taken regularly. Why would the macrophages be constantly switching back to the unhealthy state such that one would need to regularly introduce more niacin in order to restore the healthy state over and over? I'm not sure why regular correction of the macrophages' state would be necessary; is it plausible that regular correction would be necessary?

As the title says, why is the kindling phenomenon associated with GABAA receptors vs GABAB? Sorry to put this ignorantly, but does the receptor “remember” past insults? Is the GABAB recovery faster and is GABAB less prone to kindling or completely prone?

I read somewhere that the GABAA downregulation due to excessive activation leads to a transcription of this into cell material/DNA, where new cells express less GABAA density. Which seems permanent to me at least.

Also separately, if what I said is true, why are gabab agonists like baclofen not considered for PRN anxiolytic purposes as opposed to gabaa pams (if the hypothesis of GABAb resilience to downregulation and kindling is true)

https://pubmed.ncbi.nlm.nih.gov/16987222/