Rules (click)

So for example let’s take dopamine - the dopamine transporters transport released dopamine in the synapse back into the sending neuron to be used again.

Why does then monoamineoxidase also regulate dopamine by changing its structure to make it inactive?

Why is there a need to regulate dopamine by this mechanism also, when the mechanism of reuptake transporter proteins seems to be capable enough on its own?

Isn’t having to constantly create new dopamine after MAO inactivates it an unnecessary waste of energy from an evolutionary standpoint? What i’m wondering is if there are any benefits from such a mechanism that make the extra work “worth it” other than I guess just security that if one mechanism fails, there are still others that can do the job?

This question of course applies for other neurotransmitters metabolized by MAO like serotonin, norepinephrine or histamine.

I would be grateful for any insight!

https://pubmed.ncbi.nlm.nih.gov/33836221/ attaching a link to some information about MAO (having to include a link is a stupid rule, I believe my question is worthy enough to be asked here even though it doesn’t need to make a reference to any studies..)

[Hope you don't mind me posting this, if it's off topic i'll remove it.]

This study mentions Anhedonia correlates with decreased Resting-state functional brain connectivity (rsFC) between the NAc subdivisions in MDD. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930634/ https://www.reddit.com/r/neuroscience/comments/mq8bbk/anhedonia_correlates_with_functional_connectivity/

If thats true, I'm assuming that increased neuroplasticity would also then Increase Resting-state functional brain connectivity?

increased neuroplasticity, like taking semax or noopept

Looking for some science paper for MDMA. it is known that LSD acts primarily on 5HT2A receptors and causing through this stimulation hallucinations. But it is also active in cardiovascular system, where 5HT2A activation causes vasoconstriction and platelet aggregation. This can lead, when predisposed, to thrombosis or phlebitis.

This leads me to question if is it even measurable. There are known affinities but these are valid for brain? Id like to compare affinity to peripheral 5HT2A receptors for LSD and for MDMA. We know that high dose of MDMA can cause (due to metabolism of MDA) hallucinations via 2A receptors activation along with serotonin release. But does it activate peripheral 2A serotonin receptors on platelet like LSD? I can only find this article telling that MDMA, like the SSRI citalopram, but in relatively high concentrations, inhibits collagen induced platelet aggregation

https://www.researchgate.net/publication/350516380_Cardiovascular_and_temperature_adverse_actions_of_stimulants

Can anybody help me find correct answer?

It is well known that methamphetamine causes severe cases of neurotoxicity in animal studies, such as neurodegeneration, which could be detected through staining[1] or cell death markers[2](caspase for apoptosis, MLKL for necroptosis, and LC3B for autophagia) along with typical post-amphetamine symptoms such as DA and DAT depletion. However, while DA and DAT depletion are also observed in human users, cell death markers were not found in vivo[3] or in vitro[4]. There are also studies failing to find evidence for neurodegeneration through other methods[5](concurrent DAT and DA increase following methylphenidate administration?? I didn't really understand this study tbh).

At the same time, there are studies outlining persistent decrease in DAT levels[6](tbh this isn't really conclusive since there're other studies documenting recovery of DAT levels) as well as persistent structural changes[7] or in more extreme cases hypertrophy[8] which, if I understood correctly, hint at neurodegeneration.

So my question is, why is neurodegeneration seemingly not a feature of human methamphetamine users, despite its occurrence being well established in animal studies? And why do other studies find structural deficits in human users, assuming that no neurodegeneration occurred?

Hello all,

Over a year ago, I came across the potentially ground-breaking finding (more on why in a bit) that 1mg/kg of ketanserin (5HT2A antagonist) does not abolish the plasticity and antidepressant effects of psilocybin in mice. Admittedly, I did not look into the methodology of this study beyond that which was mentioned in the abstract. Later studies in humans demonstrated that ketanserin could successfully nullify the hallucinogenic effects of LSD in humans, and the concept of using ketanserin as a 'shortening agent' in psilocybin therapy is patent pending.

The idea that ketanserin pre-treatment could prevent the hallucinogenic effects of psychedelics while preserving their potential therapeutic efficacies in various psychiatric conditions is enticing, as the psychotomimetic effects of psilocybin has proven to be a substantial hurdle in the evaluation, approval, and tolerability of psilocybin.

However, the dosage of ketanserin used in the prior study has been shown to occupy ~30% of cortical 5HT2A. Studies with similar designs that have used similar doses or higher, have reported complete abolition of the plasticity-enhancing of various other 5HT2A agonists, like tabenanthalog, LSD, and DMT.

On the contrary, at least one paper using ketanserin at 2mg/kg reporting no effect on synaptic markers in mice or anti-anhedonic effects induced by psilocybin administration. It should be noted that this did not directly establish the occupancy of ketanserin, but used proxy markers like ketanserin-induced hypolocomotion and reduced head twitch response as evidence for its efficacy.

I originally planned on posting this to r/DrugNerds, but shied away from making what could be perceived as an authoritative post on a topic I haven't been able to form a strong opinion on. I invite others to comment on the research and my analysis, as well as provide some of their own as it relates to the title topic.

? for the bot.

Thanks!

Hederagenin seems to be a promising compound, supposedly a triple reuptake inhibitor (according to one study). There was minor interest on r/Nootropics some years ago, but it seems that interest on the saponin has near completely died down.

Is there a reason that the research around this compounds reuptake ability seemingly ceased?

I am also wondering if anyone here has any experience with Hederagenin or further information on its possible psychoactivity.

The extracts of Fructus Akebiae, a preparation containing 90% of the active ingredient hederagenin: serotonin, norepinephrine and dopamine reuptake inhibitor

Have you used psychedelics (including MDMA) for therapeutic purposes in the past year?

Researchers at the University of Alabama at Birmingham want to hear about your experiences, regardless of whether they were positive or negative.

What's the study about?

We're exploring under-studied aspects of individuals’ experiences during therapeutic psychedelic use. Your insights could be valuable for advancing our understanding of psychedelic therapy.

Who can participate?

- Adults 18+

- Used a full dose (i.e. anything greater than a microdose) of psychedelics for therapeutic purposes in the past year

- Not currently experiencing severe psychiatric symptoms (e.g. psychosis or mania)

What's involved?

1. 15-30 minute online survey

2. Possible 60-90 minute follow-up interview (if selected)

Compensation

$50 digital Amazon gift card for completed interviews (survey participation alone is not compensated)

Want to learn more or participate?

Visit our survey link: https://uab.co1.qualtrics.com/jfe/form/SV_3wlnATTHB8LivjM 

Questions? Contact Dan Grossman (dgrossman@uabmc.edu) 

UAB IRB Protocol #: IRB-30001336

It seems to have anti depressant, anxyiolitic, pro cognitive and anti inflammatories effect. PDE4 inhibitors produce antidepressant actions in both animals and humans via enhancement of cAMP signaling in the brain. Selective inhibitors of PDE4 have demonstrated a broad spectrum of anti-inflammatory activities including the inhibition of cellular trafficking and microvascular leakage, cytokine and chemokine release from inflammatory cells. Any ideas why something like this is not in the market or why its not used? Also I dont think its a new discovery too anyways.

Source:

https://pubmed.ncbi.nlm.nih.gov/15922015/

https://pubmed.ncbi.nlm.nih.gov/19442182/

Epidermal Growth Factor (EGF) is a protein that, when applied to a damaged peripheral nerve, enhances axon regeneration, promotes the development of larger diameter axons, and improves neurological recovery by inducing Schwann cell proliferation and the release of neurotrophic factors.

https://www.sciencedirect.com/topics/neuroscience/epidermal-growth-factor

What drugs do this?

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). I'm interested in understanding the implications of this from a safety perspective, which naturally requires consideration of potential pharmacological interactions.

According to Malcolm (2023), 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), critical 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.

I am particularly focused on the theoretical safety risks associated with possible CNS depressant effects or minor changes in neurochemical stability during the ayahuasca experience. Although my (somewhat limited) source indicates there are no life-threatening interactions, it raises the question of whether pregabalin could influence the subjective or physiological responses to ayahuasca, or if it poses any secondary risks.

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

https://redcapmed.unifr.ch/surveys/?s=C4WTHM4W898NJC8A

Hey everybody,

We are happy to invite you to take part in our survey study at the University of Fribourg, investigating the acute effects of psychedelics. This study aims to shed light on the potential psychological and cognitive changes that occur during the immediate period after psychedelic use.

Why Participate?

Psychedelics have captured the attention of researchers, mental health professionals, and the general public for their potential therapeutic benefits. By participating in this survey, you will be helping us expand the knowledge about these substances and their effects on the human mind.

Who Can Participate?

·         You are 18 years or older.

·         You had a noticeable psychedelic experience in the last 12 months.

·         You understand and write English or German fluently.

Participation Details:

·         The survey will be conducted online and will require approximately 20 minutes to complete.

·         All responses will be anonymous and treated with strict confidentiality.

·         With the participation you will support us in expanding our knowledge of the substances and their effects on the human mind.

Randomized Raffle - Win Amazon Gift Cards! To show our appreciation for your time and contribution, we are offering a chance to win one of five Amazon gift cards worth €50 each. At the end of the survey, you will have the option to enter the raffle. Winners will be selected randomly and notified via email.

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Thank you for your interest in advancing psychedelic research and for considering participation in this study.

This study was approved by the Internal Review Board of the Department of Psychology, University of Fribourg (Ref-No.: 2023 - 862).

If you have any questions or require further information, please do not hesitate to contact us at vincent.diehl@unifr.ch.

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I have been reading up on the relationship between high levels of serotonin and acetylcholine receptors. The consensus seems to be that, generally, high levels of serotonin inhibit acetylcholine. I have also been investigating the effect of ssri on nicotinic receptors and found a few papers on the subject. Here is a review of the evidence:

https://pmc.ncbi.nlm.nih.gov/articles/PMC8068400/

The paper states at one point that escitalopram has a brain concentration of about 5uM, but most of the data I can find online state that it is more likely in the nanoM range. This would put the binding efficiency at clinical levels to far below that of the investigated effects on nicotinic receptors. Most of the studies I can see put an IC50 value in the micromolar range invitro. Could there still be an effect? a3b4 is inhibited at around 5uM which would put this in the range of a few ssris, but I'm struggling to believe that this is reasonable In the context of clinical doses which bind to serotonin in the nano molar range.

To add to the point about the molar concentrations, doesn't this depend on the substrate? It makes no mention of the molar concentrations of receptors or ml of fluid. Only states the molar concentrations. In the context of brain matter, wouldn't the inhibitory effect be a ratio of the molar concentrations of the ssri over the molar concentrations of the receptors? The studies invitro seem to have micromolar concentrations inhibiting cells in a solution of milliliters worth of cells. This seems unrealistic in the context of actual brain tissue concentrations.

What do you think is going on here?

You'd think that searching for "amino acids psychiatry" or "amino acids [insert psychiatric condition]" would yield tons of scientific papers and also various reviews. Instead one of the only papers that I found was this one here:

https://pubmed.ncbi.nlm.nih.gov/33786176/

The objective of the present study was to evaluate the circulating serum amino acid levels in children with attention deficit/hyperactivity disorder (ADHD). A total of 71 children with untreated ADHD and 31 neurotypical controls aged 7-14 years old were examined. Serum amino acid levels were evaluated using high-performance liquid chromatography (HPLC) with UV-detection. Laboratory quality control was performed with reference materials of human plasma amino acid levels. The obtained data demonstrated that children with ADHD were characterized by 29, 10 and 20% lower serum histidine (His), glutamine (Gln) and proline (Pro) levels compared with neurotypical children, respectively. In contrast, circulating aspartate (Asp), glutamate (Glu) and hydroxyproline (Hypro) levels exceeded the respective control values by 7, 7 and 42%. Correspondingly, the Gln-to-Glu and Pro-to-Hypro ratios were 28% and 49%, respectively, lower in ADHD cases compared with the controls. Total Gln/Glu levels were also significantly lower in ADHD patients. No significant group differences were observed between the groups in the other amino acids analyzed, including phenylalanine. Multiple linear regression analysis revealed significant associations between circulating serum Gln, lysine (Lys) (both negative) and Glu (positive) levels with total ADHD Rating Scale-IV scores. The observed alterations in Pro/Hypro and Gln/Glu levels and ratios are likely associated with the coexisting connective tissue pathology and alterations in glutamatergic neurotransmission in ADHD, respectively. Altered circulating levels of His, Lys and Asp may also be implicated in ADHD pathogenesis. However, further in vivo and in vitro studies are required in order to investigate the detailed mechanisms linking amino acid metabolism with ADHD pathogenesis.

I did see the two below papers, but both are from the 1970s:

https://pubmed.ncbi.nlm.nih.gov/420897/

The free tryptophan and plasma neutral amino acids including kynurenine have been determined before treatment, after a single load, and during prolonged treatment with L-tryptophan on a bipolar manic-depressive patient who has shown resistance to current treatments. The data of the patient were compared with the data of healthy control subjects in order to evaluate the availability of tryptophan to the brain. A relative deficiency of tryptophan in the plasma, as measured by the ratio of tryptophan to those amino acids which compete with tryptophan during transport processes, was found in the patient. Further, the patient showed an increased area under curve of plasma tryptophan after a load, and an increase in the competing amino acids during the load compared to a decrease in the control subjects. During the treatment with L-tryptophan the competing amino acids increased in the plasma. The results suggest that the patient suffered from a dysfunction of the processes which mediate active transport of tryptophan and other large neutral amino acids into tissues including the brain.

https://pubmed.ncbi.nlm.nih.gov/5077329/

When plasma tryptophan is elevated by the injection of tryptophan or insulin, or by the consumption of carbohydrates, brain tryptophan and serotonin also rise; however, when even larger elevations of plasma tryptophan are produced by the ingestion of protein-containing diets, brain tryptophan and serotonin do not change. The main determinant of brain tryptophan and serotonin concentrations does not appear to be plasma tryptophan alone, but the ratio of this amino acid to other plasma neutral amino acids (that is, tyrosine, phenylalanine, leucine, isoleucine, and valine) that compete with it for uptake into the brain.

You would think that there'd be a robust literature on this topic, given how important these amino acids are for the functioning of the brain and of the body.

I've read that, traditionally, VMAT2 is treated as a biomarker for neurons that is stabler than things like dopamine transporter(DAT), and is thus a better candidate for assessing neuronal loss/damage following stimulant abuse.

However, the studies on it seem to be conflicted. For instance, [1] and [2] revealed increased VMAT2 binding following methamphetamine abuse, while [3] revealed persistently lower levels of VMAT2 binding following long-term meth abuse and abstinence.

Coupled with findings in [2] where apoptotic markers were not identified as well as conclusions from [4]("DAT loss in METH abusers is unlikely to reflect DA terminal degeneration"), would it be apt to conclude that VMAT2 is similar to DAT in that it is subject to down/upregulation, and is thus not a good marker of neuronal loss following stimulant abuse?

On a side note, I'm actually quite confused about a premise of this question: is "terminal degeneration" the same thing as "neuronal loss/degeneration", or could it regenerate/recover??

Thanks a lot for stopping by~

See here regarding the mechanisms that came across to me as unusually "drug-like":

https://link.springer.com/article/10.1186/s12991-020-00298-z

SAMe may play a beneficial role in biochemical mechanisms that have been associated with depression. For instance, SAMe may affect the regulation of a wide range of critical components of neurotransmission [11,12,13,14,15,16,17]. SAMe is involved in three central metabolic pathways, namely trans-sulfuration (synthesis of glutathione), transaminopropylation (development of polyamines), and methylation (synthesis of sarcosine; conversion of norepinephrine to epinephrine; catabolism and anabolism of monoaminergic neurotransmitters [11, 12, 16, 17]. Several studies have observed the dysregulation of the one-carbon metabolism, and lower levels of methionine adenosyltransferase enzyme, cerebrospinal fluid SAMe and methylation deficit in patients with MDD [11,12,13,14]. Worthy of consideration is also the possibility that SAMe enhances gene expression of brain-derived neurotrophic factor [11, 18].

...

Many patients affected by MDD continue to be symptomatic despite second, third, or fourth-line treatment approaches [44] and SAMe may represent a useful aid for the treatment for MDD, especially in those cases where the risk–benefit ratio may not justify the use of less-tolerated pharmacological treatment [5, 10]. SAMe’s mechanism of action is still unclear, but it has been shown that SAMe is able to increase the central turnover rate of dopamine and serotonin [38]. In fact, SAMe raises cerebrospinal fluid levels of both homovanillic acid and 5-hydroxyindoleacetic acid, while lowering the levels of serum prolactin [36]. SAMe is able to impact on the noradrenergic system as well. An increase in the number of beta-adrenergic receptors and in the affinity of alpha1-adrenergic receptors for the agonist phenylephrine has been observed in rats, after the administration of SAMe [45]. Hence, the administration of SAMe leads to modifications in adrenergic neurotransmission that are opposite to those that are classically produced by standard antidepressants: upward regulation of alpha-adrenergic receptors and downward regulation of beta-adrenergic receptors. Of interest, antidepressant treatments may lead to a depletion of SAMe’s concentration in tissues [45], which may be replaced by the administration of more SAMe. Indeed, SAMe’s mechanism of action likely involves different neurochemical effects, including enhanced methylation of catecholamines and increased serotonin turnover, reuptake inhibition of norepinephrine, enhanced dopaminergic activity, decreased prolactin secretion, and increased phosphatidylcholine conversion [19, 46].

And I stumbled on a paper that talks about a potential danger of SAM-e. No idea if the paper makes sense, but see here:

https://www.nature.com/articles/s42003-022-03280-5

The global dietary supplement market is valued at over USD 100 billion. One popular dietary supplement, S-adenosylmethionine, is marketed to improve joints, liver health and emotional well-being in the US since 1999, and has been a prescription drug in Europe to treat depression and arthritis since 1975, but recent studies questioned its efficacy. In our body, S-adenosylmethionine is critical for the methylation of nucleic acids, proteins and many other targets. The marketing of SAM implies that more S-adenosylmethionine is better since it would stimulate methylations and improve health. Previously, we have shown that methylation reactions regulate biological rhythms in many organisms. Here, using biological rhythms to assess the effects of exogenous S-adenosylmethionine, we reveal that excess S-adenosylmethionine disrupts rhythms and, rather than promoting methylation, is catabolized to adenine and methylthioadenosine, toxic methylation inhibitors. These findings further our understanding of methyl metabolism and question the safety of S-adenosylmethionine as a supplement.

sulbutiamine primary effect is modulating glutamate via a rather strange mechanism, which indirectly antagonizes D1. Therefore with chronic use D1 would be upregulated

"As an example, after administering this molecule to rats for 5 days, there was a significant increase in the density of dopamine D1 receptor binding sites in prefrontal and anterior cingulate cortex (+26% and +34%, respectively)" https://pmc.ncbi.nlm.nih.gov/articles/PMC7210561/

Does allithiamine also have this effect?

Hi, so my final goal is to create an inclusion complex with cluster dextrin (highly branched cyclic dextrin) and MCT oil to turn my THC tinctures into water soluble powder.

So far I've tried simply just mixing the oil into the cyclodextrin by hand, mortar and pestling the oil and cyclodextrin, and combining in an alcohol solution, but every time the cyclodextrin just releases all of the oil back into the water.

I also tried the "paste" method of slightly hydrating the cyclodextrin and incorporating the oil after, but the kneading part just squeezed the oil out of the cyclodextrin so I was left with just a puck of cyclo.

https://www.sciencedirect.com/science/article/pii/S0308814622004290

Is this something I can do at home without specialized equipment? It'd be so cool to be able to form inclusion complexes.

Edit: I think I discovered the issue: the particle size for MCT oil is too large for cyclodextrin inclusion complexes. When I used straight THC + isopropyl solution + cyclodextrin it did work better. I think my best bet is liposomal encapsulation with lecithin if I want to make MCT oil more bioavailable.

Hey,

Dear Community. I am theoretically interested in Cerebrolysin because of its neuro-restorative effects. Also due to therapeutic potential. (future work in the medical/neuropsychiatric sector)

——————

Now I want to ask what your point of view is regarding the assumptions that cerebrolysin (hereafter CB) could act as an antigen in selected cases, which subsequently leads to autoantibodies?

Thank you for your time. Let me now briefly lay out my evidence for the hypothesis:

-Ever Pharma records the following, rare, side effects: very rare - increased individual sensitivity, allergic reactions, skin reactions, neck, head and extremity pain, fever, mild back pain, dyspnea, shivering, collaptoid state.

-We know that CB exerts its effect via CNTF fragments. CNTF analogs have in the past (study on weight loss, with analog "Axokine") led to antibodies against the analog in a large proportion (>50%) of subjects. If CNTF (fragments) are artificially removed from the solution via corresponding antibodies, the effect of CB is also absent (I believe this was in an animal model)

-Anecdotally, we know of a few cases in which a negative reaction not previously experienced by the person (before CB) occurred in the short term after CB use (mostly intranasal, which I will come to) or in one case after IM use. -Strange, systemic reactions tend to make me rule out non-CB reasons. Of course, the authenticity of the sources cannot be conclusively verified.

-There are anecdotal reports that CB is less effective with increasing cycles. (Anti-drug antibodies?)

-The nose is important for immunization. However, if it is possible in principle, it would also be conceivable via IM, but at a reduced frequency.

-It is not inconceivable that side effects are concealed by the producer. Even on a much larger scale than with CB. I'm sure you know that.

-(genetic) variants are typical. Perhaps there is a variable convergence between porcine / and human CNTF?

-In the following link, pharmaceutical company Xencor describes the possibility of modifying CNTF analogs to achieve lower immunogenicity. (Less T-cell activation / MHC interactions) There is also talk of drug-induced autoantibodies - so it doesn't seem to be entirely unimportant. (https://worldwide.espacenet.com/patent/search/family/034138609/publication/WO2005014641A2?q=pn%3DUS2005064555)

-A Cochrane review on the efficacy/safety of CB talked about non-fatal, severe side effects in CB trial groups. I find this somewhat confusing, as many other studies report no lasting side effects. Unfortunately, the character of the side effects was not further specified.

———————

What is your opinion on this? I know that this topic has been addressed before, but perhaps new findings will come to light. It seems particularly important to me because of the therapeutic potential of CB.

I have experienced lifelong general anxiety disorder where normal medications have either never worked well for me or caused significant problems.

For that reason I'm often looking for alternative medications or research studies for different monotherapies that might be more beneficial. Even though I am not currently looking to take any medication for my GAD, I like to be educated on what's out there or on the horizon for treatment. I've found some info on this new medication currently in phase 2 clinical: https://www.engrail.com/enx-102/

One of these potential medications that popped up on my radar is ENX-102, a GABAª PAM. I'm interested in learning a bit more how this functions.

What can you tell me about this class of drug, GABAª positive allosteric modulators? Anything or there with similar effects? Care to opine on whether this might be worth the time to look into as a potential treatment option for people suffering from GAD?

To clarify, I'm not looking for information on a medication I'm taking, planning to take, want persuasion to take or anything that might break sub rules. Simply looking to understand a bit better and become more educated on what this class of drug looks like and its effects.

There's a study here which says "Results revealed that pterostilbene exerted a concentration dependent inhibition of the human recombinant FAAH enzyme, with an IC50 value of 5.42 ± 0.26 μM, with no significant inhibition of the MAGL enzyme. These results suggest that pterostilbene has the potential to become a candidate compound for therapeutic drug development for anxiety disorders." https://faseb.onlinelibrary.wiley.com/doi/abs/10.1096/fasebj.28.1_supplement.1144.10

I'm not sure what the equivalent dose would be for FAAH inhibition in humans

What would you think would be the advisable dose for FAAH inhibition?

Inositol triphosphate increases Gq signaling that cleaves PIP2 into IP3.

Would taking the supplement inositol result in higher inositol triphosphate levels?

"Gq-protein-coupled receptors (GqPCRs) are widely distributed in the CNS and play fundamental roles in a variety of neuronal processes. Their activation results in phosphatidylinositol 4,5-bisphosphate (PIP2) hydrolysis and Ca2+ release from intracellular stores via the phospholipase C (PLC)-inositol 1,4,5-trisphosphate (IP3) signaling pathway." https://www.jneurosci.org/content/26/39/9983

I know GPCR have sometimes longer upregulation due to prevention of beta arresting recruitment (or internalization in the opposite case) compared to ionotropic receptors. but how does it differ for like dopamine, serotonin, cannabinoids or even like orexin receptors? For example, orexin receptor is being used long term for insomnia, but wouldnt months of antagonism just lead to tolerance because the receptors are upregulated and sensitized. is there any model that relates both?

https://www.sciencedirect.com/topics/neuroscience/receptor-down-regulation#:\~:text=Receptor%20down%2Dregulation%20refers%20to,basis%2C%20taking%20hours%20to%20days.

So the recent research coming out about how truly damaging alcohol is for the brain has shown significant brain atrophy even from moderate drinking. According to Dr. Amen, a psychiatrist specializing in brain scan interpretation, has shown and stated that benzos seem to do the same thing. Is there a unique mechanism in which sedatives lead to neuronal degeneration? Is it from fluid imbalances, in particular with alcohol? I ask this because research has shown that brain shrinkage is rapidly reversed following cessation of alcohol

“Significant reversibility of alcoholic brain shrinkage within 3 weeks of abstinence”

https://pubmed.ncbi.nlm.nih.gov/7572265/

The study regarding atrophy from benzos seem to be a paid database study so I can’t cite the specific study, but here is an article stating the findings.

“Brain Volume Reduction: Long-term use of benzodiazepines was associated with significant reductions in brain volume. The most affected regions were the hippocampus and amygdala, which are crucial for memory and emotional regulation.

Hippocampal Atrophy: The hippocampus, vital for forming new memories, showed notable atrophy in long-term benzodiazepine users, suggesting a link to cognitive impairments and an increased risk of dementia.”

https://www.myneurobalance.com/articles/2024/7/7/long-term-use-of-benzos-may-lead-to-brain-shrinkage-new-study-finds

And if they do cause brain atrophy, does this have any implications or noticeable detriments in cognitive function? A lot of moderate-heavy drinkers seem to retain a significant part of their intelligence if they were intelligent to begin with

So, as you should know, opioids can rarely cause hyperalgesia or allodynia while dosing. My question is: can Ketamine use (that is used to treat allodynia\hyperalgesia) cause a chronification of those symptoms if you are experiencing it while under the effect of opioids that caused it? my reasoning is that ketamine increases BDNF and an increased neuroplasticity is key in chronifiying pain (source: https://inflammregen.biomedcentral.com/articles/10.1186/s41232-022-00199-6)

There are graphs in this document: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212038Orig1s000lbl.pdf.

1: Is there a resource that shows and compares all of the different graphs of all of the different long-release ADHD meds?

2: What does the "ideal" curve look like if indeed there is a single "ideal" curve? I saw this ( https://www.tandfonline.com/doi/full/10.1080/17425255.2019.1675636 ):

Therapeutic improvement with stimulants is dependent on how fast (ascending slope or rate of release), how long (length of time that the stimulant occupies DAT and NET), and how much (plasma concentration) stimulants occupy the DAT and NET [Citation30]. The ideal drug release profile is one that provides a slow increasing rate of release, robust but subsaturating plasma levels of neurotransmitters, and a long duration of DAT and NET occupancy by the stimulant before declining and wearing off, such that the resulting effect is an increase in tonic signaling without an increase in phasic signaling [Citation30]. This tonic drug delivery will ensure optimal efficacy without any euphoric effects that occur when DAT and NET are saturated in a phasic pulsatile manner [Citation30].

3: Regarding Jornay, how can the drug be so predictable and consistent if gut motility is such a variable phenomenon? See here ( https://www.tandfonline.com/doi/full/10.1080/17425255.2019.1675636 ):

Evening-dosed DR/ER-MPH exhibits a single-peak pharmacokinetic profile with a consistent, predictable delay in the initial release of MPH until the early morning (i.e. ~8–10 hours after ingestion), followed by a period of extended, controlled release across the day [Citation73–Citation75].

Consider this ADHD drug: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212038Orig1s000lbl.pdf. The document includes graphs that show how the medication is released from the little beads over time.

Regarding the above drug but also other ADHD drugs that release (e.g.) methylphenidate over the course of many hours, I wonder about the impact that these things have on the release:

• Irritable Bowel Syndrome

• gut motility

• pH

• gut biota

I think that the gut biota might have a big impact on drugs (on the extent to which drugs get absorbed and maybe on other things), though I'm not sure about the relevance of gut biota to ADHD drugs in particular.

What if someone who's taking a long-release ADHD drug consumed something like apple-cider vinegar? Wouldn't that have a big impact given that pH is relevant? I'm surprised that there isn't more discussion about what something like apple-cider vinegar might do.

I should mention that there are two issues. The first is which factors impact the release of the drug (and to what extent). The second is which factors impact actual absorption (or whatever) of the released drug (and to what extent). The second issue applies to all ADHD drugs and not strictly to long-release ones.

INTERPRETATION: DNA analysis has identified one copy each of the *17 and *41 decreased function alleles. This individual is predicted to have the Intermediate Metabolizer phenotype. Individuals with the Intermediate Metabolizer phenotype have a reduced level of CYP2D6 activity. The reduction in CYP2D6 activity may be enough to reduce the therapeutic efficacy of some drugs that require CYP2D6 activity for the generation of the active metabolite(s). In addition, there may be an increased risk for toxicity or adverse side effects if this individual is administered drugs that are inactivated by CYP2D6.

I tried Zoloft for 3 days a few months ago and had an adverse reaction: insomnia, sweating, headache, buzzing in the head, increased anxiety, terrible thoughts, paranoia, bad, yuck, yuck.

From some initial research it looks to me like Zoloft is on the Nono list for me. Am I interpreting this correctly?

Which anti anxiety / antidepressants are safe for me?

I will of course consult my doc also.

link to research:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8620997/#:~:text=Tricyclic%20antidepressants%20that%20are%20known,venlafaxine%20%5B10%2C50%5D.

Cheers!

As far as I’m aware the most popular theory for the neurotoxicity of MDMA is that it’s in some way caused by oxidative stress from toxic metabolites.

If one person metabolises the drug faster than another person, would this increase or decrease the overall neurotoxicity? Because on one hand I believe a faster metabolism would lead to metabolites being formed in higher concentrations, but on the other hand the overall time of exposure to the drug would be reduced.

My Google skills must be failing hard, because I just have not been able to find this drug again.

I first found out about it several years ago, but even then I believe research had been abandoned (I don't know why, but would love to know). It was an amphetamine analog that had the benefit of not just haphazardly releasing neurotransmitters all the time. But instead it just amplified natural rewards. So if you e.g. managed to sit down for 3 hours to study, it would boost the positive feelings you had from that.

It seemed like such a good idea to me. Many people on amphetamines now hate the feeling of being constantly wired (even in a low state). And of course for people who have been on it since childhood, I often hear them say the drug has made them feel like a robot. Among many other complaints which I often wonder if are related to the constant impact it has?

Of course lisdexamfetamine (unrelated but anyone know why we switch from ph to an f in amphetamine here?) appears to help a lot of people due to it being much more gradual.

I don't know why research was stopped, but would love to know. Cynical me worries it's because amphetamineis already well established and made in bulk + in the US they somehow got a patent by changing stereoisomer factors and changing the salts... Really? (meanwhile most of the rest of the world sticks with dextro...)

That doesn't explain why it would have been cancelled in other countries though. But perhaps it doesn't help with ADHD due to the fact that it's only the reward, maybe that's just not enough motive for the brain to focus without it?

Still I wonder if it might be useful for depression?

Anyway does anyone know the drug in talking about? And have any of the above answers?

I'm looking for a NaV blocker which could be used for neuropathic pain and at the same time doesn't interact with CNS monoamines (namely, serotonin, noradrenaline, acetilcholyne, dopamine and histamine).

I've seen that carbamazepine and its derivatives seem to increase serotonin levels in the hippocampus of rats. And the other usual options are not much different: topiramate increases noradrenaline expression in the brain of rats, lamotrigine blocks 5-HT3 receptors in neuroblastoma cells...they all seem to have a significant influence over CNS monoamines.

So, coming back to the original question, is there a "pure" NaV blocker that doesn't have these sort of interactions, and with possible applications in chronic pain states?

Thanks!