Rules (click)

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!

The most obvious examples of this to me are LSD and mescaline. LSD has a half-life of 2.7 hours https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7984326/ and my subjective duration of action is 8-12 hours depending on dose with multiple “ups-and-downs”, rather than slowly teetering effects. This would put its duration of action at ~3x-4.5x its half-life.

Mescaline has an elimination half life of 3.7 hours https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10517157/ and while I have never personally tried it, a close friend of mine has and placed its duration of effect on a 350mg dose at close to 14 hours, which would put its duration of action at ~3.75x its half-life.

I do understand that duration of action and the supposed “ups-and-downs” mentioned are ultimately subjective, but even then the duration of action to subjective effects ratios mentioned make very little sense to me. Thank you in advance!

Hello,

I know that THC needs to be bound to some kind of fat to facilitate the best absorption into the blood. My goal was to make THC capsules that would stay solid at room temperature and in your pocket. Sadly, the obvious choices of coconut oil or cocoa butter will melt in my pocket.

This gave me the idea to try making edibles with stearic acid, a long-chain fatty acid that stays solid until above ~150F. I tried this and it worked, but the effects of the stearic acid edible are different than the typical MCT oil edible. With the MCT oil edible, the effects peak strongly and all at once, while the stearic acid edible seemed to kick in more gradually and less intensely.

My question is essentially, how does the type of fat that THC is bound to affect its absorption rate and amount?

Thanks

https://en.wikipedia.org/wiki/Stearic_acid
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8570925/
https://www.sciencedirect.com/science/article/abs/pii/S0268005X20315782

So this is really weird and something I've personally noticed. If you're in opioid withdrawal and take 7.5mg then within ~20 minutes you'll notice significantly reduced withdrawal.

If it's strong, then upping the dose to 30mg+ etc covers it (or higher if needed). Zopiclone is pretty safe in high doses, but beware the tolerance goes up faster than any other drug in my experience - luckily it also drops back down exponentially fast as well, and always seems to return to normal given enough time (at least for me).

This is nothing like how benzos help, at least not for me. Zopiclone literally entirely removes the feeling of withdrawal, even for really strong opioids like zenes (which are competitive enough that buprenorphine doesn't block them).

Does anyone know what's going on here? More importantly I would like to know if it works with pagoclone or others, as of course Zopiclone is really good at putting you to sleep.

Zopiclone also has too short of a half life to be super useful for this. In 3-4 hours it's all but gone.

Also unsure if this is normal, but you have to take Zopiclone on an empty (preferably 6hr+) stomach. The onset doesn't change, it's just flat out doesn't work for me if I take it after eating. Even at very high doses. I don't know if it's being metabolised away or something.

Another effect is that Zopiclone also halts amphetamine in its tracks in my experience as well. If you're on it and take Zopiclone then within 20 minutes all amphetamine effects just straight up stop.

What's the cause of this? It would make one hell of a treatment if we could develop it into a version that doesn't put you to sleep and lasts 24 hours. This is assuming it doesn't fully halt everything like receptor regulation. If it does though maybe we could at least develop something that halves withdrawal severity?

For example biased antagonist where it only partially blocks one signaling while allows others (such as the beta arrestin pathway), it would be possible that way (as stated in 5HT2A receptor antagonism paradoxical occurance, keep in mind I only use this example as I am not sure if it would work simiarly in the gaba or opioid systems.). Similarly I think non hallucinogenic psychedelics may be beneficial because even when the receptor undergoes tachyphylaxis the neurogenesis benefit remains even after the drug is removed from the system.

Source:
https://en.wikipedia.org/wiki/Psychoplastogen#:\~:text=Psychoplastogens%20are%20a%20group%20of,benefit%20after%20a%20single%20administration.

https://en.wikipedia.org/wiki/5-HT2A_receptor#:~:text=The%205%2DHT2A%20receptor,HTR2A

In doing some research I see a fair amount of supplements and food can elevate or interact with acetylcholine levels (ginger, garlic, ALA, lion's mane mushroom, omega 3/fish) or simply contain a fair amount of choline itself (eggs).

What is not clear to me is if any of these could measurably contribute to cholinergic crisis in conjunction with a cholinesterase inhibitor (with the exception of something like Huperzine A maybe). Doing some research it seems like there have been reported overdoses and cholinergic crises on galantamine and pyridostigmine at ~250mg/7g where the patients survived, and supposedly huperzine A can be taken at 50-100x the recommended dose.

In addition these drugs have a wide range of half lives from the longer end (Donepezil/Huperzine A) to fairly fast elimination (galanatmine/pyridostigmine) and I'm assuming with the lower halflife drugs there's less chance for interaction.

I did see this study that combines citicholine with Cholinesterase inhibitors for Alzheimer's patients and I would assume many of these same patients are also taking some functional supplements as well like Omega3/etc.

https://content.iospress.com/articles/journal-of-alzheimers-disease/jad160808

If anyone could point me to some research or information on where to draw the line and which dietary/supplemental interactions could be harmful I would appreciate it.

A few months ago there was discussion relating to the pharmacokinetic differences of lisdexamphetamine (Vyvanse) vs dextroamphetamine, and how they pertained to the purported longer-acting effects of LDX. The pharmacokinetics of LDX appear identical to those of IR dexamph but shifted rightward by 1 hour. [graph here] Despite this, LDX is commonly referred to in passing (even within the literature) as a longer acting drug owing to its prodrug metabolism.

In the discussion, some commenters argued that clinical data suggesting that LDX may produce longer lasting effects should be taken at face value, irrespective of the pharmacokinetic graph. I agree with the notion that high quality clinical data should override mechanistic reasoning, but I didn't see this adequately substantiated. Most simply cross-compared the duration of action reported for LDX and amphetamine across different clinical trials and called it a day.

This isn't very compelling evidence as duration of action is an ill-defined metric with substantial heterogeneity between studies. Some studies may only assess the mood-altering effects of either drug, whereas others may limit their analysis to effects pertaining to to clinical efficacy. When I searched for research comparing LDX and dexamph in a head to head fashion, I only found this study, which found no differences in duration or peak of subjective effects (drug liking, drug high, stimulation, happy, well-being, and self-confidence) when accounting for the rightward shifted pharmacokinetics of LDX. [graphs here]

This runs contrary to much of the literature which presents LDX as a less euphorigenic and longer-acting drug compared to IR dexamph. I could only find this substantiated with regards to abuse potential via non-oral routes of administration, but not in relation to therapeutic dose ranges. Orally, any reduction in abuse potential may be due to a delayed onset of action rather than an inherent difference in subjective effect.

However, many patients do report feeling as though the therapeutic effects of LDX last longer and are 'smoother' than those of dexamph. It is hard to reconcile this with the available evidence. I find it hard to believe that so many would switch what was until recently a patented and expensive drug if it were only a delayed action and less abusable dextroamphetamine. LDX absorption is unaffected by gastrointestinal pH, possibly reducing dose-to-dose variability. Perhaps this consistency relative to dexamphetamine could be contributing to this perceived difference in subjective effects reported by patients.

TL;DR - Lisdexamphetamine (Vyvanse) definitely isn't a long-release form of dextroamphetamine, and evidence of its purported long-acting effects is relative to equipotent dexamphetamine nearly non-existent. We should probably stop stating this as fact.

Edit: Added bolded clarification in TL;DR. I don't doubt the reported duration of action, but I am skeptical of comparison to equipotent dexamph.

The negative regulation of NMDARs by cannabinoids is particularly relevant because their persistent activation produces a series of perturbations that may lead to neurodegenerative diseases (Lipton, 2006), mood disorders, such as depression (Maeng and Zarate, 2007), and neuropathic pain (Sigtermans et al., 2009).

...
Additionally, cannabinoid abuse produces dopaminergic hyperfunction in limbic areas and the cortex, which may cause the cannabinoid-induced cognitive deficits. This enhancement of dopamine function appears to be caused by CB1-mediated NMDAR hypofunction (Javitt, 2007).
...
While the duration of such effects is limited and the system can be recovered and reset to normality, disproportionate CB1-mediated control of NMDAR activity may reduce its recovery and produce persistent NMDAR hypofunction. Therefore, a poor or excessive CB1-mediated effect on NMDAR activation may cause a series of neural dysfunctions in the long term.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3877778/

To my understanding:

• CB1 agonists reduce NMDA activity and enhance dopamine activity
• NMDA hypofunction and dopamine hyperfunction represent psychotic/schizophrenic presentation
• NMDA activity can remain disturbed with excessive CB1 agonism
• This all applies to chronic THC use (study goes over it)

So my questions are:

• How do chronic THC users present behaviorally once NMDA hypofunction manifests?
• Should we expect an increase in negative symptoms during periods of abstinence or during periods of heavy use?

Thanks :)

Edit: title typo, remove "agonist-"

I don't mean as a result of its come down, just that some people report dysphoria (assuming all other factors equal - sleep, food, nutrition etc.).

I've read through the following studies however they don't elucidate the mechanism behind the dysphoria.

• https://pubmed.ncbi.nlm.nih.gov/3688282/

• https://www.sciencedirect.com/science/article/pii/S0149763419302350?via%3Dihub

One could hypothesize it's due to age?

• https://jamanetwork.com/journals/jamapsychiatry/fullarticle/2538518

Or could it be tolerance?

I know that 2D6 poor metabolizers generally experience more adverse reactions to drugs that are 2D6 substrates, and the substrates will take longer to leave the body.

But not much is said about how poor metabolizers react to 2D6 inhibitors. May this is because they don’t react differently to them. But I am curious.

I take it that an inhibitor doesn’t quite inhibit 2D6 activity in poor metabolizers because there is little activities to begin with. And the inhibitors will not cause as much bad interactions with substrates for the same reasons.

I’m wondering, is the inhibition part of how the inhibitors become efficacious? For example, bupropion is an inhibitor. Does it also mean that reduced 2D6 activity is part of why bupropion works for normal metabolizers. And people with poor metabolizers don’t react to bupropion properly because they cannot be inhibited by bupropion anymore?

Sources:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1874287/

https://www.pharmacytimes.com/view/2008-07-8624

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1874287/

Are there any studies that detail what the effects of intravenous infliximab (first-in-line treatment for inflammatory bowel diseases such as Crohn's) - https://en.wikipedia.org/wiki/Infliximab TNF-A inhibitors are on the brain -- specifically on neuroplasticity?

It is my understanding that TNF-alpha (cytokine that induces inflammation) alters AMPA levels, which in turn alters brain synapses (for better or for worse?!).

Is the role of TNF-alpha in the brain not affected by medication such as infliximab?

I ask because I have found many reputable sources say to be cautious with this combo without actually providing any well-reasoned arguments on WHY one should be cautious.

I have been researching the recreational potential of microdosing 5-MeO-DMT while under the influence of MDMA (read more here) and the results appear to be overwhelmingly positive.

I'm talking about normal healthy adults trying this combo, by the way.

Is my analysis incorrect?

If so, why?

I'm not particularly educated about psychopharmacology and I'm not sure whether what I'm about to write makes sense, so bear with me. But I have recently been thinking about how we view caffeine vs. other stimulants regarding their effects on wakefulness and alertness.

The way I understand it, caffeine primarily works on the adenosine (A1 and A2A) receptors. When talking about how it increases wakefulness, we typically hear that caffeine blocks the signaling of adenosine that naturally accumulates over the course of the day. When looking at how e.g. sleep researchers like Matthew Walker like to describe the effects of caffeine, this mechanism is stated as the primary course of action. But there are a couple of pieces to this puzzle that confuse me:

1. Other stimulants (e.g. amphetamines, modafinil, methylphenidate) also promote wakefulness, but don't act on the adenosine receptors at all (to our knowledge). Instead, they primarily increase dopamine and norepinephrine. [1][2]
2. Caffeine increases dopamine, albeit to a lesser degree than other stimulants. It seems to do so indirectly, by blocking adenosine at the A1 receptor, which again normally inhibits dopamine signaling. [3]
3. Experientially, some of the other stimulants seem at least as potent at producing wakefulness. But of course this also depends on dosage, and different substances have durations of effects due to different elimination half lives.

Is it useful to attribute the effects of caffeine primarily to its effect on the adenosine receptors? I.e., does its action on that pathway add anything important to the equation beyond the indirect increase in catecholamines?

The reason I am asking this is that caffeine is often singled out as not working the same way as other stimulants (at least in pop-science literature). And of course we like that explanation, because caffeine addiction is extremely normalized, whereas addiction to e.g. amphetamines is something we would commonly view as reprehensible. It seems to me that it might be more useful, and maybe accurate, to think of caffeine as simply yet another stimulant, but with a more indirect mechanism to ultimately achieve the same goal.

some biotech companies are removing the psychedelic effect and only have the antidepressant effect. something like tabernanthalog. some of them are still in phase 1 with MAD/SAD and no hallucinogenic effect is found yet, but its not phase 2. I feel like it would be a game changer, because its rapid acting, durable and less side effects. Not to mention I dont think there are withdrawls from this. Could even be used for alzheimers.

https://en.wikipedia.org/wiki/Psychoplastogen#:\~:text=Psychoplastogens%20are%20a%20group%20of,benefit%20after%20a%20single%20administration.