Hi, I have been looking into long acting opioids/extended release mechanisms and I have encountered what might be the longest acting opioid. If anyone knows any opioid that lasts longer, please let me know!

Now, to preface this, all of this is theoretical as alykl deuturated dinor-laam has never been synthesized, let alone tested on humans. This started when I was looking into deuturated levacetylmethadol, and found out that its effect came from its metabolites, mainly nor-laam. However, dinor-laam has a much longer duration of action. I found out that deuturated LAAM does not have a longer duration of action because it is a prodrug, and deuturation would mainly only delay its onset.

Deuturating dinor-laam on the other hand, absolutely can extend its already 100 hour half life. D3-dinor-laam has been synthesized, but that doesnt dramatically change the pharmacology, because the metabolism is mainly through different pathways, as it is extremely resistant to liver metabolism. The core chemical structure of dinor-laam would have to be deuturated to extend its duration, and this, to my knowledge, has never been done before.

While this is very interesting, and probably would be something I would want to try for myself, this can be very dangerous for a number of reasons. Let's assume you were able to synthesize this and were able to remove any toxic chemicals, this would still be very dangerous because:

1. Dinor-laam has a slow onset of 1-2 hours, and doesn't reach Tmax for 2-4 hours, making it more likely to redose and/or overdose.

2. Deuturated dinor-laam has an extremely long duration of action, so if you overdose on it, renarcotization is inevitable. An overdose would possibly require a multi week hospital stay and naloxone infusion to keep you alive.

3. The duration of action can also be bad because of QT prolongation. Having a constant strain on your cardiovascular system can certainly cause issues, and this is why regular levacetylmethadol was withdrawn from the market.

4. A single dose causes tolerance and dependence. While you are unlikely to experience withdrawal due to the long half life, it was shown that within 5 hours of receiving levacetylmethadol, naltrexone caused precipitated withdrawal. This would be a total nightmare to go cold turkey and would probably be easy to compulsively redose. Withdrawal from deuturated dinor-laam would probably last well over a month, which is terrifying. The half life would be somewhere between 120 and 240 hours, meaning the average would be 180 hours. Assuming it takes 5-7 half lives to be basically gone from your system, and assuming it takes 5 days to your body to adjust after it's gone, deuturated dinor-laam withdrawal could last anywhere from 43 to 58 DAYS! However, withdrawal could be minimal or nonexistent because of how slowly it comes out of your system and it would probably be pretty easy to taper.

Despite deuturated dinor-laam being potentially very dangerous, it could also be extremely helpful for hospice patients or people with OUD. Having a drug that would only have to be administered like once a week is very nice and would remain at very stable drug concentration in the body. It is likely also possible to formulate it into some sort of extended release mechanism to never have to dose again. If you were able to make a subcutaneous injection similar to Sublocade except it contains dinor-laam or deuturated dinor-laam than you wouldn't have to go through opioid withdrawal, unless your tolerance is so high that it doesn't sufficiently treat your withdrawals, like for individuals on extreme doses of fentanyl/fentanalogues, nitazenes, or orphines.

My main question is whether this could be a good medication to use for hospice patients? Do you think deuturated dinor-laam is in the proper lipophilic range for a subcutaneous injection? Do you think deuturated dinor-laam would be too dangerous due to the QTc prolongation, or the specialized overdose treatment? I know this drug is theoretical, but any extra information would be greatly appreciated.

Let me know what you think, and please share any other opioids you know of that last longer than methadone or buprenorphine as I am very fascinated by this, thanks!

Google Gemini was used for much of this research.

References:

Di Martino, R. M. C., Maxwell, B. D., & Pirali, T. (2023). Deuterium in drug discovery: Progress, opportunities and challenges. Nature Reviews Drug Discovery, 22(7), 562–584. https://doi.org/10.1038/s41573-023-00703-8⁠

Levacetylmethadol. (n.d.). In Wikipedia. Retrieved October 26, 2026, from https://en.wikipedia.org/wiki/Levacetylmethadol⁠

Levacetylmethadol. (n.d.). In ScienceDirect Topics. Elsevier. Retrieved October 26, 2026, from https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/levacetylmethadol⁠

Vaupel, D. B., & Jasinski, D. R. (1997). L-alpha-acetylmethadol, L-alpha-acetyl-N-normethadol and L-alpha-acetyl-N,N-dinormethadol: Comparisons with morphine and methadone in suppression of the opioid withdrawal syndrome in the dog. The Journal of Pharmacology and Experimental Therapeutics, 283(2), 833–842. https://pubmed.ncbi.nlm.nih.gov/9353405/⁠

Oda, Y., & Kharasch, E. D. (2001). Metabolism of methadone and levo-alpha-acetylmethadol (LAAM) by human intestinal cytochrome P450 3A4 (CYP3A4): Potential contribution of intestinal metabolism to presystemic clearance and bioactivation. The Journal of Pharmacology and Experimental Therapeutics, 298(3), 1021–1032. https://pubmed.ncbi.nlm.nih.gov/11504799/⁠

Deuterated drug. (n.d.). In Wikipedia. Retrieved October 26, 2026, from https://en.wikipedia.org/wiki/Deuterated_drug⁠

This database is free, searchable, and organizable.

The database only includes studies related to Amanita Muscaria.

Enjoy your research:

research.amanitawarrior.com

I have an interesting idea regarding THC; consider that (i) THC increases perfusion in the insula and the superior medial frontal cortex (salience network); (ii) some studies suggest that, under the influence of THC, connectivity in the nucleus accumbens decreases; and (iii) THC increases mind-wandering and reduces metacognitive accuracy regarding one's own performance. In short, THC may heighten the subjective relevance of things (such as one's own thoughts and internal sensations (whether trivial or not)) due to increased neural activity in the salience network (as noted in "i"). Furthermore, the reward circuit communicates less with areas involved in decision monitoring (as noted in "ii"), and THC impairs the accuracy of self-assessment (as noted in "iii"). Ultimately, my idea is that users under the influence of THC may tend to mistakenly overestimate the plausibility of their own insights as a result of these neurological processes.

I'm just going to be talking about opioids in particular because most overdose deaths are caused by opioids, but this question can be applied to all drugs.

With partial mu agonists, we see a ceiling effect where you get diminishing returns from taking larger doses. This is caused by near maximal receptor occupancy and doesn't lead to a fatal overdose, do to the drug only inducing a partial response unlike most opioids like morphine, heroin, fentanyl, hydrocodone, etc.

Your body is very good at maintaining an equilibrium and will adapt when there is an abnormality. When you take a drug, your body will try to adapt to it, leading to tolerance and dependence. There can be several ways your body can adapt, the three main ways are receptor downregulation, metabolism changes, and decreased receptor sensitivity.

Receptor downregulation is when your body destroys or internalizes receptors. This means there aren't as many targets for a drug to bind to, so the effects you get from it arent as strong.

Im not sure if there are studies on this, but I would assume that most healthy adults are immune to a buprenorphine overdose, especially because it is g protein biased, and the higher the opioid tolerance, the lower the risk of overdose.

So, here is my question, is it possible for your receptor concentration to become so low that it is impossible to overdose on any opioid. I would assume that a ceiling effect would be found with full agonists, we just can't observe that because non tolerant people will die before that can be found. Google AI says this is not true, because full agonists, by definition, don't have a ceiling. However, this just seems obviously true, because if there are no more receptors to bind to, a drug can't keep having an increasing effect.

Can anyone tell me if you can become temporarily immune to an overdose through receptor downregulation? Also, please explain why or why not this is true.

https://www.researchgate.net/profile/Tommaso-Costa-3/publication/17086175_The_opioid-induced_desensitization_tolerance_in_neuroblastoma_x_glioma_NG_108-15_hybrid_cells_results_from_receptor_uncoupling/links/0c9605339a4210b731000000/The-opioid-induced-desensitization-tolerance-in-neuroblastoma-x-glioma-NG-108-15-hybrid-cells-results-from-receptor-uncoupling.pdf?origin=journalDetail&_tp=eyJwYWdlIjoiam91cm5hbERldGFpbCJ9#page=19

https://pmc.ncbi.nlm.nih.gov/articles/PMC8230089/

I’m posting this because I think an important development has gone almost unnoticed, even within communities following SR-17018.

**The UK government has formally proposed making SR-17018 a Class A controlled drug. The legislation is currently awaiting parliamentary approval.**

This is not speculation. The draft *Misuse of Drugs Act 1971 (Amendment) Order 2026* was laid before both Houses of Parliament on **14 September 2026**. It explicitly names SR-17018 (5,6-dichloro desmethylchlorphine) for permanent Class A control.

SR-17018 has already been covered by a Temporary Class Drug Order since 11 June. Permanent control would go further, including criminalising ordinary possession.
**Why does this deserve particular scrutiny?**
I fully recognise the serious harms associated with emerging synthetic opioids. Several orphines have been implicated in fatal overdoses, and these risks cannot be dismissed.

But SR-17018 is scientifically unusual, and there are important distinctions worth examining.

**1. The government’s own evidence distinguishes between the compounds.**

The April 2026 Advisory Council on the Misuse of Drugs (ACMD) report describes more than 15 UK deaths involving orphines, specifically identifying cychlorphine and spirochlorphine. A separate mortality dataset identified cychlorphine and chlorphine.
I could not find an SR-17018-attributed fatality in the UK deaths described in that report.
This doesn’t establish that SR-17018 is safe. It raises a legitimate question: **has the evidence for its individual risks and pharmacology been adequately distinguished from those of other compounds in the same chemical family?**

**2. SR-17018 has published evidence of potentially valuable pharmacological properties.**

In 2019, researchers at Scripps, including Laura Bohn’s team, reported that SR-17018 suppressed morphine withdrawal and restored morphine responsiveness in dependent mice.
Subsequent studies showed a more complicated picture, including tolerance in certain experimental assays. So it is not a magic receptor reset or a dependence-free opioid.
Nevertheless, researchers at the **University of Dundee** presented findings in 2024 indicating that SR-17018 interacts with μ-opioid receptors through a mechanism distinct from other agonists they tested.
This isn’t an ordinary research chemical whose only interesting property is producing opioid effects.

**3. The first published human observational evidence has now appeared.**

A September 2026 paper in *Frontiers in Pharmacology* examined 55 self-selected people who reported using SR-17018, predominantly in the context of opioid reduction or withdrawal.
Many reported reducing or stopping their previous opioid while using SR-17018.
These were unverified, self-reported outcomes in a highly selected sample—not clinical proof of efficacy, successful complete detoxification, or safety.
But they provide testable hypotheses for properly supervised human trials.

**4. Research access matters.**

The UK already requires Home Office licensing for legitimate research involving SR-17018 under its temporary controls. Permanent scheduling would not automatically prohibit scientific investigation, but regulatory requirements can introduce practical barriers.
The question is whether the government has properly considered SR-17018’s distinctive research value and whether meaningful access will be preserved.
There is an important difference between saying a compound has **no currently authorised medical use** and saying it has **no potential future medical value**.

**What can we actually do?**

I’m based in the UK and have already contacted organisations including Transform and Students for Sensible Drug Policy, as well as academic researchers, to draw attention to this proposal.
I’m hoping this thread reaches people with the expertise or connections to help establish a serious dialogue before the legislation is approved.

In particular:

Are any UK pharmacologists, addiction researchers, toxicologists or clinicians aware of this proposed classification?

Has anybody asked the ACMD or Home Office to publish a more detailed SR-17018-specific risk assessment?
Can organisations such as Transform, Release, Drug Science or SSDP help raise the issue with MPs, peers or parliamentary committees?

Could researchers familiar with the Scripps or Dundee findings provide an independent scientific perspective?
Is there a practical way to request further scrutiny and research-access protections before the parliamentary process is complete?

**I’m not arguing that SR-17018 should be sold freely, or recommending unsupervised human experimentation. I’m asking whether the decision is sufficiently evidence-specific, proportionate and compatible with future medical research.**

The consequences of controlling a dangerous recreational opioid and those of restricting a potentially useful research compound may overlap, but they are not necessarily identical.
If we want better treatments for opioid dependence, withdrawal and chronic pain, shouldn’t we take the time to understand compounds that might offer genuinely different mechanisms?
**If you work in this field, know somebody who does, or are already involved in a UK response, please speak up. Even identifying the appropriate parliamentary or scientific contacts would be valuable.**
I’d like this to become a constructive, evidence-based discussion rather than another argument over drug prohibition.

**Sources:**
UK draft legislation (September 2026):
https://www.legislation.gov.uk/ukdsi/2026/9780348287127/article/2
ACMD research and recommendations (see seventh addendum, 30 April 2026):
https://www.gov.uk/government/publications/acmd-advice-on-2-benzyl-benzimidazole-and-piperidine-benzimidazolone-opioids
Original Scripps animal research:
https://pmc.ncbi.nlm.nih.gov/articles/PMC6901606/
University of Dundee research, British Pain Society 2024 (abstract P-45):
https://pmc.ncbi.nlm.nih.gov/articles/PMC11418731/
2026 human observational study:
https://doi.org/10.3389/fphar.2026.1899247
Parliamentary progress tracker:
https://statutoryinstruments.parliament.uk/instrument/BYXGeOCM
*No sourcing, vendors, sales or dosing advice, please. This thread is about UK legislation, pharmacology and research access.*

I am trying to design another selective grin2b negative allosteric modulator like ifenprodil.
Reason being ifenprodil has some issues
-Off target activity at sigma, adrenergic and hERG.
-Phenol is prone to glucuronidation

So what I did was remove the phenol and replace it with an indazole, remove the methyl group and the piperidine and phenyl ring altogether and I replaced it with an adamantine group with fluorine. Docked it with swissdock.ch and used 5EWJ.
It had a okay binding score, the top score was -8.251 kcal/mol. Ifenprodil scored a top score of -9.037 kcal/mol.

My main concerns is the high logP from the adamantane. Also, I am worried if Vina is biasing the results, or if the compound would not work. If it is not target selective then it is no use.

What are your guys thoughts, I am pretty new to this and it is a hobby of mine.

It‘s commonly accepted among users that prolonged use of dissociative substances like ketamine and DXM can create extremely long lasting or permanent tolerance. If anyone has experience or evidence contrary to this, I would be very interested. Even after long periods of abstinence, users often report either a minimal reduction in their tolerance, or a significant  decrease in tolerance on first use, but a rapid return to previous tolerance levels after this. I’ve not been able to find studies on NMDA tolerance myself, but found a thread here explaining potential mechanisms behind this “permatolerance”. This thread also hypothesized a link between dissociative usage and autistic symptoms, which was interesting and not something I’ve read elsewhere.

For DXM, the only dissociative I’ve used regularly, common harm reduction guidelines advise abstaining from DXM for one week per dosage plateau. This requires 1-4 weeks of abstinence between uses depending on the size of your dosage. As far as I know however, these guidelines are just estimates and not rooted in any science. I personally have followed these guidelines fairly closely, typically dosing 300 mg of DXM freebase every 2-4 weeks. I don’t think I’ve developed noticeable tolerance so far in my year of use, though this is hard to gauge, as increased familiarity with the substance affects how novel and “magic” it feels. I would like to minimize my likelihood of developing a tolerance in the future, which brings me to my questions:

1. Are there any studies exploring the development of tolerance to NMDA antagonists? 
2. Do we know if dosage or frequency plays a larger role in tolerance development? In other words, is it better to take high doses spaced further apart, or smaller doses at greater frequency?
3. Is there a gap between uses that is unlikely to develop tolerance in the long term?
4. Is there anything that can be done to reduce the development of tolerance, other than reducing usage?
5. Is there any information on how long an effective tolerance reset is, and whether this tolerance reduction persists once use resumes?
6. Is the development of NMDA tolerance associated with any adverse side affects?
7. If you’ve used DXM long term and largely followed week per plateau guidelines, have you noticed increased tolerance over time?
8. Largely unrelated, but is there any information on the link between dissociatives and autistic symptoms as hypothesized by the linked thread?

I realize these are a lot of questions, so obviously feel free to ignore any that are unanswerable or irrelevant. Thanks for the help!

Looking for answers on unexpected benefit of quviviq.

I have chronic pain and insomnia due to the pain. Tried everything imaginable over about 20 years with only marginal benefits. Some sleeping meds have worked at first but dependence builds up. Cause of chronic pain is not well understood, possibly multiple causes. Possibly pain signal amplification is a contributor after 20 years of severe chronic pain.

Doctor recently prescribed quviviq as a new way to help with sleep. Tried it 3 nights so far with very positive results. 2 of 3 nights it worked incredibly well. The night that it didn't work well, I was experiencing a significant flare up of my pain.

The thing is, it isn't just helping with sleep. About 30 mins after taking the medication, my typical severe chronic pain completely changed into a moderate tingling sensation. In 20 years, I can count on my fingers the number of nights that I would consider to be pain free when trying to sleep, so this medication has been massively beneficial so far. From severe pain to literally no pain, just tingling where I normally experience pain.

I've looked up a few published studies (ex: https://pubmed.ncbi.nlm.nih.gov/40532597/ ) and have read about any consistent benefits found for pain when taking quviviq. Does anyone know or have guesses as to what exactly the mode of action could be for this drug to help so much with pain? If I can understand why it is helping, it may help me find treatment that could help during the day or to better understand the root causes of my pain.

I do know it is possible to convert L-Tryptophan (the amino acid) into Tryptamine (And that into Dimethyltryptamine eventually) via decarboxylation but decarboxylating amino acids is not simple, they're pretty stubborn, I heard peppermint/ spearmint oil works due to the carvone content, but it is very expensive, I want a more affordable way to do this.
https://www.researchgate.net/figure/Biosynthesis-of-serotonin-and-DMT-from-tryptophan_fig8_277281153

I'm trying to understand a reproducible acute effect from a standard fish-oil capsule and whether there is any pharmacokinetic or pharmacodynamic mechanism that could realistically fit the timing.

Context

• Diazepam: 10 mg/day, long-term use, with established tolerance.
• Fluvoxamine: 300 mg/day.
• My measured nordiazepam concentration was ~1333 ng/mL, above the usual therapeutic reference range.
• The benzodiazepine taper has not started yet.
• I also have dysautonomia with marked cognitive and sensory intolerance, so I'm not assuming the effect is necessarily GABAergic; autonomic, vascular, or other mechanisms would also be relevant.

The fluvoxamine/diazepam interaction is important here. In a human pharmacokinetic study using 100–150 mg/day fluvoxamine, diazepam apparent oral clearance was reduced by approximately 65%, while mean diazepam half-life increased from about 51 to 118 hours. Elimination of its active metabolite N-desmethyldiazepam (nordiazepam) was also markedly inhibited.

I'm on 300 mg/day fluvoxamine, but I don't know of quantitative human PK data establishing exactly how much additional inhibition occurs at that dose, so I'm not assuming a specific half-life for my own case.

Study: https://pubmed.ncbi.nlm.nih.gov/7955810/

I occasionally take a single standard fish-oil capsule containing 180 mg EPA + 120 mg DHA (roughly 1 g total fish oil), usually around 7 hours after my diazepam dose.

Repeatedly, within roughly 3 hours, I experience a marked improvement in cognitive/sensory tolerance, most noticeably an increased ability to read for substantially longer.

It does not feel sedating. If anything, subjectively it feels like improved cognitive endurance.

I realize this is an N=1 observation and does not establish causality. Expectancy, coincidence, day-to-day variability, or another uncontrolled variable remain possible. I'm interested specifically in whether there is a biologically and quantitatively plausible mechanism that could fit the timing.

Relevant literature / what led me to ask

I found several experimental papers showing that DHA/PUFAs can affect neuronal membrane proteins or GABA-A function:

Søgaard et al. (2006) — GABA(A) receptor function is regulated by lipid bilayer elasticity
https://pubmed.ncbi.nlm.nih.gov/17059229/

Nabekura et al. (1998) — Functional modulation of human recombinant GABA-A receptor by docosahexaenoic acid
https://pubmed.ncbi.nlm.nih.gov/9556589/

Poling et al. (1996) — Docosahexaenoic acid block of neuronal voltage-gated K+ channels
https://pubmed.ncbi.nlm.nih.gov/8938727/

Stillwell & Wassall (2003) — Docosahexaenoic acid: membrane properties of a unique fatty acid
https://pubmed.ncbi.nlm.nih.gov/14580707/

I'm not taking these studies as evidence that an ordinary oral DHA dose can reproduce these effects acutely in humans.

In fact, that's one of the main things I'm trying to understand: whether oral exposure from only 120 mg DHA + 180 mg EPA could produce concentrations anywhere relevant to these experimental mechanisms within a few hours.

1. Could this plausibly be pharmacokinetic?

Given the prolonged disposition of diazepam/nordiazepam in this setting and my relatively high nordiazepam concentration, I find it difficult to see how one ordinary fish-oil capsule could substantially change total benzodiazepine concentrations within ~3 hours.

However, I don't want to assume that PK is irrelevant.

Could EPA/DHA acutely affect any of the following enough to alter effective diazepam/nordiazepam exposure?

• CYP-mediated metabolism;
• plasma protein binding / free drug fraction;
• tissue distribution;
• intestinal absorption;
• transporters;
• or another PK process.

More importantly, is there any reason to think the magnitude of such an interaction from only 180 mg EPA + 120 mg DHA could be pharmacologically meaningful?

A quantitative argument here would be particularly useful.

2. Could there instead be a rapid pharmacodynamic effect?

If a meaningful PK interaction is implausible, are there pharmacodynamic mechanisms that could operate within hours, without requiring weeks of incorporation of DHA into neuronal membrane phospholipids?

Possibilities I'm wondering about include:

• direct effects of circulating/unesterified fatty acids on ion channels or membrane proteins;
• acute GABA-A modulation;
• glutamatergic signaling;
• changes in membrane biophysics;
• neurosteroid signaling;
• rapidly generated lipid mediators;
• inflammatory signaling;
• autonomic or cerebrovascular effects.

The experimental literature shows that DHA can modulate some of these systems when directly available at sufficient concentrations.

What I cannot establish is whether an ordinary oral dose could generate relevant unesterified EPA/DHA concentrations in plasma or CNS tissue within ~3 hours.

That seems to be the critical missing bridge:

oral dose → absorption → circulating unesterified EPA/DHA → CNS exposure → local concentration at membrane/channel/receptor → functional effect

Is any part of that chain quantitatively plausible after such a small oral dose?

3. Does chronic benzodiazepine exposure/tolerance materially change the question?

Could chronic benzodiazepine exposure, tolerance, and receptor adaptation make the functional effect of an otherwise small perturbation in membrane or ion-channel function more noticeable?

I'm not claiming that a plasma nordiazepam level of 1333 ng/mL establishes saturated GABA-A occupancy or any particular receptor state.

I'm mentioning the concentration mainly because, together with the markedly impaired elimination expected from the fluvoxamine interaction, it makes a large and rapid fluctuation in total benzodiazepine exposure seem unintuitive.

4. Could dysautonomia provide a non-GABAergic explanation?

Given the dysautonomia, is there any plausible acute effect of EPA/DHA or downstream lipid mediators on:

• autonomic tone;
• cerebral blood flow;
• endothelial signaling;
• vascular function;
• or related physiology

that could improve cognitive/sensory tolerance within a few hours?

I'm mainly looking for mechanistic reasoning, quantitative PK arguments, or relevant literature, rather than treatment recommendations.

Hi there all. I am interested in the persistence of the phenomenon known as “kindling” with gabaergic compounds, whereby each successive withdrawal cycle from these compounds results in neuronal changes that increase the severity of subsequent withdrawals, and seemingly lower the threshold for the amount and duration of substance taken that is needed to provoke such a withdrawal.

I have seen conflicting information regarding the persistence of this. The most commonly cited research I could find claiming it is a permanent phenomenon (even after long term cessation) is from the 80s, and it doesn’t seem to provide much in the way of direct experimental evidence of this.

I understand that numerous factors make this difficult to study.

I am wondering if anyone has a good read of any theories surrounding this. Would you all speculate that this is something that, given enough time away from the offending substances, would revert to a baseline homeostatic state?

Might a few doses of a gabaergic compound theoretically put someone back in a withdrawal state after many years of abstinence?

(https://pubmed.ncbi.nlm.nih.gov/4089184/))

I’ve been taking a very low dose of a dopamine D2 receptor antagonist every night for sleep for 7 years (50 mg QυΞ†IΛ₱IИΞ).

One of the known actions of this class of medication is blocking dopamine D2 receptors, which temporarily reduces dopamine signaling (StatPearls, 2023)
https://www.ncbi.nlm.nih.gov/books/NBK459145/

My question is about the long-term picture.
Is it possible that years of this temporary lowering D2 receptors slowly reduces the overall “capacity” or total amount of dopamine the system can produce or maintain? Especially what I get to work with during the day. Like, does the bucket itself get smaller over time while I keep taking the medication for sleep?

There is this study that reports D2 upregulation after washout (Silvestri et al., 2000):
https://link.springer.com/article/10.1007/s002130000532

They took 9 people with schizophrenia who had been on higher-affinity antipsychotics for a long time (some on older drugs like haloperidol). Hard to imagine what fuckery has been done in their brains already.

SO their dopamine levels were definitely way down during the medication ALL the time.

I’m mainly interested in whether the mechanism of low-dose, chronic D2 blockade actually makes sense for impacting overall dopamine capacity over years, allowing the effects to be felt during the day while the medication is continued.

Hopefully, I'll understand replies as an Andrew Huberman podcast enjoyer. I'm not yet an ΞXPΞRT NΞUROSCIENTIST.

I have seen papers showcasing the process but I’m not sure if it’s actually possible. L-Tryptophan is an Essential Amino Acid, meaning it is not controlled as it is absolutely necessary for humans to exist, but decarboxylation seems to turn it into Tryptamine (the chemical itself) which is a known precursor to many classic psychedelics. Source of information

Basically the title. So say hypothetically I was on probation and my probation officer knew I was prescribed Klonopin, aka clonazepam, and I were to take a Xanax before my drug test, would they know I took the Xanax?

Some background on the kind of drug tests: it's a urine test where you go into a room with a two-way mirror, and the cup is put inside a metal door. You open the door and get the urine cup, and you pee into a regular, like, cup. The cup doesn't have any of the instant test stuff on the cup itself; it's just a regular cup with a twist cap on it, and I think it has a temperature strip on it. So I'm assuming it's sent to a lab instead of being an instant on-site test, but I'm really not 100% sure.

Anyways, once you pee into the cup, you put the lid back on, and you open a metal door and sit the cup inside. The person on the other side of the two-way mirror opens the door on their side and retrieves the cup of urine. By the time I wash my hands and exit the bathroom, the person on the other side of the mirror in the other room is also exiting his room about the same time. So I don't think they are performing an instant test on the urine right then and there, which is what leads me to believe it's a lab test that is done. I think they are just bagging up the urine to have it sent off to a lab, but I don't know for sure.

But anyways, I'm just wondering if I am prescribed Klonopin and am allowed to take them, but I take a Xanax, aka alprazolam, a few days before my tests, would it just show up that I have taken benzodiazepines, or would they know that I took a specific drug?

If I knew it was an instant test, I’d know the answer. But if it’s a lab test, is it possible that the lab only tests for the drug class (like benzodiazepines) the same way an instant test does, rather than identifying the specific medication?

TL;DR: I’m prescribed Klonopin (clonazepam) and I’m wondering hypothetically if taking Xanax (alprazolam) before a probation urine test would be detected as just “benzodiazepines” or if a lab test could identify the specific medication. The test uses a sealed urine cup with a temperature strip and seems like it may be sent to a lab rather than tested on-site.

FOLLOW UP QUESTION: Will 22 mg of xanax taken over a 4 day period be out of my system urine in 20 days

Thanks.

I’ve been on 400 mg hydroxyzine for three months, and then accidentally took 600 mg for a while. I thought it was relatively safe but now I’m finding out it can cause you to “get dumber”. Did I fuck up?

I’ve also been on 100mg promethazine for a week exactly, which may be more concerning. I am so scared of long term cognitive damage, my brain is all I have. I am 22F in case that matters for this fascinating research question.

https://pubmed.ncbi.nlm.nih.gov/23183138/

https://pubmed.ncbi.nlm.nih.gov/36813260/

(I am aware both of these are aimed at 40+, but I can’t help thinking that perhaps it is harmful in young people too.)

This is the MacArthur; it's the size of an entire ear of corn https://www.youtube.com/watch?v=YzgJeRS-Pc0

Overall Length: 9.5 inches (241.3 mm)

Bowl Height: 4.375 inches (111.125 mm)

Chamber Diameter: 0.75 inches (19.05 mm)

I cannot find ANY data on how long it takes to smoke a full bowl, only tobacco data that I have to extrapolate from: approx 1.5 - 3 hours

How many dabs over how many hours are equivalent, as far as we know? Figures for normal bong hits or joints/blunts, herbal vaporizers, etc welcome too.

Hi there! Can you help verify if my understanding of addiction is correct and add nuance? I've been reading up on the "wanting vs liking" system and this is what I've gathered. Thank you so much!

1. In the mesocorticolimbic system, dopamine binds to dopamine receptors on hedonic hotspots to release "happy chemicals" like endocannabinoid or opioids when you engage in a positive behavior. (How do these chemicals get released? Do the vesicles containing the chemicals have dopamine receptors, and when it binds, the vesicles empty?)

2. Drugs massively jack up baseline dopamine, so the body responds by downregulating dopamine receptors on hedonic hotspots. This downregulation occurs by desensitizing the dopamine receptors or even by receptor die off over time.

3. People with ADHD already have fewer/less sensitive dopamine receptors and/or overactive transporters along the mesocorticolimbic pathways.

4. Stimulants temporarily block the dopamine transporters (among others), meaning you have more usable dopamine in the synapse, and at appropriate therapeutic doses over time, you increase dopamine receptor count via neuroplasticity because the pathways are being used more.

So these are my biggest questions:

1. Why do these ADHD structural differences in the brain necessarily increase addiction risk? I understand the idea that extra dopamine can outpace overactive transporters, but drugs take you so far above baseline that it should go beyond just "feeling normal". Obviously the research is irrefutable that ADHD dramatically increases addiction risk, and stimulants are a critical tool in lowering that risk, but I really want to understand the exact mechanisms that create this risk.

2. How do behavioral addictions increase dopamine so high above natural levels that they can cause addiction?

It's known that (ar)modafinil can inactivate estradiol-containing birth control by inducing CYP3A4. Naturally, CYP3A4 induction dramatically increases first-pass inactivation of orally administered estradiol-containing birth control, effectively reducing its bioavailability in addition to hastening the metabolism of estradiol in circulation.

However, since CYP3A4 metabolizes both exogenous and endogenous estradiol, I'm curious as to if modafinil can actually reduce circulating concentrations of the hormone in humans. I wasn't able to find any research that specifically relates to this question, but did find a study that reported a reduction in hot-flashes. Hot flashes are typically associated with a reduction in estrogen, so this finding runs somewhat contrary to this idea, though there could also be a non-hormonal interaction here.

I stumbled upon an interesting drug candidate.
https://en.wikipedia.org/wiki/SYT-510

the interesting thing is that i dont think a true anandamide transporter has ever been confirmed, some postulate its mainly due to enzymatic degradation, however the transporter/gene remains unidentified/debated

For example, this 2003 paper suggest against the existence of a transporter
https://doi.org/10.1073/pnas.0730816100

But since the new candidate is in clinical trials, maybe the general assumption is false?

https://pubmed.ncbi.nlm.nih.gov/41243468/

A recent study showed that ALCAR increases gut TMA, which is then metabolised to TMAO in the liver. The low absolute bioavailability of ALCAR suggests that much of it is being transformed into TMA by microbes in the intestines. My first guess to reduce TMA and subsequent TMAO formation would be to either increase the bioavailability of ALCAR or inhibit the formation of TMA. However, I'm not sure of which strategies would be most likely to effective in achieving this.

So I ask, how could the TMAO-increasing effects of ALCAR be reduced?

\*This is a thought experiment\*

According to the MSDS of these tablets, the ingredients are as follows:

\\\\\\\*\\\\\\\*Inactive Ingredients\\\\\\\*\\\\\\\*
\\\\\\\[silicon dioxide\\\\\\\](https://www.drugs.com/inactive/silicon-dioxide-170.html), \\\\\\\[lactose monohydrate\\\\\\\](https://www.drugs.com/inactive/lactose-monohydrate-368.html), \\\\\\\[magnesium stearate\\\\\\\](https://www.drugs.com/inactive/magnesium-stearate-147.html), \\\\\\\[stearic acid\\\\\\\](https://www.drugs.com/inactive/stearic-acid-77.html), \\\\\\\[magnesium silicate\\\\\\\](https://www.drugs.com/inactive/magnesium-silicate-122.html), \\\\\\\[titanium dioxide\\\\\\\](https://www.drugs.com/inactive/titanium-dioxide-70.html), \\\\\\\[FD&C Blue No. 2\\\\\\\](https://www.drugs.com/inactive/fd-c-blue-no-2-243.html), \\\\\\\[polyethylene glycol 4000\\\\\\\](https://www.drugs.com/inactive/polyethylene-glycol-4000-277.html), \\\\\\\[polyethylene glycol 400\\\\\\\](https://www.drugs.com/inactive/polyethylene-glycol-400-272.html), \\\\\\\[D&C Red No. 27\\\\\\\](https://www.drugs.com/inactive/d-c-red-no-27-345.html)

Is it safe to assume anhydrous PEG is the agent in question to make these extended release or a combination of them? Hypothetically and chemically speaking, how can the sulfate be prevented from interacting with the inactive ingredients? Obviously, crushing and dissolving the pulverized pill powder in H2O would turn the solution into a goo to deter abuse. However, this manufacturer’s anti-abuse process differs from the OP or MS contin. One thought is if an A/B ext is possible? I.e. converting the sulfate into a freebase form and have it precipitate out, filter and turn it into a HCl salt? Or are there better solvents out there that won’t react with the PEG? Trying to understand the pharmaceutical chemistry better.

Tl;Dr summary of questions, ignore if you plan on reading the whole thing:

Is it possible and/or safe to upregulate cholinergic receptors long term? Can I get my choline levels scientifically measured? Once you hit levels of choline causing side effects, is it possible and safe to surpass those limits using substances that enable more cholinergic utilization? And is there any purpose to combining different sources of choline (bacopa, rhodiola, huperzine A etc) over just Alpha GPC and dietary choline?

I've been researching nootropics and racetams a lot and they've helped me with my ADHD, chronic fatigue but studies seem to show that stimulants' abilities to improve various aspects of memory are limited

https://pmc.ncbi.nlm.nih.gov/articles/PMC3489818/#b95

I was wondering if it would be viable to upregulate cholinergic receptors to achieve nootropic-like benefit regarding memory and learning even while not supplemented? Can I "permanently" increases my brain's ability to utilize choline? -even if not at the same potency as supplements and nootropics.

Right now I've only taken piracetam, phenylpiracetam, and aniracetam with Alpha-GPC or phosphatidyl choline with dietary choline sources like fish, eggs, and milk but I've been looking into bacopa, huperzine A, ginkgo, ashwagandha, rhodiola, and anthocyanins in the form of billberry extract. Surely adding all of those at much would be toxic or cause side effects of cholinergic overdose. Is there a range of choline levels suggested to be well tolerated, and would I realistically be able to have them measured rather than just relying on symptoms that could stem from a million different things? And why do people "stack" for substances in which the outcome is the same? Why would adding those herbs together have a benefit over Alpha GPC (assuming the choline is the only goal and the anxiolysis and S/D/NE activity are otherwise irrelevant)?

And as a final question, what causes these effects of choline overdose? Is it the brain's inability to use it all and the effects are caused by unused choline spilling out- in which case- would a higher dose of nootropics provide you with a safer and more sustainable higher limit?

I could be way off but the way I see it is like overclocking a computer. If you win the lottery, you can push the voltage (drugs that increase the brains ability to use choline) which allow for higher clock speeds and more efficient memory capacity in terms of both maximum limit and constant flow (I don't really need to describe the analogy for this one)

hi, i've been doing research on an experience I had with edibles. I have a vestibular condition. I smoke weed all the time at home. I ate less than 5mg in edible and noticed the dizzy/vestibular malaise in 20-30min. I took a dramamine. My friend with 0 knowledge of my experience then said, oh I feel this too, I'm dizzy. I also gave her dramamine, and we both felt better.

I was researching the mechanism and I believe that, in sensitive people, 11-OH-THC specifically pushes CB1 signaling in central balance circuitry past a threshold, producing a distinctly vestibular malaise that smoked weed does not. I have not found any papers supporting this directly and wanted to float it somewhere relevant.

https://www.reddit.com/r/trees/comments/alh0k7/how_do_i_reduce_dizziness_and_nausea_when_taking/

https://www.reddit.com/r/Edibles/comments/1641eht/violent_vertigo_after_60_mg_edible/

https://www.reddit.com/r/entitledparents/comments/1apwog5/i_inadvertently_gave_my_mom_an_edible_and_it/

So I've been thinking for a while about the deeper stimulant euphoria of amphetamines. Meaning joy/love feeling, not just pleasure. To be more clear, definition for joy would be any mostly egoless and not 'result-driven' euphoria, for love it would be simply inner feelings of abundance of energy combined with mindset 'I don't need anything for myself'. These things, whatever it's easy or not, achievable on simple racemic amphetamine, D-amph, MDMA, meth, and RC analogues.

So, these following are the requirements allowing it to happen, from most important to least important in my opinion. I'm not mentioning there obvious things like tolerance, big enough dosages, hydration, sleep, e.t.c. Also, I don't fully understand tonic/phasic aspects of neurotransmission so would appreciate any explanations.

1. DA/NE ratio; No exsess NE in general. From some studies I concluded that rush is over then %-increase-DA-line crossing with %-increase-NE-line, as DA falls sharply after increase and way faster than NE. The most obvious thing with the stimulants that the higher you can go without feeling nervous the better. Users of drugs.com praise desoxyn a lot vs adderall for having less nervous side effects, it is mostly linked to much better DA/NE ratio. [dynorphin may amp NE in regular abusers]

2. DA/5HT ratio. Analysing meth/amph/mdma reports it is clear that 5HT depo depletes faster than dopamine, resulting in less release after repeated uses. By the user reports, meth quickly loses its empathogenic qualities after just 2-3 uses, which for some are 'mdma-like'. D-amph is more euphoric than DL-amph, and so on. Maybe sensitive postsynaptic 5-ht1a receptor would contribute a lot? My theory once was that DA/5HT ratio would give the limit, the maximum of the euphoria substance can provide, it would make sense with A LOT OF stimulants.

3. Psychological 'Ego Inflation' feeling, i.e merely neuronal connections (what exact connections?) that are made after couple of uses preventing entactogenic feelings?

4. Oxidative balance that is more on pro-oxidative side, to release more energy during the rush and thus make the high. Rather than good antioxidant profile. Many antioxidants are actively countering euphoria of the amphetamines.

5. Low Gaba/Low baseline glutamate[so receptors for glutamate are sensitized]. Glutamate is rather euphoria-dampening signal in CNS; while on gabaergics acutely they tend to inhibit the euhporia; but after, for example, GHB/BDO binge, after it fully leaves the system, system is sensitized a lot for stimulant, there are many reports claiming that.

6. Endogenous phenylethylamine concentrations?..

7. Anything else...?

Post is written while not on amphetamines, unfortunately.